Abstract
Thursday, October 4, 2018
Thyroid Imaging Thursday Highlighted Oral Clinical
Thyroid ultrasound screening has been involved in routine physical examination at hospitals. However, due to the uneven development of medical resources, the diagnostic accuracy for thyroid nodules varies greatly. The aim of this study was to explore a novel artificial intelligence-assisted ultrasound diagnostic system to improve the diagnosis efficiency and accuracy for thyroid nodules. The artificial intelligence-assisted ultrasound diagnostic system was developed based on computer deep learning, training and multi-frame dynamic image recognition techniques. In order to validate the accuracy of the system, 500 pathologically confirmed thyroid nodules were selected, including 208 benign and 292 malignant. The images of all nodules, acquired from 10 different types of ultrasound equipment, were dynamically stored in the form of the consecutively longitudinal and transverse sections. Then the AI-assisted diagnostic system automatically recognized and analyzed the features of the images, and gave recommendations for diagnosis. The diagnostic accuracy of the system was compared with that of junior and senior physicians. The results showed that the sensitivity of the AI-assisted diagnostic system, junior physicians, senior physicians, combo of junior physicians and the AI-assisted system was 82.9%, 52.6%, 87.4% and 98.6%, respectively; and the specificity was 70.2%, 95.7%, 83.2% and 83.7%, respectively. The diagnostic accuracy of the AI-assisted system alone was higher than that of junior physicians (77.6% vs. 70.5%), however, the accuracy can reach 92.4% when the junior physicians was assisted by the AI-assisted system, which was higher than that of the senior physicians (85.6%). At the same time, the diagnostic tests on thyroid nodules of different sizes (<1cm, 1-2cm, and >2cm) were performed using the system. The results showed that there was no significant difference in the diagnostic accuracy among the three groups (P < 0.05). The AI-assisted ultrasound diagnostic system can effectively assist ultrasound physicians in the diagnosis of benign and malignant thyroid nodules, reduce unnecessary puncture and over-treatment, and help the junior physicians to improve the diagnosis efficiency and accuracy.
Autoimmunity Thursday Highlighted Oral Clinical
Results from a 24-week randomized, double-masked, placebo-controlled treatment trial of teprotumumab, an insulin-like growth factor 1 receptor inhibitory antibody, in 88 patients with active and moderate-to-severe thyroid-associated ophthalmopathy (TAO) have been reported (NEJM2017;376:1748). The primary endpoint response (≥2 points reduction in clinical activity score, CAS and ≥2 mm reduction in proptosis at 24 weeks) was achieved in 69% of patients receiving teprotumumab compared to placebo (20%), p < 0.001 with no deterioration in the non-study eye. The effects were rapid: at week 6, 43% of patients receiving teprotumumab responded vs. 4% of placebo patients (p < 0.001). Teprotumumab reduced proptosis significantly beginning at week 6 of treatment, effects that continued over 24 weeks as compared with placebo. Proptosis response was greater among the teprotumumab group at week 24 (71.4% vs. 20.0%, p < 0.001) We now report results assessing clinical status following multicenter treatment at week 28 and 72. Proptosis is relevant from clinical and regulatory agency perspectives since it reflects tissue remodeling in patients with TAO. At week 28 (4 weeks following treatment period), proptosis response was 73.8% in the teprotumumab group vs. 13.3% in controls (p < 0.001). 53% of week 24 teprotumumab proptosis responders maintained ≧2 mm improvement relative to baseline at week 72 (48 weeks following treatment period). Compared to baseline and placebo, CAS further decreased at week 28, mean (SE) -4.44 (0.23) vs. -2.54 (0.22), p < 0.001 and remained relatively unchanged in the teprotumumab group at week 72. These results indicate no acute rebound of disease following the 24-week treatmentTeprotumumab could represent a disease modifying therapy in TAO by reducing proptosis and CAS with sustained effects seen in the majority of patients 48 weeks following the completion of the study treatment phase. Considering the variable duration of activity in TAO (typically 2-3 years), patients might benefit from longer treatment or re-treatment with teprotumumab. These possibilities are currently being studied in an ongoing phase 3 trial.
Thyroid Hormone Action Thursday Highlighted Oral Basic
Patients with mutations of the THRA gene show growth retardation, delayed bone development, and anemia. These symptoms are due to the dominant negative action of TRa1 mutants. However, little is known about how TRa1 mutants exert their deleterious effects during early development. To understand the action of TRa1 mutants in early development, we created zebrafish expressing mutated thra genes (gene duplication in zebrafish: thraa and thrab) by CRISPR/Cas-9 mediated targeted mutagenesis. We obtained 2 fish lines expressing mutated thraa (8-base pair insertion: L405EfsX6) or thrab (1-base pair insertion: E394X), encoding C-terminal truncated TRa1 proteins, similar to those in patients. We used biochemical methods to characterize phenotypes of the mutant fish. We found that ThraaL405EfsX6 and ThrabE394X lost T3 binding activity and transcriptional capacity, showing potent dominant negative activity by inhibiting transcriptional activity of wild-type TR. Adult mutant fish had impaired growth, like patients. ThrabE394X mutant fish had more severe and persistent impaired growth than ThraaL405EfsX mutants. Expression of the growth hormone gene (gh1) in the pituitary was suppressed 96% in ThrabE394X mutants. Analysis revealed decreased ossification and abnormal shape in the cleithrum in ThrabE394X day-5 embryos, indicating delayed bone development. Interestingly, ThraaL405EfsX6 mutants exhibited abnormal patterns in blood smears versus wild-type fish, indicative of erythroid disorders as in patients. Whole mount in situ hybridization analysis revealed that the expression of erythroid-related genes such as gata-1 and alpha-globin was suppressed in 1 day-embryos, but not in ThrabE394X mutant fish. These data indicated that ThrabE394X mutant impaired growth, whereas ThraaL405EfsX6 mutant caused erythroid disorders. These two lines of mutant zebrafish reproduce growth abnormalities and erythroid disorders detected in patients. The novel zebrafish model is useful not only to understand the in vivo pathogenic actions of TRa1 mutants in early development of human disease, but also to provide a platform for rapid screening of drugs to treat abnormalities at early development.
Thyroid Hormone Action Thursday Highlighted Oral Basic
Tumour angiogenesis requires recruitment and interaction of various different cells, including endothelial cells and mesenchymal stem cells (MSCs). Thyroid hormones (TH) T3 and T4 act as proangiogenic modulators mediated by non-genomic mechanisms via cell surface receptor integrin αvβ3. The aim of this study was to evaluate the effects of T3 and T4 versus tetrac, a specific inhibitor of TH action at the integrin, on MSCs in the context of angiogenesis. Treatment of MSCs with TH in the presence of hepatocellular carcinoma (HCC) cell-conditioned medium resulted in stimulation of expression of genes associated with angiogenesis as determined by qPCR and ELISA, while tetrac reversed these effects. Adding supernatant from these MSCs to endothelial cells (HUVECs) in a Matrigel tube formation assay significantly enhanced tube formation with potent inhibition by tetrac. We further established an angiogenesis reporter gene system by placing the sodium iodide symporter (NIS) gene under control of the vascular endothelial growth factor (VEGF) promoter. MSCs transfected with this construct (VEGF-NIS-MSCs) showed enhanced perchlorate-sensitive NIS-mediated iodide uptake activity after stimulation with HCC cell-conditioned medium and either T3 or T4 that was blocked by tetrac, the PI3K pathway inhibitor LY294002 and the ERK1/2 pathway inhibitor RAF265, and tetrac and RAF265, respectively, supporting integrin αvβ3-dependency. In vivo effects were evaluated by 124I PET in an orthotopic HCC xenograft mouse model. Tumoural radioiodide uptake demonstrated successful recruitment of VEGF-NIS-MSCs after systemic application followed by VEGF promoter-driven NIS expression. In hyperthyroid animals, a strongly enhanced radioiodide signal was detected compared to euthyroid and hypothyroid mice, while treatment with tetrac markedly reduced the signal. These data confirm the in vitro data suggesting TH-mediated stimulation of VEGF that is inhibited by tetrac. Our data suggest that TH influence angiogenic signalling in MSCs in an integrin-dependent fashion, providing further evidence of the critical role of TH in the regulation of angiogenesis and the anti-angiogenic activity of tetrac in the context of tumour stroma formation.
Disorders of Thyroid Function Thursday Basic
Circulating RNA (circRNA), like exosomal circRNA, regulates various bioactivities in cells. Better understanding of the exosomal circRNA may provide novel insights into pathogenesis of Graves' disease (GD) and clinical management of patients. This study profiled exosomal circRNAs in GD vs. healthy control sera using human circRNA microarrays and then functionally analyzed these differentially expressed circRNAs (DEcR) bioinformatically. Serum samples were obtained from five primary GD patients and five healthy controls to isolate the exosome using the ultracentrifugation. After confirmed with Transmission electron microscopy, these samples were subjected to the microarray profiling of the DEcR using human circRNA microarrays. Two each of the most upregulated and downregulated circRNAs were selected for validation in 20 GD and healthy controls using quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). The circRNA/microRNA/mRNA interaction network was then assembled and assessed bioinformatically and the Gene Ontology and four other annotation tools for pathway analyses (KEGG, Biocarta, PANTHER, and Reactome) were utilized to predict the potential functions of these DEcR in GD. There were 15 DEcR revealed in primary GD cases, e.g., hsa_circRNA_102059 and hsa_circRNA_000102 were upregulated and confirmed, whereas hsa_circRNA_004939 and hsa_circRNA_072697 were downregulated and confirmed in primary GD vs. healthy controls. The bioinformatical analysis identified the most potential targeting miRNAs of these four DEcR. The functional analyses predicted involvement of these DEcR in pathways of immune system activation. Microarray profiling identified 15 DEcR in primary GD vs. healthy controls and four of them were verified by qRT-PCR, suggesting their involvement in pathways of immune system activation. The targets of these DEcR were also predicted and may involve in GD development and progression. Future study will discover DEcR expression as biomarkers for GD diagnosis and treatment.
Thyroid & Development Thursday Oral Basic
There are two highly conserved Thyroid hormone (T3) receptors (TRs) genes, TRα and TRβ, in all vertebrates, and the expression of TRα but not TRβ is activated earlier than T3 synthesis during development. In human, high levels of T3 are present during the several months around birth and T3 deficiency during this period causes severe developmental problems including the improper maturation of intestine. It is, however, difficult to study this period in mammals as the embryos and neonates depend on maternal supply for survival. On the other hand, Xenopus tropicalis undergoes a T3-dependent metamorphosis which drastically changes essentially every organ in the tadpole. Of interest is intestinal remodeling, which involves de novo formation of the adult intestinal stem cells, resembling intestinal maturation around birth in mammals. We have previously demonstrated that TRs are essential for formation of the intestinal stem cells during metamorphosis. To investigate the role of TRα in this process and the underlying mechanisms, we generated TRα deficient Xenopus by using TALEN method. We then observed that TRα knockout causes defects in intestinal remodeling, including reduced stem cell proliferation. In addition, apoptotic activity during intestinal remodeling was also decreased in TRα deficient tadpoles. By RNA-sequencing analysis (RNAseq) on intestinal RNA from wild type and TRα-deficient tadpoles treated with or without T3 for 1 day, we identified 1191 genes which were up-regulated by T3 treatment in the wild type animals. Among them, 1069 genes appeared to be specifically regulated by TRα. Gene ontology and pathway analysis revealed that the TRα-regulated genes were enriched with cell cycle-related genes. Our findings indicate that TRα is the predominant TR mediating the effects of T3 on intestinal remodeling and that TRα controls intestinal stem cell formation and/or proliferation at least in part by regulating cell cycle genes. Our findings indicate that TRα is the predominant TR mediating the effects of T3 on intestinal remodeling and that TRα controls intestinal stem cell formation and/or proliferation at least in part by regulating cell cycle genes.
Iodine Uptake & Metabolism Thursday Oral Basic
I– transport defect (ITD) is an autosomal recessive disorder whose hallmark is the inability of the thyroid follicular cell to mediate active I– accumulation. ITD is an uncommon cause of dyshormonogenetic congenital hypothyroidism due to loss-of-function mutations in the Na+/I– Symporter (NIS)-coding slc5a5 gene. Here, we aimed to determine whether a pediatric patient with a clinical phenotype of ITD harbors an inactivating mutation in the slc5a5 gene, and if so, to ascertain the molecular mechanisms of the effect of the mutation on NIS function.
The whole coding region of the slc5a5 gene was PCR-amplified and subjected to Sanger sequencing, and in silico computational and in vitro functional studies of a newly identified NIS mutation were performed. We report a novel homozygous missense and loss-of-function mutation in the slc5a5 gene as a cause of dyshormonogenic congenital hypothyroidism. The proband carries a G > A transition at position +1.682 in exon 14 resulting in a Gly to Glu substitution at residue 561 (G561E) located in the intracellularly facing NIS carboxy-terminus. We show that G561E markedly reduces I– uptake when the protein is heterologously expressed in MDCK-II cells, because the transport of G561E NIS to the plasma membrane is severely impaired. Significantly, G561Q NIS, like G561E, is severely retained in the endoplasmic reticulum. Bioinformatics reveal fully conserved tryptophan-acidic (WD) motif whose disruption (W565A/D566A NIS) leads to NIS retention in the endoplasmic reticulum. Computational and biochemical analysis indicates that G561E impair the recognition of the adjacent WD motif by the kinesin light chain (KLC) 2, thus impairing mutant NIS exit from the endoplasmic reticulum. Moreover, short-hairpin RNA-mediated KLC2 knock-down in FRTL-5 cells reduces NIS expression at the plasma membrane, and consequently minimal NIS-mediated I– accumulation.
Altogether, our data indicate that G561E shifts the equilibrium of the unstructured WD motif towards a more structured and rigid conformation unable to interact with KLC2, thus severely affecting NIS maturation beyond the endoplasmic reticulum and reducing I– accumulation in the thyroid follicular cell.
Thyroid & Development Thursday Oral Basic
Anuran amphibians such as Xenopus tropicalis offer a unique opportunity to study how the adult organs and their organ-specific stem cells are formed in vertebrates during the so-called postembryonic development. The postembryonic events such as the maturation/remodeling of many organs are totally regulated by thyroid hormone (TH). Of particularly interest among TH target gene is PRMT1, which methylates histone H4R3 and functions as a TH receptor co-activator. We have shown previously that PRMT1 mRNA and protein expression peaks at the climax of metamorphosis in the intestine when adult stem cells are forming de novo and rapidly proliferating, and that transgenic PRMT1 overexpression increases the number of adult intestinal stem cells during metamorphosis. To determine the function of the endogenous PRMT1 gene, we adapted the gene editing technology, transcriptional activator–like effector nuclease (TALEN), to knock out PRMT1 gene in X. tropicalis. After generating PRMT1 heterozygous frogs (F1) with out of frame mutations, we produced PRMT1−/−animals by intercrossing the F1 frogs. We then measured the survival rate, animal size, the developmental stage and histone H4R3 di-methylation level by western blot of the F2 resulting tadpoles. Additionally, to analyze the effect on the TH-induced metamorphic changes, we treated tadpoles with 10nM TH in rearing water, and then analyzed TH-inducible gene expression by quantitative RT-PCR. These studies revealed that all PRMT1−/− tadpoles died within 14 days after fertilization although they completed embryogenesis to form apparently normal feeding stage tadpoles. In addition, morphological analysis showed that PRMT1−/−tadpoles had delayed development and growth. Finally, histone H4R3 di-methylation level and TH-inducible genes expression were significantly reduced in PRMT1−/−siblings. Our findings indicate that PRMT1 is not required for embryogenesis but is important for tadpole growth and survival prior to natural metamorphosis. We are now taking advantage of the ability to precociously induce metamorphosis by treating with physiological levels of TH to investigate how PRMT1 knockout affect TH-induced metamorphosis and adult intestinal stem cell development.
Thyroid Cancer Thursday Oral Basic
Anaplastic thyroid cancer (ATC) is the most lethal human malignancy in endocrine system, but its molecular characteristics are not fully unveiled. Twenty-seven ATCs from Korean patients and the additional 86 advanced thyroid cancer (TC) including 15 poorly-differentiated thyroid cancers (PDTCs), 28 focal ATC/PDTCs, 12 widely invasive follicular thyroid cancers (wiFTCs), and 31 metastatic papillary thyroid cancers (PTCs) were sequenced by whole-genome, whole-exome, or targeted sequencing to reveal the key genomic events which prompt the progression of TC. Also, RNA sequencing data from 13 ATCs and 162 differentiated thyroid cancers (DTCs) were analyzed to elucidate the transcriptomic changes during TC progression. In ATC, BRAF (40.74%) and RAS (44.44%) were the most recurrently mutated driver genes, but no fusion gene was found. Also, AKT1/PIK3CA and EIF1AX were frequently co-mutated with BRAF and RAS, respectively and those mutations were mutually exclusive with each other. Tumor suppressors such as TP53 (44%) and CDKN2A (22%) were altered in 70% of ATC, and this incidence was greatly higher than advanced TCs. In particular, ATC and advanced TC patients with CDKN2A loss represented shorter disease-specific survival (p = 0.03 and p < 0.001, respectively). TERT alteration was the second most prevalent mutation in ATC (56%), but, interestingly, it was more frequently found in wiFTC (92%). We identified PDE8B-TERT and TERT upstream translocation which triggers enhancer hijacking in wiFTC. We found the new molecular subtype of TC, ATC-like, in addition to BRAF-like, RAS-like, and NBNR. Moreover, the up-regulation of two immunotherapeutic target genes, CD274 and PDCD1LG2 which encode PD-L1 and PD-L2, respectively in ATC, compared with DTC. With differentially expressed gene and pathway analyses, the activation of JAK-STAT signaling pathway in FTC origin ATC and notch signaling pathway in PTC origin ATC which commonly stimulate the overexpression of MYC were found. In this study, we revealed the genomic and transcriptomic characteristics which induce the progression and aggressiveness of TC. We expect that our result would allow us to find tailored diagnostic and therapeutic strategies for this fatal disease.
Thyroid Cancer Thursday Oral Clinical
Tropomyosin receptor kinases (TRKs) are encoded by neurotrophic tyrosine receptor kinase genes (NTRK). Fusion proteins involving NTRK genes are oncogenic and have been reported in a wide variety of malignancies, including non-medullary thyroid cancer (TC). Larotrectinib is a potent and highly selective oral TRK inhibitor. In a recent pooled analysis from three studies involving 55 patients with TRK fusion cancer, the ORR was 75% according to independent review (IRC) (Drilon et al., NEJM 2018). Here, we summarize the activity and safety of larotrectinib in advanced TRK fusion TC. Patients with previously treated TRK fusion TC were treated under clinical trial (NCT02122913, NCT02637687, NCT02576431) and enrolled based on NTRK gene fusions identified by local testing. Most patients received the dose equivalent of 100mg BID on a continuous 28-day schedule. Efficacy was assessed by IRC using RECIST v1.1. As of July 17, 2017, seven patients with TRK fusion TC were enrolled; histologies included 5 papillary and one each with follicular and anaplastic TC. Median age was 57 (range 15-75). Four patients harbored an ETV6-NTRK3 fusion, and one each with TPM3-NTRK1, PPL-NTRK1 and IRF2BP2-NTRK1 fusions. All patients had undergone thyroidectomy, 5 had received prior systemic treatment (median of 3 prior lines), and 3 had received iodine-131. All 5 patients with measurable disease responded with a median time of first response of 1.8 months; per IRC, there was 1 complete response and 4 partial responses. The duration of response ranged from 1.9 to 18.8 months, with 4 ongoing in response. The patient with anaplastic TRK fusion TC progressed after 3.7 months in response but remained on treatment post-progression. Larotrectinib was very well tolerated, with treatment-related adverse events being predominantly grade 1. All patients continued to receive larotrectinib treatment at time of data cutoff. Larotrectinib is highly active and very well tolerated in patients with TC harboring NTRK gene fusions across all histologies reported here. These results strongly support the inclusion of NTRK gene fusions as part of routine molecular testing for patients with advanced TC.
Disorders of Thyroid Function Thursday Oral Clinical
Thyroid hormone is essential for fetal neurodevelopment. The relationship between maternal thyroid dysfunction in pregnancy and pregnancy outcomes as well as offspring brain development have been well evaluated. However, limited evidence was provided regarding the relationship between preconception thyroid stimulating hormone (TSH) level of women planning for pregnancy and preterm birth (PTB). This study aimed to examine the association between preconception TSH level and risk of PTB. We conducted a historical cohort study which recruited 4320584 rural reproductive age women participated National Free Pre-pregnancy Checkups (NFPC) in 2013-2016 in China. Data on preconception TSH, history of pregnancy and diseases, and other variables were obtained from the physical examination record in NFPC. Follow-up evaluation was conducted from June 2013 to Dec 2017. Successful conception and pregnancy outcomes were documented during the follow-up period. In the present study, PTB which is defined as any birth within 28 to 37 weeks of gestational age were the end point event of the cohort. Participants who are failure to get pregnant within 6 months, suffered from fetal death, still birth abortion, and multiple gestation were excluded from the analysis. Logistic models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) after adjusting for confounding variables. Restricted cubic spline models were applied to evaluate the dose-response relationships. Until Dec 2017, 283854 (6.57%) PTB events were documented. The PTB incidence was lowest in women with TSH of 1.00-1.49 mIU/l (6.23%), while the PTB incidence was highest in women with TSH of ≥10.00 mIU/l (7.46%). Compared to women with TSH of 1.00-1.49 mIU/l, the multivariable-adjusted OR (95% CI) for PTB was 1.20 (1.18-1.22) for women with TSH <0.44 mIU/l, 1.09 (1.08-1.11) for 0.44-1.00 mIU/l, 1.02 (1.01-1.03) for 1.5-2.49 mIU/l, 1.15 (1.13-1.18) for 4.00-9.99 mIU/l, and 1.19 (1.12-1.27) for ≥10 mIU/l, respectively. Our study identified a V-shaped relationship between maternal preconception TSH level and PTB risk. Decreasing or increasing preconception TSH levels can significantly increase the risk of PTB.
Disorders of Thyroid Function Thursday Oral Clinical
Programmed cell death protein ligand-1 (PDL-1) inhibitors are novel anti-cancer therapies but are associated with potentially therapy limiting immune-related adverse effects (IRAEs). We aimed to characterize thyroid-related IRAEs in order to improve case detection and overall patient management. We conducted a retrospective cohort study of cancer patients receiving PDL-1 inhibitors between 6/1/2016 – 1/30/2018 at the Mayo Clinic. Clinico-pathologic and laboratory data, including overall survival (OS) was collected. Of 91 patients treated with PDL-1 inhibitors (median age 68 years, 52% male) with a median follow up of 5 (IQR 2 – 9) mo, 42 (46%) developed an IRAE, including 23 (25%) thyroid IRAEs (22 from atezolizumab, 1 from avelumab). The median time to thyroid IRAEs was 1.4 mo or after 2 doses of PDL-1 inhibitor. Acute thyroiditis occurred in 5 (22%), of which 3 progressed to hypothyroidism. New onset hypothyroidism occurred in 14 (61%) patients, 4 overt and 10 subclinical, of which 2 resolved. Worsening hypothyroidism occurred in 4 (17%). Management included observation in 52% and levothyroxine in 48%. Thyroperoxidase (TPO) antibodies were elevated in 4/13 (31%) at baseline, of which 2 developed thyroid IRAE. TPO antibodies were elevated in 4/18 (22%) at the time of thyroiditis/hypothyroidism (median titer 220 IU/mL). Diffusely elevated fluorodeoxyglucose (FDG) thyroid uptake on positron emission tomography (PET) scan was present in 6/24 of which 5 developed thyroid IRAE (p = 0.001). The mean OS since start of PDL-1 inhibitor therapy was 9.2 mo, and on subgroup analysis, was 12 mo in patients with thyroid IRAE versus 9.9 mo without (p = 0.03). Thyroiditis, presenting as acute thyrotoxicosis progressing to hypothyroidism or as new onset hypothyroidism, is the most common endocrine IRAE following PDL-1 inhibitor therapy and has comparable and/or higher incidence than with other immune checkpoint inhibitors. Diffuse thyroid uptake on FDG-PET scan but not elevated TPO antibodies appears to identify patients at risk for thyroiditis/hypothyroidism. Whether patients developing thyroiditis, or other IRAEs, may be a biomarker of anti-tumor immune response and improved overall survival requires additional study.
Disorders of Thyroid Function Thursday Oral Clinical
To show how fetal dysthyroidism (FD) and neonatal dysthyroidism (ND) can be predicted from perinatal variables. We performed a retrospective multicenter study using data from the medical records of all patients monitored for pregnancy from 2007 to 2014 in 10 obstetric centers of the Assistance Publique des Hôpitaux de Paris Women with Graves' disease who were positive for TRAb at least once during pregnancy were included. Among 280,000 births, 2,288 medical records of women with thyroid dysfunction were selected and screened and 417 women with Graves' disease and positive for TRAb during pregnancy (estimated prevalence of Graves' disease 0.15%) were finally included. Multivariate regression analysis revealed that the TRAb level in the mother and child was the strongest independent predictor of FD and ND. The expected frequencies were not significantly different from the observed frequencies using the Hosmer-Lemeshow test (P = 0.84 for TRAb level at days 0 to 5; P = 0.76 for maternal TRAb level). Using the maternal TRAb levels, the cutoff value of 2.5 IU/L best predicted for FD, with a sensitivity of 100% and specificity of 64% positive predictive value (PPV) of 26%, negative predictive value (NPV) of 100% and the optimal cutoff value for predicting ND was 5.9IU/L (sensitivity of 100%, specificity of 82%, PPV of 26%, NPV of 100%) Using the newborn TRAb levels, the cutoff value of 6.8 IU/L best predicted for ND, with a sensitivity of 100% and a specificity of 94%, PPV of 50%, NPV of 100%.the risk of FD and ND increases with maternal hormonal imbalance and is also greater in the patients receiving antithyroid drugs (ATDs) during pregnancy. In our study, 65.0% of women with a history of Graves' disease did not receive ATDs during pregnancy but were still at risk of ND. We have clearly shown in a large number of cases that precise TRAb cutoffs can be used to establish the best perinatal follow-up and that fine tuning of the mother's thyroid status. In pregnant women with TRAb levels ≥2.5 IU/L, fetal ultrasound monitoring is essential until delivery. All newborns with TRAb levels ≥6.8 IU/L should be examined by a pediatrician with special attention for thyroid dysfunction and treated, if necessary.
Disorders of Thyroid Function Thursday Oral Clinical
In Graves' disease (GD), brain-derived symptoms are prevalent. During the hyperthyroid state, the volumes of medial temporal lobe (MTL) structures, e.g. the hippocampi, are reduced. This has been attributed to the high thyroid hormone levels, but we hypothesize that the structural changes and mental symptoms may be due to autoimmunity per se. Here, autoimmunity directly related to the thyroid as well as other autoimmunity may be important. The aim of the present paper was to determine the relations between non-thyroid autoimmunity and MTL volumes during hyperthyroidism in GD. The CogThy project is a longitudinal observational prospective case-control study where 65 premenopausal women were evaluated within 2 weeks after the diagnosis of GD with FT4 > 50 pmol/L (reference 12-22) and after 15 months of anti-thyroid treatment. Thyroid-stimulating hormone receptor antibodies (TRAb), thyroid stimulating immunoglobulins (TSI), angiotensin II type 1- (anti-AT1), beta 1 adrenergic- (anti-B1) and M2 muscarinic- (anti-M2) receptor antibodies were measured in the hyperthyroid state. MTL structures were assessed with a 3-Tesla MR scanner to determine hippocampal and amygdala volumes using automatic segmentation with MAPER and normalisation to intracranial volume. We here report preliminary data on the non-thyroid antibodies at baseline in patients. Data on the thyroid antibodies are reported separately. There was a negative correlation between the volume of the left amygdala and the levels of anti-B1 (r = -0.28, p = 0.030) and anti-M2 (r = -0.40, p = 0.002).
Anti-AT1 correlated negatively with the volume of the right hippocampus (r = -0.27, p = 0.043).
There were no correlations between TRAb or TSI vs anti-AT1, anti-B1 or anti-M2.
These data support our hypothesis that autoimmunity that is not directly connected to the thyroid may be involved in the impairment of brain function in GD, and introduce a new concept that needs further evaluation. Longitudinal measurements and control data are awaited from the CogThy study.
Autoimmunity Thursday Poster Basic
Endogenously expressed TSH receptors (TSHR) in orbital fibroblasts from patients with Graves' ophthalmopathy (GO) utilize crosstalk with insulin-like growth factor 1 receptors (IGF1R) to induce hyaluronan secretion, a major component of GO. We previously showed that this phenomenon occurred upstream of mitogen-activated protein kinase (ERK) phosphorylation and proximal to both receptors. Since G protein-coupled receptor/β-Arrestin/ERK complexes have been reported in several cell types, we sought to test whether β-Arrestin 1 or 2 was a necessary component of TSH/IGF1 receptor crosstalk. Protein knockdowns of IGF1R, β-Arrestin 1 and β-Arrestin 2 were performed in orbital fibroblasts obtained from GO patients. Secreted hyaluronan was measured following treatment with TSHR-stimulating antibodies M22 or KSAb1. Associations between TSHR and IGF1R were confirmed microscopically using the Duolink Proximity Ligation Assay. As previously shown, treatment with M22 resulted in biphasic dose-response stimulation of hyaluronan secretion, where the high-potency phase was IGF1R-dependent and the low potency phase was independent of IGF1R. KSAb1 produced a monophasic dose-response, whose potency was lowered, i.e. its EC50 was right-shifted at least 10-fold, following IGF1R knockdown. β-Arrestin 1 knockdown similarly inhibited M22's high-potency phase and lowered KSAb1's potency. β-Arrestin 1 was also necessary for TSHR/IGF1R proximity as shown by the proximity ligation assay. In contrast, β-Arrestin 2 knockdowns did not show these effects. TSH and IGF1 receptors must be in close vicinity for crosstalk to occur, and this depends on β-Arrestin 1. These findings further support a model of crosstalk where signaling pathways converge proximal to the receptors.
Autoimmunity Thursday Poster Translational
Serum levels of TSH receptor (TSH-R) stimulating antibodies (TSAb) correlate with clinical activity/severity of Graves' thyroidal disease (GD) and associated orbitopathy (GO). We hypothesized a highly significant differentiation between patients with GD versus GD+GO by analyzing TSAb levels in serially diluted serum samples. Twenty GD and 20 GD+GO patients were investigated. Serial 1:3 dilutions were performed on each patient sample (200μl) into TSAb-negative control serum (400μl) up to a final dilution of 1:6561. Results from the TSAb bioassay (Thyretain, Quidel, cut-off SRR% 140) were compared with five TSH-R-Ab binding immunoassays: Kronus ELISA (cut-off 1IU/L), Dynex ELISA (2U/L), Cobas (Roche, 1.75IU/L), Immulite (Siemens, 0.55IU/L), and Kryptor (Thermofisher, 1.8IU/L). All undiluted samples of hyperthyroid GD patients were positive in the TSAb bioassay (median SRR% 237, range 217-336) and became negative at dilution 1:27. In contrast, all undiluted samples of hyperthyroid GD+GO patients were positive in the bioassay (median SRR% 627, 576-752) and all remained positive at dilutions 1:3, 1:9, 1:27, and 1:81, all p < 0.001. At high dilutions 1:243, 1:729, 1:2187, and 1:6561, the rate of TSAb-positivity for GD+GO patients was 75%, 35%, 5%, and 0% respectively (all p < 0.001). Even after methimazole treatment, all euthyroid GD+GO samples were still positive at the high dilution of 1:729. TSH-R-Ab positivity with the Cobas binding assay was 85% in undiluted GD-only samples and 50% at dilution 1:3 whereas TSH-R-Ab positivity of undiluted GD+GO samples and at dilutions 1:3-1:243 was 100%, 85%, 85%, 75%, 15%, and 5%, respectively. The five binding ELISA and/or automated immunoassays confirmed this marked difference of anti-TSH-R-Ab detection between GD versus GD+GO observed with the TSAb bioassay; however the Kronus, Dynex, Cobas, Immulite, and Kryptor binding assays were all negative in GD-only samples at low dilutions of 1:27, 1:9, 1:9, 1:9, and 1:9, respectively. This novel TSAb dilution analysis significantly differentiates between GD and GD+GO. It also emphasizes the higher sensitivity of anti-TSH-R-Ab detection in the TSAb bioassay versus all ELISA and automated binding assays.
Autoimmunity Thursday Poster Clinical
Diagnosis of autoimmune poly glandular syndrome type 2 (APS 2) is often difficult due to the non-specific and insidious nature of symptoms and signs. Usually stressful insults such as infection, surgery or trauma may precipitate adrenal crisis (AC).
45 year old Caucasian women with known Hashimoto's Thyroiditis for 2 years, on levothyroxine 50 mcg daily, came to our ER with nausea, vomiting and diarrhea for two days. She reported 20 lb weight loss, lethargy, skin darkening, muscle aches, insomnia and anxiety over 6 months. Family history was significant for Grave's Disease and Hashimoto's Thyroiditis.
Patient appeared sick and confused. BP 88/50. HR 100. Exam showed signs of dehydration and tanned skin tone.
Labs: Sodium 116mmol/L, Potassium 5.1mmol/L, Bicarbonate 17 mmol/L, TSH 0.073uIU/ml, T3 234ng/dl, T4 14.8ug/dl, serum cortisol on admission 2 ng/dl. Adrenal antibody titer 1: 40 (normal <1:10) antiTG 4, antiTPO 131, TSI 564. Initial work up for infectious causes was negative. Upon follow up 4 weeks after hospital discharge, patient was doing well on hydrocortisone and fludrocortisone and was clinically and biochemically euthyroid.
She was negative for TSI when she was initially diagnosed with Hashimoto's Thyroiditis.
APS2 is characterized by autoimmune adrenal insufficiency (AI) associated with autoimmune thyroid disease and/or Type 1 Diabetes mellitus. When thyroid disease is associated with APS2, 50% is Graves' disease and 50% is either Hashimoto's or atrophic thyroiditis. Our patient did not have any identifiable stressor for AC. Development of TSI and subsequent hyperthyroidism while on levothyroxine therapy was deemed to be the precipitating factor.
In undiagnosed AI, initiation of thyroxine replacement may induce AC due to increased cortisol metabolism, but our patient was on a stable dose of levothyroxine for over 1 year prior to development of symptoms of AI. Clinicians should have a high index of suspicion for AI in those with a family history of autoimmune disease and in patients with one autoimmune disorder who develop nonspecific or serious illness.
Autoimmunity Thursday Poster Clinical
In Graves' disease (GD), hyperthyroidism per se may entail tachyarrhythmia, atrial fibrillation and heart failure. Known GD complications are, however, of autoimmune origin.
In GD patients with heart complications, stimulatory autoantibodies targeting the cardiovascular system (CardAbs) are frequent. Although previous studies were relatively small and used non-standardized methods, we hypothesize that CardAbs are frequent in GD in general and affect heart function. We used standardized ELISA assays to determine if CardAbs 1) were more frequent in hyperthyroid GD patients than controls, 2) were influenced by antithyroid drugs (ATD), 3) correlate with heart related symptoms or biomarkers. Our preliminary data with higher beta1 adrenergic receptor antibody (anti-B1) levels in GD that decreased after ATD strengthen our hypotheses. Premenopausal women (n = 60) with FT4 > 50 pmol/L (ref 12-22) were evaluated at diagnosis and after 7.5 months for CardAbs (anti-B1, muscarinic type 2 receptor (anti-M2) and angiotensin II type 1 receptor (anti-AT1) antibodies), symptom score, NTproBNP (marker of heart failure) and Troponine-I (TNI, marker of cardiac myocyte damage). In matched controls, CardAbs and heart biomarkers were assessed once. Anti-B1 and anti-M2 were higher (p < 0.0001) in patients at baseline compared to controls (anti-B1: median 1.9 (IQR 2.7-1.3) vs 1.1 (1.7-0.8) μg/ml, anti-M2: median 20.5 (38.3-14.0) vs 6.0 (9.9-3.2) U/ml), but anti-AT1 did not differ. Anti-B1 and anti-M2 decreased at 7.5 months (both p < 0.001), but were still higher than in controls. NTproBNP was higher in patients than in controls (median 240 (372-134) vs <35 (67 to <35) ng/L, p < 0.0001). TNI was below the detection limit in most subjects, but still higher in GD than controls (p = 0.02). NTproBNP and TNI normalised by ATD. CardAbs did not correlate with heart symptoms or biomarkers. Our first hypothesis was confirmed, and interestingly various CardAbs behaved differently. Although no correlation between CardAbs and heart function was observed, an autoimmune effect on the heart cannot be excluded in subpopulations, as the functional properties of antibodies remain to be determined.
Autoimmunity Thursday Poster Clinical
Autoantibodies are useful biomarkers for the prediction of autoimmune diseases. Thyroid autoantibodies are associated with an increased risk of clinical hypo or hyperthyroidism. Therefore, the aim is to determine the prevalence of thyroid autoantibodies and their associated factors in euthyroid individuals. In this study, 200 euthyroid subjects chosen by stratified sampling from an inception cohort of 1403 individuals were included. None of the subjects was under treatment. Thyroid function was evaluated by measuring serum levels of TSH (0.3-4.5 μIU / ml) and T4L (5.2-12.7μg/dl). In addition, anti-peroxidase (TPOAb), anti-thyroglobulin (TgAb), and anti-TSH receptor (TrAb) antibodies were evaluated together with 14 additional autoantibodies. The analysis included sociodemographic, clinical, and environmental characteristics. Data were analyzed by using chi-square (χ2), Kruskal-Wallis, Mann-Whitney and logistical regression tests. Thyroid autoimmunity was observed in 16.5% of the cases (TPOAb in 13% and TgAb in 2%). In three individuals, both autoantibodies were seen. No TrAb was detected. Subjects with African-ancestry had a higher risk of positivity for TgAb (OR: 7.2 95% CI: 1.4-46.8) while individuals with Amerindian-ancestry appeared to be protected (OR: 0.2, CI 95%: 0.03-0.9). The multivariate analysis confirmed a greater presence of TgAb in individuals of African descendant compared to other ethnic groups (p = 0.023, β = 7.82, 95% CI: 1.3-46). Additionally, TgAb levels were associated with years of smoking exposure (Rs = -0.17, p = 0.015), anti-CCP3 levels (Rs = 0.31 (p < 0.001), and years of exposure to wood smoke (Rs = 0.24, p = 0.001). In relation to TPOAb, its positivity was determined by the familial autoimmunity (OR: 2.5, 95% CI: 1.1-5.9), a result also confirmed by multivariate analysis (p = 0.03, β = 2.5 CI: 1.1-5.9). Subclinical thyroid autoimmunity is not rare. Environment and immunological factors as well as ancestry are associated risk factors. These results will facilitate the implementation of screening strategies in order to provide timely diagnosis and treatment.
Autoimmunity Thursday Poster Case Report
While Hashimoto's thyroiditis and Graves' disease are common causes of hypothyroidism and hyperthyroidism in adults, respectively, the development of Graves' hyperthyroidism in a hypothyroid patient with Hashimoto's disease is very rare. A 68-year-old woman with 28-year history of hypothyroidism treated with Levothyroxine (LT4) 88mcg daily and bilateral thyroid nodules presented for a regular 6-month follow up. The patient reported 3-month history of weight loss >20 pounds associated with hyperadrenergic symptoms. On examination, global increase in thyroid gland size was noted compared with prior evaluation. During the clinic visit, TSH was found to be <0.01mIU/mL (0.4-4.0) with elevated fT4 1.73ng/dL (0.7-1.5) and fT3 5.0pg/mL (2.18-3.98). In spite of gradual LT4 dose decrease and then discontinuation over next 5 months, she remained biochemically hyperthyroid. At this point, serum autoimmunity markers were measured and showed elevation of titers of thyroid stimulating immunoglobulin of 682% (<140) and thyroid peroxidase antibody of 920IU/mL (0-8) suggesting presence of Graves' disease; therefore, methimazole therapy was initiated. Biopsy of two enlarging dominant nodules showed abundant Hurthle cells and scant colloid. Hurthle cell carcinoma was suspected and total thyroidectomy was performed. Final surgical pathological report demonstrated Hashimoto's thyroiditis with extensive Hurthle cell change and no evidence of malignancy. The patient was post-operatively started on LT4 therapy and remains euthyroid. The conversion of hypothyroidism to Graves' hyperthyroidism is quite rare. Patients with Hashimoto's disease develop hypothyroidism due to antibody mediated destruction of the thyroid gland. Graves' disease is caused by production of antibodies that target the TSH receptor within the thyroid gland, resulting in stimulation of thyroid hormone production. Initial hypothyroidism in patients who later develop Graves' disease may be the result of TSH receptor blocking antibodies which then convert to stimulating antibodies. Euthyroid patients with Hashimoto's thyroiditis on chronic LT4 therapy who experience new onset hyperthyroidism should undergo biochemical evaluation for Graves' disease.
Disorders of Thyroid Function Thursday Poster Basic
Thyrotropin-secreting pituitary adenomas (TSHomas) are a rare cause of hyperthyroidism, but the number of reported cases have been increased in the last decade. Although a few cases are associated with mutation of the multiple endocrine neoplasia type1 (Men1) gene or thyroid hormone receptor beta gene, the cause of TSHomas remain largely unknown. We have recently reported an analysis of genetic abnormalities in TSHomas using next-generation sequencer. We found six somatic DNA variants as candidate driver mutations, but no variants were so far recurrent. However, SNP array analysis revealed multiple somatic focal and chromosomal arm-length copy-number abnormalities in 8 cases of TSHomas. Therefore, the objective of this study is to investigate the specificity of this copy-number abnormalities in TSHomas. We performed a Single Nucleotide Ploymorphism (SNP) array analysis of tumor DNA extracted from twelve TSHomas and twelve non-functional pituitary adenomas (NFPAs). SNP array analysis were also performed for DNA extracted from peripheral blood leukocytes of eight TSHomas. These analyses revealed multiple focal and chromosomal arm-length copy-number abnormalities in tumor DNA form TSHomas. We observed that 75.0 % (9/12) of TSHoma samples were involved in at least one gain, copy neutral LOH (cnLOH) and loss event respectively. In these copy-number abnormalities, copy number gain were fairly common compared to copy number loss and chromosomal arm-length gain was most frequent on 4p, 5p, 5q and 7p. In addition, we found several broad regions of cnLOH were found in 5 cases of TSHomas. All copy-number changes examined were somatic changes, because these changes were not found in blood samples. In contrast, only focal copy number abnormalities were found in NFPAs, although only one case had a chromosomal arm-length loss. Furthermore, the number of chromosomal arm-length copy-number gain was significantly higher than that of non-functional pituitary tumors. The somatic copy-number abnormalities, which are specifically found in TSHomas, may be involved in the tumorigenesis of TSHomas.
Disorders of Thyroid Function Thursday Poster Basic
Gestational hypothyroidism has detrimental effects on the fetus leading to cognitive deficiency like impaired learning and memory. The molecular mechanisms that underlie these effects are unknown. Cytokines and their receptors are able to modulate synaptic plasticity, learning and memory. Interleukin-4 (IL-4), a pro-inflammatory cytokine, seems to play a role regulating memory and learning processes. IL-4 knockout mice presented impaired spatial memory and adoptive transfer of IL-4 secreting lymphocytes recovers their learning and memory ability. In this work the following hypothesis was evaluated: “The offspring gestated in hypothyroidism has low plasmatic levels of IL-4 and its exogenous administration improves their learning capacity”. Gestational hypothyroidism was induced in mice C57BL6 and the offspring were used at the age of P55 days old. IL-4 serum levels were analyzed in the offspring gestated in hypothyroidism and the cognitive capacity was evaluated using Barnes Maze and the Novel object recognition test. Before test mice were i.p. injected with IL-4 and the cognitive capacity and IL-4 serum and brain levels were evaluated. IL-4 serum levels were analyzed in the offspring gestated in hypothyroidism and significantly low levels were detected in the brain compared to control offspring. The offspring gestated in hypothyroidism showed low performance in cognitive tests like Barnes Maze and Novel object recognition. Interestingly, the offspring gestated in hypothyroidism improved their cognitive capacity after they were i.p. injected with IL-4 before the test. The level of IL-4 in the brain increased after exogenous injection of IL-4. The significant increase of IL-4 observed in the brain of injected Control and Hypo mice correlate with an improvement in learning and memory. These findings contribute with new knowledge regarding the mechanisms that underlie the cognitive deficiency in the offspring gestated in hypothyroidism. The administration of IL-4 can be used as a therapy for the cognitive impairment in the progeny gestated in hypothyroidism.
Disorders of Thyroid Function Thursday Poster Basic
Congenital hypothyroidism (CH), the most common neonatal metabolic disorder, is characterized by impaired neurodevelopment. In neonates, a complete diagnosis of CH should include clinical examination, biochemical thyroid tests, ultrasound, and radioiodine or technetium scintigraphy, however, the molecular diagnosis underlying the pathogenesis of CH remains to be elucidated. One-hundred and ninety-two patients with primary CH were recruited in this study. All exons and exon–intron boundaries of 21 candidate genes for CH were analyzed by next-generation sequencing. And the intertance pattern of causative genes was analysised by the study of family pedigrees. Our results showed that 93 patients (48.44%) carried biallelic mutations (containing compound heterozygous mutations and homozygous mutations) in seven genes (DUOX2, DUOXA2, DUOXA1, TG, TPO, SLC5A5 and Autosomal recessive inheritance of CH caused by mutations in DUOX2, DUOXA2, TG and TPO was confirmed by analysis of 22 familiy pedigrees. Additionally, fifteeen mutations in five transcription factors (FOXE1, NKX2-1, PAX8, NKX2-5 and HHEX) that lead to thyroid dysgenesis were identified in fourteen probands, of which, only one patient carried biallelic mutations in FOXE1 and the other 13 cases had heterozygous mutation in those transcription factors. Family study indicated hypothyroidism was not observed in parents of these 14 probands. The genetic pathophysiology of the CH for 94/192 Chinese patients were definite by comprehensive screening of 21 candidate genes while a second mutation could be existed due to technical limitations of the direct sequencing analysis of 21 genes for the remaining patients that the phenotype caused by a monoallelic defect.
Disorders of Thyroid Function Thursday Poster Clinical
To discuss the clinical characteristics of hyperthyroid heart disease (HHD) and explore the strategy to guarantee radioiodine-131 therapy (RAI) safety. Analyze the clinical data and treatment regimens of 40 HHD patients who were admitted into our department from 2012-2016. The incidence of atrial fibrillation (AF) was 45.0%. Heart failure (HF) is always left ventricular ejection fraction (LVEF) reserved (80.0%); the severity of HF was accompanied with serum brain natriuretic peptide (BNP) increase and LVEF decrease. Liver function was moderate-medium impaired (61.5%), direct bilirubin positively correlative with the degree of HF (R = 0.390, P = 0.012). The RAI one-dose cure rate for hyperthyroidism was 77.5%. ATD use before RAI has no effect on the cure rate. Four patients who can't be treated with ATD deteriorated after RAI, two of them died because of seriously infection and HF, the other two recovered with saturated solution of potassium iodide or lithium. Familiar with medical therapy of comorbid conditions and using ATD before RAI is very important for HHD, if ATD is contraindicated, glucocorticoids, saturated solution of potassium iodide or lithium are the choices according to the patients' conditions.
Thyroid Cancer Thursday Poster Clinical
PD-L1 expression is being considered a potential biomarker for response of anti-PD-1 or anti-PD-L1 agents in various tumors. However, the correlation between PD-L1 expression and the specific clinicopathological features in papillary thyroid carcinoma (PTC) of Chinese patients has not been investigated. We evaluated the PD-L1 expression in Chinese PTC patients. A total of 226 patients were included (female = 172, male = 54, low risk = 91, intermediate risk = 111, high risk = 24 and 142 patients' tumor size ≤1cm). We evaluated the frequency of PD-L1 expression by immunochemical staining with a rabbit monoclonal antibody (clone SP142). The correlation between the PD-L1 expression with the clinicopathological features, TERT promoter and BRAF V600E mutation was evaluated.PD-L1 was positively expressed in 39.4% PTCs, and its expression was positively correlated with female gender (P = 0.025), tumor size (P = 0.011) and tumor number (P = 0.012). There was no significant association between PD-L1 expression and other clinicalpathological factors, including age, tumor extension or invasion, lymphnode metastases, distant metastases, recurrence risk, and background chronic lymphocytic thyroiditis (CLT). In addition, PD-L1 expression showed no significant correlation with BRAF V600E and TERT promoter mutation. Our results have not found that the PD-L1 expression is related the important clinicalpathological factors which may have effects on patients' overall survival and recurrence. We need enlarge our study to verify this primary result.
Thyroid Cancer Thursday Poster Clinical
Cytological diagnosis of “suspicious for malignancy (SFM)” under Bethesda system is reserved for aspirates with cytological features that raise a strong suspicion for malignancy but are not sufficient for conclusive diagnosis. Reported prevalence of SFM is 1-6% of thyroid fine needle aspiration (FNA) biopsies with estimated cancer risk of 60-75%. As per ATA 2015 thyroid nodules guideline, additional mutational testing may be considered in nodules with SFM cytology. Diagnostic surgical excision is the long established standard of care for management of SFM cytology nodules. No recent isolated study has evaluated incidence of thyroid cancer in patients especially with this category. We performed retrospective chart review of patients with cytological diagnosis of SFM on FNA of thyroid nodule specimens received at Upstate University Hospital between 1/2007 to 1/2018. We obtained demographic, clinical, laboratory, cytological and histological data. Incidence of malignancy in patients with cytological diagnosis of SFM was similar to that reported in 2015 ATA thyroid nodule guidelines. About 17% of patients who had benign disease might have benefited from molecular studies which could have avoided thyroidectomies and related complications and lifelong hormone replacement therapy. Our study suggests consideration of a more conservative approach for patients with thyroid nodules that belong to cytologically indeterminate “SFM” category. Incidence of malignancy in patients with cytological diagnosis of SFM was similar to that reported in 2015 ATA thyroid nodule guidelines. About 17% of patients who had benign disease might have benefited from molecular studies which could have avoided thyroidectomies and related complications and lifelong hormone replacement therapy. Our study suggests consideration of a more conservative approach for patients with thyroid nodules that belong to cytologically indeterminate “SFM” category.
Disorders of Thyroid Function Thursday Poster Case Report
Thyroid hormones impact many organ systems including cardiovascular system. Cardiac manifestations of hypothyroidism include reduction in cardiac output, stroke volume, heart rate, systolic blood pressure, and pulse pressure. Pericardial effusions are present in approximately 25% of hypothyroid patients. We present a case of waxing and waning pericardial effusion correlating with serum levels of free thyroxine (FT4) in patient with central hypothyroidism. 38 y female with history of Sheehan's syndrome complicated by central hypothyroidism, central adrenal insufficiency and growth hormone deficiency presented with worsening chest pain for 3 weeks. Vitals were stable. Physical exam revealed loud P2, holosystolic murmur and pedal edema. Echocardiogram showed massive pericardial effusion with impending cardiac tamponade and newly reduced ejection fraction of 30-35%. Patient admitted non adherence with Levothyroxine (LT4) with FT4 of 0.16 ng/dL (0.93 - 1.70 ng/dL). She was continued on oral LT4 125 mcg daily. Repeat echocardiogram 3 days later showed significant improvement in mitral flow velocity but unchanged pericardial effusion. She was treated conservatively. Echocardiogram 2 months later showed complete resolution of pericardial effusion and normalization of FT4. From chart review, it was noted that patient has multiple hospital admissions with similar presentation and noted to have waxing and waning pericardial effusion correlating with levels of serum FT4. Hypothyroidism causes decreased synthesis of albumin and increased capillary permeability leading to loss of albumin from intravascular to extravascular compartment resulting in increased interstitial fluid volume and impaired lymphatic drainage. This mechanism is thought to cause pericardial effusion in hypothyroidism. This process occurs slowly over a period of time, and therefore rarely causes hemodynamic compromise. It responds rapidly to treatment with LT4. Our patient showed resolution of pericardial effusion following normalization of FT4, and reaccumulation once levels of FT4 became sub therapeutic. Uncontrolled hypothyroidism remains one of the important differential diagnosis of pericardial effusion.
Disorders of Thyroid Function Thursday Poster Clinical
This study investigated the association between lifestyle factors and thyroid dysfunction in the She ethnic minority in South China.
We performed a cross-sectional study to determine the prevalence of thyroid dysfunction and its epidemiological characteristics, as well as its association with lifestyle factors. A total of 5154 permanent residents of She ethnic residents aged 20-80 years were enrolled in our study. life style information was collected using a standard questionnaire. Body mass index (BMI), Blood pressure and serum TSH, TPOAb, triglycerides (TG), total cholesterol (TC) and high–density lipoprotein cholesterol (HDL) were collected. The study showed that people who drank, had higher education or suffered from insomnia have lower incidence of hyperthyroidism (P < 0.05). On the other hand, smoking, alcohol consumption, exercise, undergoing weight watch and chronic headache were associated with decreased incidence of hypothyroidism (P < 0.05). Using multivariable logistic regression analysis, we found that alcohol consumption was associated with decreased probability of hyperthyroidism, hypothyroidism, as well as positive TPOAb. The amount of cigarettes smoked daily displayed a positive correlation with hyperthyroidism among smokers. Accordingly, smoking seemed to be associated with decreased risk for hypothyroidism and positive TPOAb. Exercise and maintaining a healthy weight might have a beneficial effect on thyroid health. Interestingly, daily staple amount showed an inverse correlation with incidence of positive TPOAb. Within the Chinese She ethnic minority, we found associations between different lifestyle factors and the incidence of different thyroid diseases. Understanding the nature of these associations requires further investigations.
Disorders of Thyroid Function Thursday Poster Clinical
TSH levels are unreliable for assessing thyroid status in patients with pituitary diseases. Endocrine Society recommended low or low normal free thyroxine (fT4) levels as a diagnostic test for central hypothyroidism. We wanted to know the diagnostic performance of TRH stimulation test and basal free T4 levels for predicting central hypothyroidism in pituitary surgery patients. Among 164 patients who underwent pituitary surgery at Chonnam National University Hwasun Hospital from 2006 to 2012, 119 patients had postoperative combined pituitary stimulation test (insulin hypoglycemia, LHRH and TRH stimulations). Postoperative basal fT4 levels and TSH responses to TRH stimulation were analyzed according to the need for levothyroxine replacement during the follow-up period (at least over 12 months). 28 patients (23.5%) needed T4 replacement and most patients were accompanied with panhypopituitarism. T4 replacement group showed lower basal fT4 (1.12 ± 0.41 vs. 1.34 ± 0.3 ng/dL, p = 0.003) lower TSH (1.04 ± 0.99 vs 2.5 ± 2.03 mU/L, p < 0.001), and lower peak TSH levels after TRH stimulation (3.18 ± 3.58 vs.10.67 ± 9.15 mU/L, p < 0.001). While TRH stimulation test was more sensitive (85.7%, specificity 54.9%), basal fT4 levels were more specific (94.5%, sensitivity 21.4%) and accurate (77% vs. 62.2% in TRH stimulation test). Both basal fT4 and TRH stimulation tests showed suboptimal performance in receiver operating characteristics curve analyses. Postoperative basal fT4 levels are more accurate in predicting central hypothyroidism in pituitary surgery patients, but the diagnostic performance is suboptimal. The decision for thyroid hormone replacement in pituitary surgery patients is not easy immediately after the surgery, it should be determined in clinical context during follow-up period.
Disorders of Thyroid Function Thursday Poster Clinical
Thyroid disease can result from a defect anywhere in the hypothalamic-pituitary-thyroid axis. In the vast majority of cases, it is caused by thyroid itself. Much less often it is caused by pituitary gland. Thyroid function tests are useful for evaluating the causes of thyroid disease. However, sometimes it is difficult to distinguish the two causes especially when they are accompanied. This study is to see how many cases would accompany thyroid disease in patients who undergoing transsphenoidal adenomectomy (TSA) for pituitary disease. We reviewed the medical records of patients who underwent TSA for pituitary disease during the 10 years from 2008 to 2017 at Severance Hospital. Among the 2202 patients, 297(13.5%) patients had thyroid disease before TSA. Hyperthyroidism, hypothyroidism, thyroiditis, thyroid nodule and s/p thyroidectomy were accompanied by 45(2.0%), 107(4.9%), 5(0.2%), 72(3.3%) and 73(3.3%) patients, respectively. There were 17(0.8%) patients of primary hyperthyroidism, but 6(0.3%) patients of them were suspicious. One patient who had undergone total thyroidectomy due to Graves' disease 18 years ago was finally diagnosed with TSH-secreting pituitary adenoma. Secondary hyperthyroidism was accompanied by 28(1.3%) patients, and 25(1.1%) patients of them were confirmed by pathology. Primary hypothyroidism was accompanied by 44(2.0%) patients, but 11(0.5%) patients of them were of dubious causes. Secondary hypothyroidism was accompanied by 63(2.9%) patients. Out of the total patients, 133(6%) patients had samples that stained positively for TSH. We should be careful because thyroid disease sometimes accompany with pituitary disease and it may be due to a different cause than originally thought.
Disorders of Thyroid Function Thursday Poster Clinical
ATA guidelines emphasize shared decision making when selecting between medication, radioactive iodine, and surgery for Graves' Disease treatment. There is limited literature on the effect of TPOAb on success with anti-thyroid medication. TPOAb has been associated with lower relapse rates after remission. This is a retrospective analysis of patients with Graves' disease (defined by clinical presentation, imaging features, or TSI+) who presented to Scottsdale Endocrinology Institute between 1/2011-04/2017 and received pharmacological treatment. Exclusion: <1 year of follow-up, thyroid cancer, pregnancy. Wilcoxon Rank Sum test and two-sided Wald test were used in analysis. Of the 107 patients with a new hyperthyroidism diagnosis, 40 patients (age: 46.90 ± 16.53; BMI: 23.68 ± 3.52 kg/m2; 62.5% female; 55% white, 7.5% Hispanic, 15% Asian, 10% African American) met inclusion criteria. 67.5% had TPOAb. The mean number of presenting symptoms was 4.35 ± 2.30 with a mean of 1.93 more symptoms in TPOAb+ patients. Lower TPOAb levels were associated with more symptoms. TPOAb+ patients had more sleep disturbances, anxiety/depression, and dry skin. Although symptoms significantly decreased with treatment, TPOAb positivity was associated with an average of 1.50 more persistent symptoms. Average post-treatment BMI was 1.62 kg/m2 higher for TPOAb+ patients, although non-significant. Mean time to euthyroid was 68.7 days for TPOAb+ patients and 62.5 days for TPOAb- patients (nonsignificant difference). 19.05% of patients seen in clinic for >2 years achieved full remission and an additional 29.41% required only minimal maintenance dose therapy. TPOAb was not associated with remission. Presence of goiter, fatigue, palpitations, Vitamin D deficiency, and progression to hypothyroidism were also not associated with TPOAb. Initial TPOAb level impacted initial symptoms but no other outcomes. Although time to euthyroidism and remission rates were similar, patients with TPOAb positivity, especially low level positivity, exhibited more symptoms of thyroid dysfunction and had persistent symptoms despite normalization of thyroid function. Larger multi-center studies could further inform the use of anti-thyroid therapy for TPOAb+ patients.
Disorders of Thyroid Function Thursday Poster Clinical
It was difficult to deal with the Graves' Disease (GD) which has a huge-size, whatever the function controlling or the operation. To this kind of GD, antithyroid drugs (ATDs) and radioiodine (RAI) sometimes show little effect while operation may bring serious bleeding and hazard of thyroid storm. The team tried to settle the problem by multi-disciplinary treatment and strict peri-operative period management. There were 8 GD cases with huge-sized thyroid treated in PUMCH during Jan. 2006 to Dec. 2016. All the cases proved to be ATDs and RAI non-sensative/non-effective/contraindicational (allergy/liver damage/granulopenia). We sitll use ATDs to controll the thyroid function to the best and then strictlly iodine drink. In 24 hours pre-operation, interventional radiologist carry on main arterial embolization of thyroid. The changes of thyroid size/blood supply pre-operation/bleeding and other things in-operation/function and relapses post-operation after ATDs/iodine preparation/arterial embolization before operation were observed and analysed. The patients got little bleeding in or after operation, no thyroid storm cases. Long-term follow up showed satisfactory thyroid function. After standard ATDs/iodine preparation and main arterial embolization of thyroid, patients got little bleeding in operation/smooth recovery/perfect long-term effects. Multi-disciplinary treatment and peri-operative period management are very important to those huge-sized GD, main arterial embolization of thyroid can decrease the in-operation- bleeding effectively.
Disorders of Thyroid Function Thursday Poster Clinical
Serum thyroid-stimulating hormone (TSH) level and cerebro-cardiovascular events (CVE) increase with age, but their relationship remains unclear. Our objective was to examine the association between serum TSH levels and the history of CVE (hCVE) in middle-aged/elderly subjects. This was a retrospective cross-sectional study of cases collected from Takasaki Hidaka Hospital between 2003 and 2007. Overall, 11,197 participants of health checkups were analyzed. The mean age was 48 ± 9 years (age range: 22–88 years). Rates of subclinical hypothyroidism (SCH) defined by normal thyroid hormone level but elevated TSH level were 6.1% in women and 3.3% in men. However, the serum TSH level increased with age, with the 97.5th percentile being 8.6 mU/liter at 70∼ years old in men and 10.0 mU/liter in women. In 2,752 men over 50 years old, multivariate logistic-regression analyses revealed that the serum TSH levels in subjects with hCVE were significantly higher than in those without hCVE (1.8 ± 1.1 mU/liter vs. 2.2 ± 2.8 mU/liter: p = 0.0179), but SCH had no effect. In fact, sixteen out of 135 (12%) subjects diagnosed with SCH had a history of CVE, but patients with SCH and serum TSH level above the 97.5th percentile in each decade of life had a higher percentage (11 out of 66 subjects, 17%). The adjusted odds ratio (OR) of hCVE in patients with SCH and serum TSH level above the 97.5th percentile was 2.7 (95% CI, 1.1-5.1; p = 0.005). However, other metabolic factors had no effects. In women, diastolic blood pressure and serum triglyceride were higher in SCH compared with those in euthyroid subjects. Higher age-adjusted serum TSH level appeared to be related to hCVE in middle-aged/elderly men.
Disorders of Thyroid Function Thursday Poster Clinical
The most frequent cause of central hypothyroidism (CH) is pituitary adenomas, however, its details remains unclear. Objective of this study was to investigate thyroid status and the involvement of Growth Hormone (GH)/IGF-1 to CH in large scale of untreated patients with pituitary adenomas, particularly nonfunctioning and GH-secreting adenomas. This is a retrospective cross-sectional study of cases collected from Gunma University and Toranomon Hospitals between 2007 and 2010. One hundred-thirty nine cases of non-functioning pituitary adenoma (NFA) and 150 cases of GH-secreting pituitary adenoma (GHoma) were analyzed. The correlation between the thyroid status and several clinicopathological parameters and its involvement to GH/IGF-1 system were examined. Twenty-four percent of the NFA showed CH, and the severity did not correlate with the tumor size, age, gender, or other hormonal deficiency, and it is of interest to note that all cases showed a normal TSH level. In contrast, only 8.7% of GHomas showed CH, and about half exhibited a normal TSH level and the rest showed a low. The mean serum TSH levels in GHoma were significantly lower, and the free T4 and free T3 levels were higher than those in NFA. Furthermore, about one fourth of GHoma showed a normal free T4 and a low TSH level. In addition, the serum free T4 level positively and the serum TSH levels negatively correlated with the serum IGF-1 levels. T4/T3 ratio is not significantly different between the two groups.1) High prevalence of CH with a normal TSH level in NFA pituitary adenomas, 2) Low frequency of CH in GHoma, which may be due to the stimulation by high level of IGF-1.
Disorders of Thyroid Function Thursday Poster Clinical
Subclinical hypothyroidism (SCH) and metabolic syndrome (MetS) increase with age; however, their relationship remains unclear. To investigate the relationship between SCH and indices of metabolic syndrome. Overall, 11 498 participants of health checkups were analyzed in the cross-sectional and longitudinal follow-up studies. Serum free T4 levels were lower in women than men in most of the age groups. The prevalence of SCH was 6.3% in women vs 3.4% in men, and prevalence increased with age, reaching 14.6% in 70+ year age group of women. Multivariate logistic-regression analyses revealed that waist circumference and the serum triglyceride and low-density lipoprotein-cholesterol levels among women were significantly higher in subjects with SCH compared to those without SCH. Reflecting these findings, the adjusted odds ratio of MetS in patients with SCH was higher than in the euthyroid women participants with an odds ratio of 2.7 (95% confidence interval 1.1–5.6; P .017) but not in male participants. Furthermore, progression from euthyroid into SCH resulted in a significant increase in the serum triglyceride levels but not low-density lipoprotein-cholesterol in women. Japanese women exhibited a high prevalence of SCH associated with low free T4 levels. There was a strong association between SCH and several indices of metabolic syndrome in women. SCH may affect serum triglyceride levels and be a risk factor for metabolic syndrome.
Disorders of Thyroid Function Thursday Poster Clinical
In addition to heredity and living habits, the risk of environmental pollutants affecting the thyroid hormone levels and interfering with thyroid function cannot be ignored. A high concentration of pentachlorophenol can be detected in drinking water in Shanghai continuously. Pentachlorophenol has been confirmed as an environmental pollutant that can interfere with thyroid hormones. This study in one community in Fengxian District, Shanghai which has a high incidence of thyroid disease to find out the association between the level of pentachlorophenol exposure and thyroid hormones;the thyroid disrupting effect of pentachlorophenol at population level. A method was established to detect the concentration of pentachlorophenol in human serum. A total of 100 cluster random samples in this community were taken from the population to collect blood and urine. Thyroid function indicators (FT3, FT4, TSH, TgAb and TPO) were measured. Also the concentration of pentachlorophenol in serum and urinary iodine (as indicators of iodine levels in the body) was measured. Considering age, gender, iodine (urine iodine) and other factors on the impact of thyroid function in the population, the association between the exposure of pentachlorophenol and the interference of thyroid hormone was analyzed. The results indicate that the pentachlorophenol exposure in serum in the investigation population is at the nanogram level (ND-5.30 ng/mL) and the detection rate is 98%. The results of correlation analysis (controlling urinary iodine) indicate that there is a negative correlation between the exposure level of pentachlorophenol and FT4 levels (r = 0.682, P < 0.05), but no significant correlation with other thyroid hormone markers. People in the community generally contain pentachlorophenol. Although the concentration of pentachlorophenol in the body is at trace level, the exposure of pentachlorophenol at the nanogram level can interfere with thyroid hormone in the body and disturb thyroid function. In the future, a large-scale population epidemiological investigation is needed to further clarify and confirm whether pentachlorophenol is a potential risk factor accounting for high incidence of thyroid disease.
Disorders of Thyroid Function Thursday Poster Case Report
We report a classic case of myxedema coma, presenting with altered mental status, hypothermia, hypoglycemia, hypotension, hyponatremia, and bradycardia, in a patient with amiodarone-induced hypothyroidism.73 year-old female with history of iatrogenic hypothyroidism due to amiodarone presented with lethargy. Vitals revealed hypotension (90/40 mmHg), bradycardia (40 beats/minute), and hypothermia (35.2° C). She was minimally responsive with tremors, dry skin, periorbital and pretibial edema. Labs showed glucose 50, TSH 99.589 uIU/mL, and sodium 134 meq/L. Urinalysis with >900 WBCs, prompting cefepime. IV Levothyroxine 75mcg was started, as well as stress dose IV hydrocortisone, which resulted in rapid improvement. Hypoglycemia was corrected with 1 amp D50. AM cortisol was 5.7 mcg/dL, which ruled out concurrent adrenal insufficiency. The patient was given Levothyroxine 50 mcg IV daily with repeat TSH 40.293 uIU/mL, free T4 0.48 ng/dL, total T3 0.2 ng/mL. Upon discharge, vitals, mental status, and edema had normalized. The presumed etiology was medication non-compliance, as well as a precipitating UTI. Myxedema coma is rare due to wide availability of thyroid replacement therapy. The condition could be precipitated by many events, including infection. Despite the name, patients more often present with lethargy and confusion rather than coma. Stress dose steroids should be administered until concurrent adrenal insufficiency is excluded1. Amiodarone's thyrotoxic profile has been well established but amiodarone associated myxedema coma has only been outlined in a handful of reports. Given its high mortality, it is crucial to recognize myxedema coma, so prompt treatment can be initiated for this life-threatening disorder. Our case also argues for the importance of routine thyroid function tests for patients on amiodarone, as myxedema coma occur.
Thyroid Cancer Thursday Poster Case Report
We present a rare case of a patient with pre-existing hyperthyroidism who developed non-Hodgkin's lymphoma of the thyroid.61-year-old male with a 10 year history of hyperthyroidism presented with 2 months of right-sided neck swelling. The palpable mass was further evaluated with CT neck that revealed an enlarged homogenously enhancing nodule under the right sternocleidomastoid concerning for a pathologic lymph node, and a smaller satellite node. The dominant lymph node was excised, and pathology showed low grade B cell lymphoma consistent with marginal zone lymphoma. No bone marrow involvement was noted on biopsy. PET scan showed diffuse asymmetric thyroid activity prominent in the right isthmic region, possibly due to thyroiditis. At that time, the patient was taking Methimazole 10 mg daily. He was biochemically euthyroid with negative thyroid stimulating immunoglobulin. Thyroid ultrasound showed a heterogeneously enlarged thyroid with a 4cm hypoechoic nodule within the right lower pole, and an 11mm hyperechoic nodule in the left lower pole. Right thyroid nodule cytology and flow cytometry revealed non-Hodgkin's lymphoma. The patient was diagnosed with marginal zone lymphoma of thyroid and right cervical nodes, stage IIE and is being managed with radiation therapy. Primary thyroid lymphoma is an incredibly uncommon condition with an annual incidence of approximately 0.000002. When it does occur, it is mostly in the setting of Hashimoto's thyroid disease. There are very few cases reporting thyroid lymphoma in patients with pre-existing hyperthyroidism. Since there are few cases demonstrating an association between hyperthyroidism and thyroid lymphoma reported, clinicians may not easily recognize the importance of certain diagnostic tests. In regards to our case, we would like to highlight the importance of obtaining flow cytometry based upon clinical context, especially since diagnosis may alter treatment.
Disorders of Thyroid Function Thursday Poster Case Report
A thyroid storm is a life-threatening presentation, with congestive heart failure and tachyarrhythmias being common manifestations. We describe a patient who was admitted for a thyroid storm precipitated by pneumonia, who later developed an acute flail mitral valve from chordae tendineae rupture. A 55 year-old lady with no past medical history was admitted with fever, dyspnea, lower limb swelling and hemoptysis. She was febrile, tachycardic and in fluid overload. Her heart sounds were dual and no murmurs were heard. Initial investigations indicated primary hyperthyroidism and pneumonia. She was diagnosed with a thyroid storm precipitated by a pneumonia, complicated by heart failure. Her Burch-Wartofsky score was 70. She was started on IV hydrocortisone, PO propylthiouracil, PO lugols's iodine and PO cholestyramine, together with IV amoxicillin-clavulanate and IV furosemide. She continued to deteriorate in the Medical Intensive Care Unit with worsening hypoxia and hypotension. Echocardiography showed an acute flail posterior mitral valve leaflet with torrential mitral regurgitation due to rupture of the chordae tendineae. She subsequently underwent a bioprosthetic mitral valve replacement. An acute flail mitral valve precipitated by thyroid storm leading to refractory cardiogenic shock is rare. Factors contributing to the rupture of valve chordae tendineae include the effect of hyperthyroidism on papillary muscle function, a hyperdynamic circulation leading to vulvular stress, as well as pre-existing mitral valve pathology. A flail mitral valve from chordae tendineae rupture can also be a cause of worsening heart failure and cardiogenic shock in a thyroid storm, albeit a rare complication.
Disorders of Thyroid Function Thursday Poster Case Report
This case describes a patient who was admitted for a thyroid storm 1 month after radio-iodine treatment. A 71 year-old Chinese lady was admitted to the emergency department for a 3 day history of fever and confusion. She had a history of toxic multinodular goitre diagnosed 2 years ago and had been on carbimazole 5mg OM until 4 months ago when she was found to be neutropenic on routine testing. Carbimazole was stopped and she was started on choleystramine 4g OM and sent for radio-iodine treatment. A bone marrow aspirate done later showed good marrow production, although she was persistently leukopenic despite stopping carbimazole for more than 4 months. 20 mCI of Iodine-131 had been administered to her 1 month before her admission.
Her Burch-Wartovsky score on admission was 80. She did not complain of any neck pain or swelling. She was started on IV hydrocortisone 100mg 8H, PO propranolol 10mg 8H, PO cholestyramine 4g 8H. Propylthiouracil was also started at 100mg 8H cautiously. There was no evidence of any stroke or myocardial infection, and her procalcitonin level was low. Antibiotics were started for a presumptive urinary tract infection. She improved clinically and was continued on a tailing dose of steroids on discharge. Post-radioiodine thyroiditis is usually asymptomatic and typically manifests a few days to 2 weeks therapy after administration, with a temporary exacerbation of thyrotoxicosis in previously hyperthyroid patients. Contributing factors include ineffective anti-thyroid pharmacotherapy due to ongoing evaluation for possible carbimazole-induced agranulocystosis, large radio-iodine dose relative to goitre size, as well as precipitating infections.
Thyroid storm is a rare complication of post-radioiodine thyroiditis.
Disorders of Thyroid Function Thursday Poster Case Report
Thyrotroph hyperplasia is a rare heterogeneous entity, often seen in severe hypothyroidism. It is postulated that this pituitary enlargement occurs due to persistent stimulation from the lack of thyroxine. Barring any emergent indications such as visual impairment- treatment is levothyroxine replacement. Reports have described that resolution of the hyperplasia with levothyroxine occurs between months to years. Herein, we describe a patient who had thyrotroph hyperplasia which has improved significantly with complete resolution of visual field defect, galactorrhea, hyperprolactinemia.
25-year-old woman presented with galactorrhea was found to have a 2 cm pituitary mass impinging on optic chiasm. Visual field testing revealed mild field cut bilaterally although she denied visual deficit. Her pituitary hormonal evaluation revealed elevated prolactin and TSH. Mild hyperprolactinemia was likely due to stalk effect. A hook effect was ruled out by prolactin dilution assay. Interestingly, she was found to have elevated TSH (150 mIU/L) with low free T4 (0.3 ng/dl) with positive anti-TPO antibody. She was started on levothyroxine resulting in resolution of galactorrhea, hyperprolactinemia, more importantly, a significant reduction of the size of the pituitary mass and resolution of the visual field defect.
Not every patient with galactorrhea, hyperprolactinemia and a pituitary mass has a prolactinoma. Thyroid hormone replacement can reverse pituitary enlargement due to thyrotroph hyperplasia.
Thyroid Cancer Thursday Poster Case Report
Radioiodine-avid thyroid cancer lesions usually are 18F-FDG -nonavid, and vice versa. There are very few reports showing thyroid cancer with both uptakes of 18F-FDG and 131-I. Herein, we report a case of follicular and poorly differentiated thyroid cancer (PDTC) with both 18F-FDG and RAI uptake at the metastatic site.
A 47-year-old female with follicular thyroid cancer with a large right hip bone metastasis. Her pathology of thyroidectomy specimen showed follicular thyroid cancer with a poorly differentiated component. FNA of her hip lesion showed follicular thyroid cancer. Seeing a component of PDTC, a18F-FDG PET/CT scan was done to evaluate iodine avidity of her bone metastases. This revealed 18F-FDG uptake in the metastatic site. Given her high risk for recurrence, she was treated with 200 mCi RAI. A post-therapy scan showed marked uptake in the metastatic right hip which did light up on PET/CT scan. The true effectiveness of RAI therapy for her hip metastasis is unknown because she was only recently treated. Interestingly, RAI treatment resulted in marked reduction of thyroglobulin level and the size of the hip mass.
Disorders of Thyroid Function Thursday Poster Case Report
Seaweed is known to affect thyroid function because of its iodine content. Here we discuss a case of hyperthyroidism that was further exacerbated by seaweed consumption during inpatient admission despite use of antithyroid drugs.
A 54 year old female with a history of untreated Graves' disease presented with progressive dyspnea for two months. She had heat intolerance, diaphoresis, weight loss, increased appetite, hair loss, dry skin, dyspnea, palpitations, and fatigue. On physical exam, she was anxious, tachycardic, had lid lag but no other ophthalmic findings, and fine tremors in hands and feet. Chest radiograph revealed pulmonary edema. EKG showed sinus tachycardia. Troponin increased from 0.16 to 3.48. Coronary angiogram showed nonobstructive coronary artery disease in the right coronary artery. Thyroid stimulating hormone (TSH) was <0.01, free T4 (FT4) was 7.18, and free T3 (FT3) was 12.7. Methimazole 30mg daily and metoprolol XL 50mg daily was initiated with improvement in labs and symptoms. Patient was discharged, but returned four days later with increased anxiety and dyspnea. TSH was <0.01, FT4 2.93, FT3 12.2. Methimazole was increased to 20mg BID. After four days of treatment, FT4 increased from 2.93 to >8.00. Although patient initially denied consumption of iodine containing foods, she was found consuming seaweed snacks and seaweed juice while in the hospital. She stopped all seaweed containing products and thyroid function tests normalized. Thyroid hormone synthesis requires iodine 150 μg daily, while kelp and seaweed are very iodine rich and contain between 16 μg/g and >8000 μg/g. The thyroid gland has intrinsic regulatory mechanisms that maintain normal thyroid function even in the presence of iodine excess, however patients with Graves' disease are prone to develop iodine-induced hyperthyroidism. Excess iodine in hyperthyroid Graves' disease may also reduce the effectiveness of antithyroid drugs. Both of these phenomena were observed with our patient. Patients with thyrotoxicosis, especially from Graves' disease, should be counseled about iodine containing products as these can exacerbate their thyrotoxicosis and make antithyroid drugs less effective.
Disorders of Thyroid Function Thursday Poster Case Report
Older individuals often present with a subdued presentation of hyperthyroidism, termed apathetic. While systemic manifestations such as tremor and diarrhea are absent, cardiac manifestations such as tachyarrhythmias will prevail. The presence of cardiomyopathy (CMO) in the setting of overt thyrotoxicosis or thyroid storm, has been attributed to several etiologies including tachycardia-induced and takotsubo's (stress induced) CMO. A 77-year-old woman with no medical follow up presented to the emergency department complaining of shortness of breath, malaise, poor oral intake, palpitations and orthopnea for the past week. Patient also endorsed 40-pound weight loss over the past year. On physical exam it was noted to have a BMI of 17 and was in atrial fibrillarion (AF) at a rate of 160's. The exam showed evidence of proptosis and jugular venous distension. Laboratory data was pertinent for an elevated troponin (0.113 ng/mL) and BNP (3294 pg/mL). Hemoglobin A1C was 10.8%. Thyroid studies revealed TSH <0.01 mIU/L, free T4 1.48ng/dL (0.7-1.48ng/dL), total T3 0.66 ng/mL (0.58-1.59ng/mL). Thyroid ultrasound showed multinodular goiter. Thyroid Stimulating Immunoglobulin 488 (<140 % baseline) and thyroid microsomal antibody 263.65 IU/mL (<5.61). Iodine uptake scan was deferred to the outpatient basis. Transesophageal echocardiography demonstrated severely reduced ejection fraction of 10-15%. All four chambers of the heart demonstrated extensive clot burden with chamber dilations. Hypercoagulable workup was pertinent for Protein C antigen 45% (70-140 %). She was started on apixaban, methimazole and metoprolol succinate with improvement in hemodynamics. While, conditions such as AF and CMO alone may predispose to cardiac thrombi, overt hyperthyroidism has been suggested to independently be associated with a hypercoagulable state through unclear mechanisms. Previous reports have suggested that elevated free T4 levels, increased TBG, and rare reports of protein C deficiency, have been reported in associated with hyperthyroidism and the hypercoagulable state. Further investigation is needed to identify the duration of the hypercoagulability once patient is euthyroid in order to manage duration of anticoagulation.
Disorders of Thyroid Function Thursday Poster Case Report
Thyroid dysfunction is a known cause of menstrual irregularities, including oligomenorrhea, amenorrhea and menorrhagia. We present a patient with life-threatening anemia due to menorrhagia in the setting of newly-diagnosed hypothyroidism. A 43-year-old female with no significant history presented with worsening fatigue, lightheadedness and menorrhagia for the past 6 months. Her menstrual cycle had become heavier, irregular and of longer duration. On presentation, she was found in hemorrhagic shock with a systolic blood pressure of 76 and heart rate of 138. Physical exam was remarkable for skin and conjunctival pallor, proximal muscle weakness and dark blood with clots in the vaginal vault. Laboratory tests revealed a hemoglobin of 5.6 g/dL. She received 3 L of IV fluids and 2 units of packed red blood cells with subsequent improvement of hypotension. A transabdominal and transvaginal ultrasound were unremarkable, ruling out organic disease of the genital tract. Upon further workup, the patient was found to have a TSH level of 188 mIU/L, FT3 of 0.4 pg/mL and FT4 < 0.10 ng/dL indicative of hypothyroidism. She was started on levothyroxine 125 mcg daily and iron supplements and was discharged to follow-up with Endocrinology after stabilization of her hemoglobin levels. Thyroid disorders are associated with a wide spectrum of reproductive disorders ranging from abnormal fetal development, menstrual irregularities and infertility. Menorrhagia and metrorrhagia can be complicated presenting symptoms of profound hypothyroidism, a consequence of anovulatory dysfunctional uterine bleeding and hemostasis disturbance. It is known that with thyroid hormone replacement therapy, TSH levels normalize and abnormal uterine bleeding usually resolves within 3 to 6 months. The American Thyroid Association estimates that 1 in 8 women develop a thyroid disorder at some point in their lives. Thyroid dysfunction should be strongly considered and screened in patients presenting with menstrual abnormalities. Correction of thyroid abnormalities can significantly improve abnormal uterine bleeding, avoid life threatening complications and invasive surgical interventions.
Disorders of Thyroid Function Thursday Poster Case Report
The incidence of pericardial effusion in hypothyroidism is 3% in the early mild stage and up to 80% in patients with myxedema. We present three cases of severe hypothyroidism causing cardiac tamponade.
CASE 1. 61-year-old woman with Hashimoto's thyroiditis who initially presented with generalized muscle weakness, found to have a large pericardial effusion with tamponade physiology. Initial labs revealed TSH 198.74 and FT4 < 0.10. Pericardiocentesis was done draining 1.5 L of fluid.
CASE 2. 63 year-old woman with no past medical history presented after a mechanical fall, found to have an acute basal ganglion ischemia. TTE was obtained to complete CVA work-up revealing a large pericardial effusion with with tamponade physiology. labs were notable for a TSH 47.
CASE 3. 66 year-old woman with hypothyroidism presented with lethargy and dyspnea. TTE revealed large pericardial effusion with tamponade physiology. CT chest revealed a large pericardial effusion that was narrowing the distal left mainstem and left lower lobe bronchi. Pericardiocentesis was done draining 1.1 L of fluid. Pericardial effusion in hypothyroidism is due to increased capillary permeability and impaired lymphatic drainage with subsequent leakage of fluid rich proteins and glycosaminoglycans into the interstitial space. Factors affecting capillary permeability include absence of FGF signaling and decrease in adrenomedullin, resulting in destabilization of the VE-cadherin/β-catenin complex at the cell–cell junctions. There has been no correlation with TSH levels and the existence of effusion.
Clinical symptoms of tamponade are uncommon due to slow accumulation of fluid and pericardial distensibility. It is hypothesized that heart rate is within normal range or bradycardic due to decrease sympathetic activity.
The color of the fluid is most commonly straw-colored or gold. And the cells are predominantly lymphocytes.
The treatment should be individualized. The effusion can be reversed only with levothyroxine because the slow rate of accumulation. Pericardiocentesis is only done when there is hemodynamically instability. Cardiac tamponade presenting with normal or low heart rate with high TSH is highly suggestive of hypothyroidism as the culprit.
Disorders of Thyroid Function Thursday Poster Case Report
Amiodarone-induced thyrotoxicosis (AIT) develops in 3% of amiodarone-treated patients in North America. Its long half-life allows its effects to persist for months. In a patient with unstable cardiac function, uncontrolled AIT can be life-threatening. We present a case of severe cardiac disease and a prolonged course of AIT treated with a total thyroidectomy. A 61-year-old man with congestive heart failure (CHF) is admitted with worsening heart failure and recurrent ventricular arrhythmia.
Six months prior, the patient received one dose of amiodarone at an outside hospital and subsequently, was found to have new hyperthyroidism with a TSH 0.00 uIU/mL (0.5-4.8), free T4 2.8 ng/dL (0.9-1.8), and total T3 220 ng/dL (87-178). Thyroid antibodies were normal. A thyroid ultrasound showed a homogeneous gland with no nodules. An I-131 thyroid scan showed uptake of 1.7% (10-30%). He was treated with prednisone for presumed thyroiditis.
One month ago, he was admitted with worsening CHF and ventricular tachycardia (VT). He reported noncompliance with prednisone and was found to have a TSH <0.008 uIU/mL, free T4 3.1 ng/dL, and total T3 0.87 ng/mL. Echocardiogram showed ejection fraction (EF) of 30%. He was treated with a beta blocker, prednisone 40mg daily and methimazole 30mg daily.
He is now readmitted with recurrent VT. TSH is <0.008, free T4 5.1 and EF has decreased to 12%. Due to the worsening cardiac status and persistent hyperthyroidism, a total thyroidectomy is recommended after symptomatic control with prednisone and beta blocker. The pathology shows thyroid parenchyma with changes consistent with type 2 AIT. Amiodarone-induced thyrotoxicosis (AIT) can develop in patients with underlying thyroid abnormalities (type 1) or in patients with normal thyroid glands (type 2). Differentiating type 1 from type 2 AIT is crucial as it has therapeutic implications. Type 1 is treated with anti-thyroid drugs while type 2 is treated with steroids. Uncontrolled and persistent hyperthyroidism is associated with an increased incidence of ventricular arrhythmias and a rapid decline in cardiac function. A total thyroidectomy needs to be considered in unstable patients when AIT is persistent and difficult to control.
Disorders of Thyroid Function Thursday Poster Case Report
The mainstay of treatment for amiodarone induced thyrotoxicosis (AIT) type 2—a form of destructive thyroiditis—is the use of oral glucocorticoids. However, the literature offers limited insight into the impact of the type and route of glucocorticoid on treatment response. We present a case of AIT type 2 which required the administration of intravenous (IV) glucocorticoids in order to achieve euthyroidism. A 64 year-old male presented to our hospital in thyrotoxicosis (initial labs showed TSH 0.03 mIu/L and free T4 3.66 ng/dL) complicated by atrial fibrillation with rapid ventricular rate and exacerbation of congestive heart failure. He had been maintained on amiodarone for a history of persistent atrial fibrillation despite prior ablation. We initiated methimazole 40mg daily and prednisone 30mg BID after stopping amiodarone given concern for AIT. Type 2 AIT was ultimately suspected based on low thyroid uptake and scan, negative thyroid antibodies, elevated interleukin-6 level, and unremarkable neck ultrasound; methimazole was therefore discontinued. After 17 days, the patient's poor clinical status and free T4 level were unchanged. His persistent volume overload raised the suspicion of enteral malabsorption, and we therefore transitioned from oral prednisone to IV hydrocortisone 50mg every six hours. Within four days, his free T4 decreased by half with resolution of atrial fibrillation, and the patient was rendered euthyroid within two weeks. Prednisone 0.5-0.7mg/kg per day is recommended for mixed AIT or AIT type 2, though rates of free T4 normalization are often slow. Compared to prednisone, parenteral hydrocortisone has the advantages of higher bioavailability and immediate activity without first requiring hepatic conversion to an active steroid metabolite. Equipotent IV glucocorticoid therapy has shown greater efficacy compared to oral administration in the treatment of other conditions, such as Graves' ophthalmopathy. This case demonstrates that parenteral glucocorticoids should be considered for recalcitrant disease in select AIT type 2 patients, particularly those with critical illness or refractory hyperthyroidism. Larger, placebo-controlled studies are needed to support this approach.
Iodine Uptake & Metabolism Thursday Poster Clinical
Sialadenitis is among the most common complications of thyroid carcinoma treated with radioactive iodine (RAI). Symptoms include pain, xerostomia, and swelling. To date there are a paucity of studies that characterize ultrasound findings in patients with RAI sialadenitis. The objective of this study is to demonstrate ultrasound findings in patients with a history of radioactive iodine exposure (RAI) and suspected RAI associated sialadenitis.22 patients with a history of thyroid carcinoma treated with RAI who presented for evaluation of sialadenitis were identified. Ultrasound (US) examination was performed in each patient. Ultrasound findings studied included intraglandular and/or main ductal dilation, presence of echogenic foci with or without posterior acoustic shadowing, echotexture, and vascularity of the gland. Representative images were captured, and relevant measurements were taken. The mean age of patients was 47 years. The majority (20/22) of the patients were female (91%). The parotid gland was most affected (90%) followed by the submandibular gland (10%) The average cumulative dose of RAI was 165 mCi with a SD of 108 mCi with a 95% CI (115,215).
US examination demonstrated obstruction in 19 patients (86%), ductal dilation was present in 14 patients (63%) and intraglandular dilation was noted in 17 (77%). Gland parenchyma appeared homogeneous in 9 (41%) and heterogeneous in 11 (50%). 18/22 (81%) glands were considered to be normovascular. No calculi were identified in this cohort.
US examination demonstrated obstruction in 19 patients (86%), ductal dilation was present in 14 patients (63%) and intraglandular dilation was noted in 17 (77%). Gland parenchyma appeared homogeneous in 9 (41%) and heterogeneous in 11 (50%). 18/22 (81%) glands were considered to be normovascular. No calculi were identified in this cohort. The ultrasound findings of RAI sialadenitis can vary. The most common finding noted is ductal dilation, which suggests obstruction. The majority of the glands are of normal vascularity. Heterogeneity of the gland is a less consistent finding.
Thyroid Cancer Thursday Poster Clinical
Sialadenitis is among the most common complications of thyroid carcinoma treated with radioactive iodine (RAI). Symptoms include pain, xerostomia, and swelling. Treatment focuses on prevention of the symptoms by promoting the excretion of the isotope by gland massage, use of sialogogues, radioprotective antioxidants, and muscarinic receptor agonists. However, once sialadenitis symptoms become present, treatment options for patients nonresponsive to conservative management have been previously limited to sialadenectomy. Recently sialendoscopy was introduced as an alternative. This study examines sialendoscopy as treatment option for RAI induced sialadenitis. This study is retrospective review of 22 patients with persistent sialadenitis symptoms related to RAI treated with sialendoscopy. All patients sought evaluation of sialadenitis after failure of conservative measures. The parotid gland was affected in 90% and submandibular gland in 10%. Symptoms were periprandial in 75% of patients and included pain (65%), xerostomia (50%), discharge (40%) and swelling (100%) with unilateral presentation in 80% of patients. Average time between symptom onset and evaluation was 11 months. Symptoms manifested an average of 10 months after RAI treatment was completed. The average dose of one time RAI was 168 mCi. Sialendoscopy revealed strictures in 17 patients (75%), inflammatory sialadenitis changes in 3 patients (15%) and normal ducts in 2 patients (10%). All patients demonstrated mucosal discoloration, mucous plugs, and debris.
Symptom improvement was achieved in 20/22 patients (91%) after intervention. Three patients had symptom recurrence. Repeat sialendoscopy on two of these patients led to permanent resolution of symptoms. One patient did not follow up. Sialendoscopy is a functional, minimally invasive option for treating sialadenitis and strictures induced by RAI treatment for thyroid carcinoma refractory to conservative management.
Iodine Uptake & Metabolism Thursday Poster Clinical
Bariatric surgery is highly effective for the treatment of obesity. Nutrient deficiencies are common post-bariatric surgery, especially after Roux-En-Y gastric bypass. Iodine absorption occurs primarily in the proximal small intestine. To date, there have been few studies assessing iodine status following gastric bypass. We aimed to assess urinary iodine concentrations (UICs) pre- and post-bariatric surgery and to determine predictors of postoperative UICs.
This was a prospective observational cohort study. Patients undergoing bariatric surgery at Boston Medical Center from January 2014 - July 2016 were enrolled. Individuals using thyroid medications, amiodarone, lithium or with recent exposure to iodinated contrast media were excluded. Spot UICs, serum TSH, vitamin B12, iron, ferritin, folate, thiamine and 25-OH-vitamin D levels were collected prior to and 3-6 months post-bariatric surgery. A questionnaire including 24-hour dietary recalls and multivitamin use was administered at the pre- and post-operative visits.
85 patients (86% female) were included. Mean age was 36.0 ± 11.1 years. Roux-En-Y gastric bypass surgery and sleeve gastrectomy were performed in 60 and 25 patients, respectively. Dehydration, numbness, ataxia, anemia, and/or severe electrolyte abnormality occurred in 8 subjects. Median UIC was higher after surgery than at baseline (331 [range 72-1500] vs. 201 [range 16-2176] μg/L, p < 0.001). Post-operative UICs were positively correlated with ingestion of eggs (r = 0.53, p 0.01) and the number of daily servings of high-iodine foods (bread, seafood, dairy, eggs) (r = 0.28, p 0.04). Serum TSH after surgery was lower than at baseline (1.53 ± 0.50 vs. 1.12 ± 0.54 U/mL, p < 0.001). Although serum TSH levels decreased after surgery, they remained within normal range. The TSH change was not associated with weight change, UICs, vitamin supplement or high-iodine foods.
Median UIC was higher after bariatric surgery than before, due to changes in diet. Iodine deficiency did not occur preoperatively or postoperatively in this sample.
Thyroid Nodules & Goiter Thursday Poster Clinical
Thyroid nodules (TN) are common with aging. Fine needle biopsy (FNB) with molecular testing of indeterminate TN (ITN) biopsies is a cost-effective method to detect malignancy. Surgery is the preferred treatment for suspicious/malignant TN. The aim was to understand TN features in older patients (≥70 yrs). This is a retrospective case series study. Between 2/2015 – 6/2016, 453 sequential FNBs were performed on TN >1 cm. TN size by ultrasound evaluation, cytology including molecular studies and surgical pathology were collected. Results were compared between TN from the older (O: ≥70 yrs) and younger (Y: <70 yrs) patients. Of the total thyroid FNBs, 17.7% (80/453) were in the O patients (76.1 ± 5.0 yrs) and the rest were in the Y patients (49.5 ± 12.6 yrs). Compared with the Y group, in the O patients, male to female ratio was higher (23.8% vs 13.4%, P = 0.02), multiple TN was more common (97.5% vs 85.5%, P < 0.01), while the mean TN size was similar (2.6 ± 1.1cm vs 2.6 ± 1.4cm, P = 0.54). Cytology results in the O patients were 13.7% unsatisfactory, 57.5% benign, 23.8% indeterminate (Bethesda III/IV/V) and 5% malignant. Unsatisfactory cytology (13.7 vs 9.9%, P = 0.05) and benign cytology (57.5% vs 49.3%, P = 0.03) were more frequent while indeterminate results were less frequent (23.8% vs 36.2%, P < 0.01) in the O vs Y patients. ThyroSeq V.2 molecular testing of ITN, had a similar positive rate in the O vs Y patients (36.8% vs 35.8%, P = 0.74). Rates of surgery were significantly lower in the O vs Y patients in the entire series (18.8% vs 29.0%, P = 0.01), in the subgroup of benign (6.5% vs 15.7%, P < 0.01) and ThyroSeq-positive ITN (28.6% vs 53.5%, P < 0.01). Surgically confirmed malignancy occurred similarly in 9/80 (11.3%) and 36/373 (9.7%) of the O and Y patients, respectively (P = 0.66). TN of the older patients (≥70 yrs) was more likely to occur in men with a multinodular gland while insufficient and benign cytology was more common and indeterminate was less likely to occur. Aging may not affect the risk of a positive ThyroSeq V.2 test in ITN. Older patients were less likely to have surgery for both benign and molecular positive ITN.
Iodine Uptake & Metabolism Thursday Poster Clinical
The Swedish iodine fortification program with 50 μg iodine/g table salt has been considered sufficient for an adequate iodine nutrition in the population. Therefore, there have been no systematic monitoring. We recently reported from a national study that mild iodine deficiency (ID) was present among pregnant women. We have formulated the hypothesis that mild ID has not emerged now, but been persistent for a long time. The aim of this study was to explore iodine intake and iodine excretion in early pregnant women in samples from 2006. Pregnant women (n = 65) were included during the first trimester at the maternal health care centre in Kungälv in 2006. This cross-sectional study included registration of a food frequency questionnaire for calculation of iodine intake, blood samples for thyroid hormones, thyroglobuline (Tg) and urine samples both collected as spot urinary iodine concentration (UIC) and as 24 hours urinary iodine excretion (24-UIE). Urinary iodine was analysed with the Sandell-Kolthoff reaction. Six pregnant women were excluded from this preliminary analysis because of miscarriage, one because of mola hydaditosa and three did not complete the study. In those remaining 56 women, supplements that included iodine were used by 13 women (22.8%). The iodine intake was 220 μg for the whole group including supplements. For the women not taking supplements, the intake of iodine was 148 μg. Thyroid hormones and Tg did not differ between groups. Median spot UIC and 24UIE among all were 80.0 (IQR 62.5-137.5) μg/L and 158.3 (130.1-233.2) μg/day, respectively. In the supplement users median spot UIC was 89.0 (IQR 65.5-173.0) μg/L and in non-supplement users 78.0 (60.0-131.0) μg/L, p = ns. The corresponding values for 24UIE were median 312.6 (266.6-418.9) μg/day and 149.3 (122.5-173.0) μg/day for supplement and non-supplement users, respectively, p < 0.01. Low UIC and 24UIE in non-supplement users imply ID already 12 years ago that can be attributed to insufficient intake of fish, milk and dairy products. The most important is, however, to increase the use of fortified salt in ready-made products and half made productions instead of using non-iodinated salt.
Thyroid & Development Thursday Poster Basic
Although adequate folic acid or multivitamin intake can prevent up to 70% of neural tube defects (NTDs), the cause of NTDs in some cases remains unknown. Other risk factors are thought to be involved, such as a high level of total homocysteine (tHCY). In this study, we examined the serum levels of thyroid hormone and tHCY among pregnant women with NTDs fetuses. A case control study was performed in a rural mountain area of China, where a high prevalence of NTDs was reported between 2007 and 2009. A marked increase in fT4 levels above the normal range before 20 gestational weeks was observed in the control group, but not in the pregnant women with NTDs fetuses. No significant difference in serum tHCY levels was seen between the controls and the cases at ≤20 gestational weeks. Among the women with fT4 levels ≤15.2 pmol/L, the tHCY levels were significantly higher in the NTDs group than in the control group (P = 0.003). According to a logistic regression model adjusted for gestational week, maternal age and urine iodine, the odds ratio of the serum levels of coexisting fT4 levels ≤15.2 pmol/L and tHCY >13μmol/L was 5.3 (95% confidence interval: 1.6-17.8), but no increased NTDs risk was observed for the other conditions. Thyroid hormone was an effect-measure modifier of tHCY using a logistic regression model analysis. Thyroid hormones reportedly increase the activities of enzymes involved in riboflavin metabolism, thereby augmenting the synthesis of flavin adenine dinucleotide, a cofactor of methylenetetrahydrofolate reductase that maintains methylenetetrahydrofolate reductase activity, and decreasing the serum levels of HCY. Therefore, a biologic interaction between relatively a low level of thyroid hormone and a high level of tHCY cannot be ruled out.
Thyroid & Development Thursday Poster Basic
TAZ is a transcriptional co-activator (transcriptional co-activator with PDZ-binding motif) known to regulate the activity of thyroid transcription factors PAX8 and NKX2-1 by direct interaction and is, therefore, a central player in thyroid-specific transcription This interaction leads to significant enhancement of the transcriptional activity of PAX8 and NKX2-1 including their binding to the thyroglobulin (TG) gene promoter, one of the specific genes involved in thyroid differentiation. We previously reported that a small molecule called ethacridine, identified as a TAZ activator, was able to induce thyroid specific transcription in endodermal cells differentiated from human embryonic stem (hES) cells. In order to understand the mechanism of ethacridine transcriptional regulation we studied the epigenetic changes in methylation and acetylation in the promoter region of selected genes in human embryonic stem cells (hES) undergoing thyroid cell differentiation. On examining the predicted CpG islands for methylation using methylation- specific primers we observed only very low amounts (<10%) of methylation in the NKX2-1 promoter and no signbificant methylation in the PAX8 and TAZ promoters which are key drivers for human thyroid cell differentiation. In contrast, the promoter activity of NKX2-1, PAX8 and TG was highly induced in ethacridine and Activin A treated hES cells as measured by acetly-histone H4 immunoprecipitation (ChIP) assay (64 fold, 4 fold, and 6 fold respectively) suggesting active chromatin states of these promoters. These results indicated that the small molecule ethacridine is able to induce an acetylation mediated open chromatin state in human ES cells leading to a path for thyroid speciation. Thus epigenetic changes are likely to be a hallmark of thyroid cell speciation.
Thyroid & Development Thursday Poster Basic
Cone photoreceptors mediate high acuity vision in daylight. Cones also mediate color vision, which requires cone sub-populations that respond to different regions of the light spectrum. In most mammals, these cone sub-types express M and S opsin photopigments for response to medium-longer (M “green”) and short (S “blue”) wavelengths of light, respectively. The generation of cone diversity is fundamental to visual function but the underlying mechanisms are poorly understood. We previously found that thyroid hormone receptor b2 (TRb2) encoded by Thrb is essential for M opsin expression in mice. Mutations in the human THRB gene have been associated with photoreceptor abnormalities. We generated a knockin mouse that expresses fluorescent GFP protein in cones to allow isolation of cones from control or TRb2KO mice for single cell RNA-sequencing. Cones were collected from dorsal and ventral retinal regions that are enriched for M and S cone types, respectively. More than 150 single-cell RNA-seq libraries were analyzed. Results were corroborated by analysis of pools of cone cells. Selected genes were further validated by quantitative PCR (qPCR), in situ hybridization or immunohistochemical analyses. A modest number of genes including those encoding M and S opsins showed significantly different expression between dorsal and ventral retina in control samples, suggesting that in mice, cone types are defined by gradients of expression of opsins and limited groups of other genes. In TRb2KO mice, only a small group of cone genes displayed disrupted expression but this group included a high proportion of gradient genes. Investigation of TRb2 genomic binding sites using chromatin-affinity purification identified binding sites in a substantial proportion of genes that show disrupted expression in TRb2KO mice, suggesting a direct mechanism of regulation. Our single cell analysis reveals that TRb2 regulates genes that define cone diversity. in TRb2KO mice, cones display a relatively undifferentiated transcriptome indicating a key role for TRb2 in the generation of cone diversity.
Thyroid & Development Thursday Poster Case Report
Congenital Hypothyroidism occurs in 1:2000 to 1:4000 live births1. Thyroid function is critical to neurologic development and growth. Newborn screening, while standard in many countries, is not universal. Here we present a case of delayed diagnosis of congenital hypothyroidism, presenting with severe menorrhagia, short stature, and incomplete fusion of multiple growth plates. The patient is a 33 years old nulliparous female with no past medical history, born at term in Mexico, who completed secondary school. All family members are of normal height. She had repeated menorrhagia and critical anemia Hgb of 2.1g/dL (1.3 mmol/L). She was treated with dilatation and curettage twice (hyperplasia without atypia, features suggest endometrial polyps), iron and Norethindrone followed by IUD placement. Yet the vaginal bleeding persisted. On transvaginal US: an enlarged uterus without fibroids. Physical exam significant for: short stature (4 feet 2 inches; 127cm), brachydactyly, short neck, absence of palpable thyroid tissue, normal nasal bridge, normal shape and position of ears, no café-au-lait spots, waddling gait and mild bowing of legs. She had a TSH of 78.15 uIU/mL, free T4 by Equilibrium dialysis <0.20 ng/dL. TPO Ab 9 IU/mL (range 0 – 34 IU/mL). No normal thyroid tissue identified on ultrasound. Cortisol rose from 16.5 to 28.8ug/dL (455 to 795 nmol/L) after cosyntropin. Bone survey revealed irregular fusion of inferior pubic rami and incomplete fusion across the lesser trochanter apophyses bilaterally. Mild coxa valga deformity of femurs. Mild widening of sacroiliac joints. Chromosomal analysis with 46XX karyotype ruled out Turner's syndrome. Levothyroxine was initiated and titrated to 112mcg daily. She ultimately required transabdominal hysterectomy, bilateral salpingectomy and left oophorectomy. Late diagnosis of congenital hypothyroidism is potentially quite morbid. Severe, persistent menorrhagia warrants further evaluation for secondary causes. Given the growing diversity of our global population it is imperative to consider alternative culprit etiologies, congenital defects, and latent childhood illnesses.
Thyroid & Development Thursday Poster Clinical
Intratracheal thyroid (ITT) is rare. Because of the hidden site, slow growth and insufficient knowledge, ITT can always be misdiagnosed and the patients will suffer from inappropriate treatments. It is also a challenge for the surgeon to remove the ITT without tracheal stenosis. Our study is a systemic review of ITT with 38 cases, which includes 4 new cases (the largest cases in one report in the past 60 years) of our hospital and 34 cases electronically searched in the PubMed since 1958. We analyzed the details of these 38 cases and summarized the epidemiological data, clinical features and therapeutic regimens, and we also put our new interpretations on the mechanism of ITT.ITT was less common in men than women (male/female ratio of 1:3). We found that the symptoms of ITT could emerge from neonates to 85-year-old, which was different from the data (30-50 years old) provided in the old literatures. 50% of our ITT cases have goiters in normal neck thyroid. Our data also showed the malignant change accounts for 5% (2 cases), and it was much lower than the widely-cited 11% reported in 1962. Imaging examinations showed that the center of ITT lies at the post-lateral tracheal wall of the 1st ∼3rd ring, which is the common site of the ligament of berry (LOB). In most cases, more than 70% of the tracheal lumen is occluded when ITT is diagnosed. Stalks between the ITT and normal thyroid lobe were clearly seen in 10 cases during surgeries. 32 cases underwent surgical treatments (27 cases through tracheal fissure, 5 cases through endoscopic resection), one neonate received thyroid suppression therapy, one ITT case with PTC accepted radiotherapy and died of recurrence, and the left 4 cases died before treatments. We firstly hypothesize that the over attachment of LOB during embryonic development maybe play an important role in the occurrence of ITT. Surgical resection is an effective treatment for ITT. We also provide some clinical experiences for the protection of tracheal function.
Thyroid Cancer Thursday Poster Clinical
The thyroid locates at the root of the neck, and locally advanced thyroid cancer is likely to invade the mediastinum. The sternal splitting approach is the conventional surgical approach for mediastinal tumor as the mediastinum is surrounded by the bony thorax. In order to avoid the injuries of the major arteries, lungs and other important organs, the surgical field should be exposed adequately. Our study summarized and evaluated the surgical treatments for differentiated thyroid cancer with mediastinal invasion (MIDTC). A total of 21 MIDTC patients who had been admitted between January 2008 and May 2018 were retrospectively analyzed, and the mediastinal invasions were caused by the primary/metastatic tumor. They included 5 men and 16 women, median age 53 years (range 21–73 years), whose pathology included PTC (n = 20) and thymic-like thyroid cancer (n = 1). In 20 cases, the tumors were limited to the supra-aortic region, while in one case the infra-aortic region was invaded. All the patients underwent surgical treatments through transsternal approach (3 cases through sternal splitting approach, 5 cases through manubrium splitting approach, 8 cases through partial resection of sternoclavicular joint and manubrium approach, and 5 cases through partial resection of clavicle and manubrium approach). They all received a dose of 200-300mCi for RAI therapy after the operations. The mean follow-up was 60 months (range 1 to 120 months). All the tumors were removed completely with a safety margin macroscopically. All patients discharged on Postoperative Day 5-21 except one patient died of bleeding on Postoperative Day 5. The complications caused by surgeries included unilateral vocal cord paralysis (n = 1), permanent hypoparathyroidism (n = 1) and bleeding of the invaded internal carotid (n = 1). Overall 3- and 5-year survival rates were 65% and 48%, respectively. Most MIDTC with an invasion of the supra-aortic region can be removed completely through partial resection of sternoclavicular joint, clavicle and manubrium (PSSI), which can effectively expose the surgical field and avoid the severe complications caused by the sternal splitting incision. PSSI is one of the optimal approaches for the surgical treatment of MIDTC.
Thyroid Cancer Thursday Poster Basic
Aldo-keto reductase family 1, member C2 (AKR1C2) gene encodes for a member of the AKR superfamily and participates in the metabolism of various drugs. Moreover, thyroid tumor and adjacent normal tissues show an evident difference in the expression level of this gene. We downloaded and analyzed the data consisting the clinicopathological features of 490 papillary thyroid carcinoma (PTC) tumor tissues and 59 normal thyroid tissues from The Cancer Genome Atlas (TCGA) cohort. Diverse statistical methods, such univariate and multivariate Cox regression analyses, and Kaplan–Meier survival curves were used. PTC cell lines with transfection of plasmid were utilized to investigate the functions of AKR1C2 gene, including migration assays and invasion assays. We divided all patients into AKR1C2 under-expressed (n = 245) and over-expressed groups (n = 245) from TCGA cohort. We subsequently analyzed the data and obtained the following findings: (a) AKR1C2 was significantly down-regulated in PTC (p < 0.001), (b) Kaplan-Meier revealed that high expression levels of AKR1C2 were correlated with favorable survival in PTC (p = 0.043), and (c) AKR1C2 expression was a biomarker independently associated with recurrence-free survival (hazard ratio [HR], 0.819; p = 0.041). The cell experiment revealed that the overexpression of AKR1C2 significantly weakened the abilities of migration and invasion in PTC cell lines. Our results indicate that AKR1C2 exerts inhibitory effects on PTC oncogenesis, elevated AKR1C2 expression is associated with the favorable prognostic biomarker in recurrence free survival and AKR1C2 may act as a druggable target in PTC.
Thyroid Cancer Thursday Poster Clinical
Few studies on prognostic indicators for primary thyroid lymphoma (PTL) have been presented due to the uncommon nature of the tumor. This is the first study to explore the independent prognostic factors in the two PTL subtypes. We retrospectively reviewed 1,653 cases of PTL. The cases comprised 28 Chinese patients and 1,625 patients from the SEER database from 1973 to 2013. Statistical analysis was performed to determine the demographics and prognostic factors of PTL patients. The disease-specific survival (DSS) and prognostic indicators were significantly different between patients with extranodal marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT) and patients with diffuse large B-cell lymphoma (DLBCL). Patients with MALT lymphoma were younger (P = 0.011) and had lower clinical stage (P = 0.014) compared with patients with DLBCL. Cox regression analysis revealed that age, treatment modalities employed, clinical stage, and number of other types of cancer were independent prognostic factors for DLBCL patients. PTL demonstrates specific clinical features and is associated with a relatively good prognosis. Older age is associated with poor DSS in both MALT patients and DLBCL patients. Additionally, combination of different treatment modalities is associated with improved DSS in DLBCL patients.
Thyroid Nodules & Goiter Thursday Poster Clinical
Substernal goiter occurs in 2-48% of thyroidectomies. Reports on substernal goiters typically come from goiter endemic regions, with a paucity of literature from the United States. We report outcomes of thyroidectomy for substernal goiter at a tertiary-referral center. Retrospective review of 111 patients having thyroidectomy for substernal goiter from November 2003 - June 2017. The incidence of substernal goiter was 8.7%. Total thyroidectomy was done in 49% with a transcervial approach in 138 and sternotomy in 8 patients. Operating times were 210 ± 80 and 138 ± 56 minutes in patients having sternotomy and transcervical approach respectively. Estimated blood loss was 213 ± 125 mL with sternotomy and 83 ± 58 mL without. Length of stay was 3.8 ± 4.3 days following sternotomy and 1.0 ± 1.4 days after transcervical approach. The rate of transient hypocalcemia was 25% after sternotomy and 7.2% after transcervical approach. IV calcium was needed by 2.9% of patients after transcervical approach. Temporary voice changes occurred in 37.5% of patients with sternotomy and 19.6% without. Permanent RLN injury occurred in 2.9% of patients with transcervical operation while one patient with sternotomy had RLN sacrifice. There were no neck hematomas in either group. Thyroidectomy morbidity is increased by substernal extension of a goiter. Most studies note higher rates of hypocalcemia and RLN injury associated with substernal goiter, but some high-volume centers have reported complication rates similar to those for cervical goiter. Outcomes in the United States are less well established, likely due to a lower incidence of substernal goiters than endemic goiter regions. Complication rates at our center were similar to many reports by surgeons in goiter endemic regions; however, temporary hypocalcemia and transient voice changes were seen at higher rates than reported by some other high-volume centers. Sternotomy was associated with higher rates of transient hypocalcemia and transient voice changes compared to a transcervical approach. These findings support the referral of substernal goiters to high volume centers to maximize patient outcomes.
Thyroid Cancer Thursday Poster Basic
SRC-kinases are a group of genes encoding for cytoplasmic nonreceptor protein kinases. Multiple signaling pathways important in oncogenesis and cancer progression mediate through SRC. SRC plays critical roles in cell proliferation, survival, motility, migration, cell-matrix adhesion dynamics, and cytoskeleton regulation, via multiple downstream signaling pathways. SRC-kinases are over-expressed in human neoplasms including thyroid carcinoma. Aggressive thyroid carcinoma has been linked with aberrant activation of SRC [1-2]. However, inhibiting SRC alone is not very effective. Multiple signaling cascades mediate C-SRC activation via interaction with alpha-6 integrin (α6β4), an epithelial-specific integrin that functions as a receptor for members of the laminin family of extracellular matrix proteins [3]. The signaling function of α6β4 contributes to a motile and invasive cancer phenotype [4]. Study showed that α6β4 signals through SRC and Akt to increase S100 expression [2]. Pharmacologic inhibition of SRC activity by small molecule inhibitor (PP2) in breast cancer cells effectively blocks α6β4-dependent invasion in a concentration-dependent manner, suggesting that SRC is indeed an important mediator of α6β4 signaling. In this study, we characterized expression of c-SRC/α6β4 by immunohistochemistry in matched samples of benign and malignant thyroid tissues (WDTC, PDTC, and ATC). The expressions of c-SRC/α6β4 were analyzed in 36 benign and 43 WDTC, PDTC, and ATC. c-SRC/α6β4 were expressed in most benign thyroid epithelium but were up-regulated at moderate or strong levels in 14 of 18 node-positive thyroid carcinomas. In seven samples of PTC, c-SRC/α6β4 was overexpressed. Weak expression of c-SRC/α6β4 were detected in the benign thyroid epithelium. In PDTC/ATC thyroid cancers, c-SRC/α6β4 were overexpressed at moderate or strong levels in 13 of 15 tumors. These results provide the first evidence that c-SRC/α6β4 expression is variably upregulated in thyroid cancer and suggest that up-regulation occurs at an early stage of tumorigenesis.
Thyroid Cancer Thursday Poster Basic
Although many studies have reported that estradiol (E2) has tumorigenic effects on thyroid carcinomas, the role of BRAFV600E mutation in estrogen responsiveness of thyroid cells is still unknown. We aimed to elucidate the effect of BRAFV600E on increased metastatic potential induced by E2in a normal human thyroid cell line Nthy-ori 3-1 (Nthy). In this study, we used the two newly-established cell lines Nthy/BRAFWT (Nthy/WT), Nthy/BRAFV600E (Nthy/V600E) and another BRAF-positive thyroid cancer cell line B-CPAP. Expression of estrogen receptors (ER) was evaluated by RT-qPCR and Western blot analysis. Metastatic phenotypes induced by E2 were investigated by migration, invasion and Soft-agar assays. To exclude the influence of E2 and other steroid molecules present in fetal bovine serum (FBS), the cell were starved for 48h using phenol red-free RPMI1640 supplemented with 2% dextran-coated charcoal-treated FBS (DCC-FBS) prior to migration and invasion assays. All cell lines were expressing ER alpha and beta, and Nthy/V600E showed higher ESR1/2 ratio than that of Nthy/WT. Similarly, ESR1/2 ratio in BCPAP was decreased by knock-down of BRAFV600E. The BRAFV600E mutant cells showed increased migration, invasion, and anchorage-independent growth induced by E2 compared to their counter parts. Our data show that BRAFV600E mutation plays a crucial role in estrogen responsiveness of thyrocytes. These findings suggest the clinical importance of E2 might be variable depending on BRAFV600E-mutational status in thyroid cancer patients, and would help further studies for hormone therapies based on estrogen signaling pathways.
Thyroid Cancer Thursday Poster Basic
BRAFV600E is the most common mutation found in thyroid carcinomas. However, direct relationship between BRAFV600E and initiation of human thyroid carcinoma has not been proven. To investigate the role of BRAFV600E in thyroid carcinogenesis, we utilized a mouse xenograft model for different tumor formation capacity of a normal human thyroid cell line Nthy-ori 3-1 (Nthy) depending on BRAF mutation status. We previously established the two cell lines Nthy/BRAFWT (Nthy/WT) and Nthy/BRAFV600E (Nthy/V600E), where two cell lines having the same genetic background differ only by the mutation status of BRAF. Each cell line was subcutaneously injected into the right flank of the NSG mice and the dimension of grown tumors was measured with a caliper. Four weeks after injection of each cell line, the xenografted mice were sacrificed to collect tumors at the initial injection site as well as tumors formed at different organs. The acquired tumors from primary sites and metastatic sites were formalin-fixed and paraffin-embedded, and Hematoxylin and Eosin (H&E) stain was performed for histological analysis of the tumors. While Nthy/WT did not form a tumor, Nthy/V600E formed tumors in all the injected mice. In Nthy/V600E-injected mice, tumors were observable a week after injection and showed a rapid growth after two weeks of injection. The mean volume of the tumors was 2420 mm3 (SEM = 331.53, n = 11) and the mean tumor weight was 1.94 g (SEM = 0.172, n = 11) in a month after injection. A significant weight loss occurred only in Nthy/V600E-injected group at the end-point of experiments (Mean with SD; 29.49 ± 2.8 vs 27.79 ± 3.2, n = 11, p = 0.0038). As a result of an end-point autopsy, metastasis to the right axillary lymph node was found in about 63.6% of Nthy/V600E-injected mice (n = 11). Our data show that expression of BRAFV600E enable a normal human thyroid cell line to form a tumor and spread to a lymph node in a mouse xenograft model. It suggests that BRAFV600E plays a crucial role in a tumor initiation and explains a poor prognosis of BRAFV600E-positive human thyroid carcinomas. This mouse xenograft model using Nthy/V600E would be able to contribute to further studies on BRAFV600E-initiated thyroid cancers.
Thyroid Cancer Thursday Poster Basic
Mutations are fundamental to thyroid tumorigenesis, the biological consequences of each specific mutation varies across a spectrum from strong, highly predictive of cancer (BRAF V600E), to low drivers being present in both benign and malignant states (RAS, PAX8/PPAR). Thyroid cancer itself is biologically heterogeneous making a mutational only approach less efficient in risk stratifying indeterminate nodules. Here we report on an expansion panel of mutations and RNA fusions designed to work in concert with a complementary microRNA (miRNA) profiling assay, which together enable a greater understanding of the role of low driver mutational states without diminishing rule in and rule out diagnostic and predictive testing properties. Mutational analysis was carried out using our expanded oncogene panel. In combinations with our miRNA classifier to further characterize the malignancy risk for individual thyroid nodules. Clinical validation was performed by blinded review of molecular results of 73 needle aspirates from nodules with known surgical pathology outcome. From the combination of both test results, risk of malignancy to individual specimens, for the combined test were determined. At 24% thyroid cancer prevalence, combination testing showed 92% negative predictive value and 100% positive predictive value for subset of thyroid nodules with no detectable mutational change, low mutational drivers and strong drivers. miRNA profiling effectively detected malignancy is a subset of nodules lacking detectable mutational change and low driver states thus both ruling in and ruling out cancer where currently such binary prediction is not possible. Clinical performance of combined testing was superior to mutational analysis or RNA classifier determination performed alone. Furthermore, the % malignancy risk was accurately predicted for all individual indeterminate thyroid nodules. The combination testing approach, employing miRNA to independently predict risk of malignancy, maintained highest performance in ruling out cancer in low risk nodules and ruling in cancer in high risk thyroid nodules including those with no detectable or low driver mutations, thereby optimizing clinical decision making.
Thyroid Cancer Thursday Poster Basic
Mutational analysis is an important component source of diagnostic and predictive information for resolving cytologic indeterminate thyroid nodules accomplished most comprehensively by next generation sequencing (NGS). Technical hurdles can arise requiring novel solutions when expanding the existing scope and number of mutations and fusions detected, especially when starting material is limited in both quality and quantity. We recently expanded the mutation detection and RNA fusions tested as of our combination testing approach and here we describe critical issues that had to be addressed to maintain highest accuracy and analytic sensitivity of the sequencing results.
An existing platform of DNA mutations and RNA fusions (ThyGenX) was expanded to include additional DNA oncogene point mutations (RET, ALK, PTEN, PNAS, GNAS), TERT promoter mutations (GC rich segment) and 32 RNA oncogenic fusions (BRAF, NTRK, THADA, ALK, TERT and other fusion families) reported in thyroid cancer. High GC molecular targets were separately amplified and merged into overall library prep thereby removing potential amplification bias. Validation of the NGS results of the expanded panel, ThyGeNEXT, using 162 patient samples showed 100% concordance with ThyGenX test results. In addition, in 17 of these samples (∼10%), we were able to detect alterations specific to ThyGenNEXT: TERT and RET DNA mutations, and THADA fusions. Precision and reproducibility of detection (CV) for the DNA markers was found to be within 1-12%, and 100% for RNA fusions on yes/no basis. Lower limit of detection (LLD) for the DNA markers was 2% VAF, and about 300 copies of RNA fusions (∼2% TBP) for most of the fusion transcripts.
Critical modifications to library prep proved sufficient to expand DNA and RNA based mutational analysis without compromising molecular testing performance, analytic sensitivity for mutation detection (2%) or depth of sequencing. Separate handling of G/C rich sequence targets was crucial in achieving these goals, which maintained diagnostic and prognostic characteristics of this test.
Thyroid Cancer Thursday Poster Basic
Tall cell variant papillary thyroid carcinoma (TCPTC) is reportedly associated with aggressive clinicopathological parameters and poor outcomes; however, the molecular mechanisms underlying TCPTC remain poorly understood. We aimed to clarify the molecular alterations and identify novel diagnostic biomarkers for TCPTC. The gene mutation types and mRNA expression profiles of patients with TCPTC were obtained from The Cancer Genome Atlas (TCGA) database. Differentially expressed genes (DEGs) were identified. Pathways in the interaction network and the diagnostic approaches of candidate markers for TCPTC were investigated.BRAF mutation was particularly prevalent in TCPTC with a mutation frequency of 78%. TCPTC was associated with a patient age >45 years, tumor multifocality, extrathyroidal extension, a higher T stage, advanced AJCC TNM stages, BRAF V600E mutation, and poor disease-free survival. We identified 4138 TCPTC-related DEGs and 301 TCPTC-specific DEGs. Intriguingly, the gene expression pattern revealed that the dysregulated levels of both putative oncogenes and tumor suppressors in TCPTC were higher than those in classical/conventional variant PTC (cPTC). Functional enrichment analyses revealed that these DEGs were involved in several cancer-related pathways, including the PI3K-Akt and MAPK signaling pathways. A protein-protein interaction (PPI) network was constructed from the 301 TCPTC-specific DEGs, and 3 subnetworks, and 8 hub genes were verified. Receiver operating characteristic (ROC) analyses revealed that 6 hub genes, including COL5A1, COL1A1, COL10A1, COL11A1, CCL20 and CXCL5, could be used not only for the differential diagnosis of PTC from normal samples, but also for the differential diagnosis of TCPTC from cPTC samples. Our study might provide further insights into the investigations of the tumorigenesis mechanism of TCPTC and assists in the discovery of novel candidate diagnostic markers for TCPTC.
Thyroid Cancer Thursday Poster Basic
Papillary thyroid carcinoma (PTC) is the most common endocrine malignancy and its incidence has increased over the last few decades. The molecular mechanisms underlying PTC tumorigenesis and progression are still unclear.miRNAs expression patterns of PTC were revealed by miRNA mircroarray analysis and validated with the TCGA data. Promoter DNA methylation rates of miR-204 were analyzed by Sequenom Methylation MassArray analysis and validated with TCGA data. The underlying molecular mechanisms of miR-204 involved in PTC were studied by bioinformatics analyses. A total of 181 differentially expressed miRNAs (89 downregulated and 92 upregulated miRNAs) between PTC and normal tissues were detected in this study. We identified miR-204 as one of the most significantly downregulated microRNAs in PTC. Downregulation of miR-204 was related to PTC extrathyroidal extension, higher T stage, lymph metastasis, BRAF V600E mutation and more aggressive tall cell variant. Sequenom MassArray results indicate that most of the CpG sites located at the promoter of miR-204 were hypermethylated in PTC tissues compared with normal tissues. The promoter methylation rates of miR-204 in PTC were negatively correlated with the expression levels of miR-204 and its host gene Transient Receptor Potential Cation Channel Subfamily M Member 3 (TRPM3). Downregulated miR-204 expression was related with a series of significant pathways and mechanisms involved in tumorigenesis and progression. Promoter DNA methylation-silenced miR-204 could be served as a potential biomarker in PTC diagnosis. Downregulation of miR-204 may play an important role in PTC via the involvement in many tumor-related pathways. Novel target genes and putative mechanism of miR-204 in PTC need to be further validated.
Thyroid Cancer Thursday Poster Basic
The incidence of papillary thyroid carcinoma (PTC) is increasing globally. While the majority of patients with PTCs have an excellent prognosis, select patients present with more aggressive disease. These cases of PTC are associated with genomic alterations. However, little is known about the role of DNA methylation abnormalities in these PTCs.
In order to address this, we profiled the DNA methylome of 20 formalin-fixed paraffin-embedded PTCs comprised of high (HR) (stage IV) (n = 14) and low risk (stages I/II) (LR) (n = 6) disease. Supervised analysis was performed between the groups, followed by gene ontology (GO) and motif analyses of probe-related genes/regions.
In relation to the LR group, the HR PTCs presented 246 differentially methylated CpG probes (DMPs) (118 hypermethylated and 128 hypomethylated), distributed across CpG islands (CGI) (n = 21, 9%), shores (Sh) (n = 52, 21%) and intergenic/open sea regions (OpS) (n = 173, 70%). The nearest genes associated with the hypermethylated CGI/Sh DMPs were enriched for pathways related to response to stress, brain development and Rap-1 signaling, involved in metastasis of several cancers, while hypomethylated Sh/OpS genes were enriched for amine response and IL-12 signaling pathways. DMP located in the OpS regions overlapped with 151 predicted enhancers, known to be active. Hypomethylated enhancers were enriched for bZIP motifs, binding sites for AP-1 complex - Fra1, Fra2, Fosl2, JunB (p < 0.0001), which have been shown to be involved in tumorigenesis/progression in cancer. Our results suggest that distinct DNA methylation patterns in promoter and non-promoter regions are associated with genes/pathways involved in cell migration and invasion and cancer growth (e.g. Rap-1, AP-1) and novel pathways.
These results bolster the hypothesis that DNA methylation participate in the regulatory control of PTC aggressiveness. Further validation of these findings may also offer opportunities to develop drugs targeting PTC growth and recurrence.
Thyroid Cancer Thursday Poster Basic
The better biological behavior of papillary thyroid cancer (PTC) may relate to its immunogenicity. Here we explore the expression of potential tumor antigen in papillary thyroid carcinoma by both transcriptome sequencing and mass spectrometry.
The tumor tissues and corresponding thyroid tissues from 10 patients with pathologically confirmed PTC were obtained for transcriptome sequencing on Illumina Hiseq platform. Data Independent Acquisition method of mass spectrometry was performed of tumor tissues and adjacent tissues from 17 patients with PTC. Differentially expressed proteins and their genes that were consistently differentially expressed were analyzed. Neoantigens were analyzed by combining the somatic mutations and gene fusions of tumor tissue with the corresponding HLA allele results from transcriptome sequencing by netMHCpan method.
When the criterion of differential expression was |log2FoldChange|≥1 and Padj ≤0.05, there were 26 high-expressed molecules and 8 low-expressed molecules in tumor tissues by combining transcriptome sequencing and mass spectrometry. When the criterion of differential expression was |log2FoldChange| ≥ 2 and Padj ≤ 0.05, the expression of FN1, THBS1, POSTN, ANXA1, PDLIM4, PROS1, MFGE8 and VCAN were higher in tumor tissue than in adjacent tissue by both transcriptome sequencing and mass spectrometry. Two nonamer epitopes, KSAELSPFL (KSR1-LGALS9) and RASCQLTVL (FARSA-SYCE2), were predicted and filtered out by genetic fusion data. Three nonamer epitopes were filtered out by genetic variation data: LAHPGFFYF (P4HA1), KTYERLFYM (PHLDB3), LLYSNGYNY (IGKV2(D)-28).
The expression of FN1, THBS1, POSTN, ANXA1, PDLIM4, PROS1, MFGE8 and VCAN were higher in tumor tissues by combining transcriptome sequencing and mass spectrometry, they may contribute to the development of PTC. KSAELSPFL (KSR1-LGALS9), RASCQLTVL (FARSA-SYCE2), LAHPGFFYF (P4HA1), KTYERLFYM (PHLDB3) and LLYSNGYNY (IGKV2(D)-28) have their own HLA class I restrictions, and they may be immunogenic enough for further study.
Thyroid Cancer Thursday Poster Basic
There is an urgent need for the development of effective targeted therapies for advanced thyroid cancer. While our lab has shown Src is a key mediator of growth, invasion and metastasis in thyroid cancer, single-agent inhibitors targeting Src have had limited efficacy in solid tumors. We recently reported that combined Src and MAPK inhibition results in synergistic inhibition of growth and increased apoptosis in BRAF- and RAS-mutant cells, while PIK3CA-mutant cells are resistant (Beadnell et al 2016; 2018). Using an unbiased proteomics approach, we identified a previously unrecognized regulation of the PI3K/AKT pathway by Src in thyroid cancer, and that combined inhibition of Src and MEK1/2 promotes growth arrest and apoptosis through the inhibition of Src, MAPK, and PI3K/AKT. Here, we have further delineated the mechanism(s) of synergy, and the molecular mechanisms of apoptosis in this response. Western blotting was performed on BRAF- (BCPAP, SW1736), RAS- (Cal62, C643), or PIK3CA-mutant (T238, TCO1) thyroid cancer cell lines treated with the Src inhibitor, dasatinib, combined with the MEK1/2 inhibitor, trametinib. Growth and apoptosis assays were performed on cells ectopically expressing a constitutively active AKT (myr-AKT) or empty vector. We show BRAF- and RAS-mutant cell lines exhibit a 4- to 6-fold induction of apoptosis in response to Src/MEK inhibition, which correlates with a 6- to 12-fold induction of the pro-apoptotic protein, BIM. As expected induction of BIM was not observed in PIK3CA-mutant cell lines. Ectopic expression of myr-AKT nearly abrogated the apoptotic response driven by Src/MEK inhibition in BCPAP cells compared to empty vector expressing cells (p < 0.02), and blocked inhibition of pAKT and induction of BIM. Finally, myr-AKT promoted resistance to growth arrest in response to combined Src/MEK inhibition by >300-fold in the BCPAP cells (EV IC50 0.05nM; myr-AKT IC50 18 nM). Combined inhibition of Src and MEK1/2 promotes growth arrest and apoptosis through the inhibition of three key signaling nodes: Src/FAK, MAPK, and PI3K/AKT, and induction of BIM is important for the apoptotic response of combined Src and MEK inhibition.
Thyroid Cancer Thursday Poster Basic
In recent years, it was shown that high nitrates concentration in drinking water (NCDW) increased carcinogenic effect of thyroid irradiation in children of Belarus after Chornobyl. We compared the incidence rate (IR) of pediatric thyroid cancer (PedTC) and NCDW among irradiated (born before Chornobyl) and unirradiated (born after Chornobyl) persons aged up to 18 years at surgery in different regions of Ukraine. Patients with PedTC from the Clinical-morphological register of post-Chornobyl thyroid cancer (395 potentially radiogenic and 188 sporadic) were selected from three northern Ukrainian regions (NUR) and three southern ones (SUR). The IR of PedTC in irradiated groups was significantly higher in NUR than in SUR (p < 0.001), which was associated with higher 131I thyroid doses in NUR (from 58 mGy in Chernihiv to 87 mGy in Zhytomyr region) than in SUR (<15 mGy in every region). Certain influence of NCDW on the IR of PedTC was observed in both NRU and SRU. In Chernihiv region (NUR) with lower 131I thyroid dose, but with high NCDW (174 mg/l), the IR (3.64) was higher than in Zhytomyr region (2.74) with higher 131I thyroid dose, but lower NCDW (39 mg/l). In Kherson region (SUR), with low 131I thyroid dose (14 mGy), but with a high NCDW (163 mg/l), the IR (0.96) was higher than in Zaporizhzhya region (0.35) with the same 131I thyroid dose (11 mGy), but lower NCDW (75 mg/l). In persons born after Chornobyl, there were no significant differences in the IR of PedTC, both in NRU and SRU.
The high NCDW could increase the carcinogenic effect of 131I due to Chornobyl, both in most and least contaminated regions, which indicates the need to continue studies of combined effect of radiation and nitrates on thyroid carcinogenesis.
Thyroid Cancer Thursday Poster Basic
Yearly incidence of thyroid cancer has nearly tripled in the past four decades, due to improvement and better use of diagnostic proceedings, which allows to detect tumors of smaller size, such as papillary microcarcinoma (MPC), defined as equal or less than 10 mm.
The aim of our study was to validate the increasing incidence rate, to describe the characteristics and the circumstances of discovery of MPC, based on the Marne-Ardennes thyroid cancer register, from 1975 to 2014. Our observational, descriptive, historical cohort study is based on data from the specialized thyroid cancer register, which includes all subjects living in the Marne or Ardennes French departments, who were diagnosed with thyroid cancer between 1975 and 2014. 2671 patients with thyroid cancer between 1975 and 2014 were included, whose 966 (36.2%) were MPC. This percentage increases from 18.9% to 45.1% between the 1975-1984 period and the 2005-2014 period.
Standardized incidence rates per 100,000 PY increased from 0.86 to 6.20 between the 1975-1984 period and the 2005-2014 period. Incidence was higher in women (1.15 in 1975-1984; 8.91 in 2005-2014) then in men (0.20 in 1975-1984; 2.54 in 2005-2014).
Incidence rates increased more in ≥50 year-old people (from 0.41 in 1975-1984; to 4.21 in 2005-2014) then in <50 (0.45 in 1975-1984; to 1.99 in 2005-2014). Most of MPC (80.4%) were incidentally discovered on histological examination. They were mainly unifocal (79.4%).
There tumors were associated with excellent morbidity and survival rate: there were few evolutive events (1.9%); no patient died from MPC (91 deaths due to other cause). Our retrospective study demonstrates a large rise in the incidence of MPC. Most of MPC were incidentally discovered on histological examination in the context of surgery for benign pathology. Changes in access to health care, and physician's and pathologists' practices are likely explanations of our results.
Thyroid Cancer Thursday Poster Translational
Medullary thyroid carcinoma (MTC) is a malignant tumor originating from thyroid C cells, which may occur in the hereditary form (20-30%), as part of multiple endocrine neoplasia type 2 (MEN 2) syndrome, or as sporadic form (70-80%). The development of both sporadic and hereditary MTC cases have been associated with mutations in the RET gene. Clinical heterogeneity observed within and among families with same RET point mutation, or even absence of RET mutation in some sporadic cases, suggests that additional genetic event might be involved in the tumorigenesis of MTC. Somatic copy-number alterations (SCNAs) are an important type of structural variation that might be associated with tumor pathogenesis. In this study, we sought to investigate whether CNA might be related with the pathogenesis of MTCThree frozen MTC samples (cases) were compared to their respective paired blood sample (control) using SNP Array and analyzed by PennCNV and Genotyping Console software. To evaluate whether the selected CAN were functional, their expression was assessed in a series of paraffin embedded MTC. mRNA expression was evaluated by qPCR in 10 MTC sample and protein expression was evaluated by immunohistochemistry in 27 MTC samplesGenome wide analysis identified over 80 CNAs. To identify CNAs that are more likely associated with a tumor phenotype, we selected those CNAs that were found in at least 2 cases (out of 3 total cases) but absent in controls. We identified seven focal regions that met these criteria. Validation analysis confirmed that two genes located at 14q32.2 and 22q11.21 chromosome regions, which were mapped within CNAs, presented copy number gain (p < 0.0001). Moreover, qPCR analysis showed that both genes were overexpressed in MTC samples when compared to blood samples (p < 0.0001). Immunohistochemistry analysis confirmed their overexpression in most MTC samples, while its expression was not detected in normal thyroid tissueThis study identified two copy number gains involving genes that are likely functional might be involved in the pathogenesis of MTC
Thyroid Cancer Thursday Poster Translational
Hereditary medullary thyroid carcinoma (MTC) represents 25% of all MTC and is associated with an autosomal dominant mutation of RET gene. Other endocrine neoplasia are usually associated with MTC giving origin to different phenotypes: Multiple Endocrine Neoplasia type 2A (MEN2A) with pheocromocytoma (PHEO) and parathyroid adenomas, MEN2B with PHEO and marfanoid habitus and an isolated familial form of MTC (FMTC). So far the MEN2A has been considered the most prevalent form.
Aim of this study was to evaluate the prevalence of the 3 phenotypes of MEN2 syndromes after the introduction of the RET genetic screening; we also evaluated the correlation between phenotype, genotype and onset modality of MTC. Clinical, biochemical and genetic data of MTC patients belonging to 165 RET positive families were analysed.
We distinguished 112 FMTC families (68%), 40 MEN2A (24%) and 13 MEN2B (8%): this prevalence was significantly different from that reported in the literature. Eighty-six/165 (52%) families were diagnosed as hereditary with the RET genetic screening since their index cases, although “apparently sporadic”, carried a RET germline mutation. The mean age at diagnosis of the “apparently sporadic” index cases (IC), of their affected family members (AFM) and their gene carriers (GC) was 48.3 + 12.4yrs, 46.3 + 17.9yrs and 35 + 16yrs respectively. At variance, the mean age of the familial IC, of their AFM and their GC was 31 + 14yrs, 31 + 17yrs and 18 + 9yrs, respectively. We confirmed that MEN2B patients have a worse prognosis than those with MEN2A or FMTC. A worse prognosis was also found to be associated with RET highest/high risk mutations, that are associated with MEN2A phenotype. At variance, no difference of the outcome was observed in IC and their AFM diagnosed as hereditary with the RET genetic screening respect to those presenting as familial.
In conclusion, the introduction of the RET genetic screening in the diagnostic workflow of MTC cases allowed to identify hereditary syndromes apparently sporadic at diagnosis determining a significant increase of the prevalence of FMTC phenotype compared to the others (MEN2A and 2B), however the late diagnosis did not affect the outcome of this subgroup of MTC patients.
Thyroid Cancer Thursday Poster Translational
Thyroid cancer incidence, especially papillary carcinoma (PTC), has increased worldwide during the last decade. Ecuador presents the highest incidence among Latin American countries and the world. Molecular studies report that BRAF oncogene mutations are involved in the carcinogenesis and prognosis of PTC. The aim of this study was to determine the prevalence of the BRAFV600E mutation in PTC patients from the northern Ecuadorian Andes.169 tumors were classified according to the TNM system (AJCC 7th edition) and the patients were managed based on the 2015 ATA guidelines from June 2014 to December 2017 in Hospital Eugenio Espejo in Quito-Ecuador. PTC genomic DNA from FFPE tissue were analyzed for exon 15 of the BRAF oncogene by Sanger Sequencing.BRAFV600E mutation was found in 128/169 (75.6%). The BRAF codon 600 status was related to clinical-pathological characteristics as sex, age, family history, BMI, geographical area of residence, tumor size, PTC variant, extrathyroidal extension, focality, capsular and vascular invasion, lymphatic and distant metastases. BRAFV600E showed a significant correlation with BMI >30 (32.1%, p = 0.03), tumor size >10mm (66.3%, p = 0.037) and Hashimoto's thyroiditis (10%, p = 0.03).
Although the increase in TC is currently attributed to the overdiagnosis (lesions <10mm), in the present investigation, tumors larger than 10mm were significantly correlated with the BRAFV600E mutation. The high prevalence (75.6%) of the mutation in this particular Ecuadorian studied population versus other published worldwide series draws attention. The majority of patients (58.6%) comes from the northern region of Ecuadorian Andes where certain environmental characteristics (average altitude >2000 masl and constant exposure to volcanic ash) could impact in the higher incidence of PTC with BRAF mutation. Environmental factors as altitude and volcanic ash content may be related with higher mutation prevalence of BRAF oncogene in PTC patients from northern Ecuadorian Andes.
Thyroid Cancer Thursday Poster Translational
Papillary thyroid carcinoma (PTC) is the most prevalent form of thyroid cancer, making up about 85% of the cases. Although in recent years several genes (e.g. BRAF, RAS, RET/PTC, TERT) have been demonstrated to play crucial roles in PTC, the molecular basis of carcinogenesis is not well understood. Using a bioinformatics tool, we investigated, through a network unbiased approach, the genes and pathways involved in this complex landscape. We exploited SWItchMiner (SWIM) software to analyze gene expression profiles available on The Cancer Genome Atlas. SWIM is able to identify a small pool of regulatory genes (switch genes), which are likely to be critically associated with drastic changes in cell phenotypes. We built networks based on switch genes (nodes) and their correlation value > |0.7| (connection). Finally, we selected those genes that were present only in the tumor or in the normal network. Comparing RNA-sequencing data between thyroid cancers and thyroid normal tissue samples, we identified 131 switch genes out of 1718 differentially expressed genes. We selected forty of them: four were present only in normal network while the others 36 in cancer network. Most of the selected genes are involved in cAMP-dependent pathway and phospholipase C signaling, and suggest a potential inhibition of the former and activation of the latter, with a release of Ca(2+) from the endoplasmic reticulum into the cytoplasm. Moreover, there was an over-expression of genes promoting cellular cycle, NFkB and Wnt/bcatenin pathways and a down-regulation of genes involved in apoptosis and in the non-homologous end joining. Genes involved in metabolism suggest an increase in glycine and lipid synthesis, with an increase in the storage of the latter in lipid drops. Network analysis may provide an additional approach to explore the molecular basis of cancer and to select the main mechanisms involved in carcinogenesis. Although the data obtained need to be validated by vitro experiments, they may result in significant progress in diagnosis, prognosis and therapy of PTC.
Thyroid Cancer Thursday Poster Translational
Anaplastic thyroid carcinoma is a rare but aggressive cancer. Recurrently, there was lack of effective treatment options. Immune checkpoint inhibitors, like Anti-programmed cell death ligand 1 (PD-L1) have recently proved to be effective in some cancer, like lung, melanoma, and lymphoma. The role of Anti-PD-L1 on ATC is still understudied. In this study, we examined the prevalence of PD-L1 expression in the tumor cell in patients with ATC. We also correlated with pathological status, prognosis and outcome with PD-L1 expression. Slides from 17 patients who diagnosed with ATC by biopsy or surgical resection were retrieved. By using immuo-histo-chemical stain and Tumor Proportion Score, the PD-L1 expression on tumor cell was assessed. Positive on PD-L1 expression was defined as TPS >1% and high PD-L1 expression defined as TPS >50%. Findings of PD-L1 expression were correlated with clinicopathological profile and overall survival. Slides from 17 patients with median age of 80 at diagnosis were included. Median overall survival was 11 weeks. Median TPS was 60% (0-100%). and PD-L1 was positive in 15 patients (88.2%). Patients with positive PD-L1 had a poor overall survival (7 vs 178 weeks, p = 0.014) and tended to present with extra-thyroidal invasion, lymph node, and distant metastasis. Overall survival was also correlated to the degree of PD-L1 expression. (Negative vs. PD-L1 expression vs. high PDL1 expression: 178 vs. 15 vs. 7 weeks, p = 0.033)
The PD-L1 expression is prevalent in ATC tumor cell. The degree of expression correlated with aggressiveness of tumor in patients with ATC. Patients with PD-L1 positive ATC should be treated aggressively and clinical role of anti-PD-L1 should be further evaluated.
Thyroid Cancer Thursday Poster Clinical
In recent years, there has been an increase in the development of assisted reproductive technologies and other reatments to overcome infertility, so there are now more women who use fertility drugs than in the past. Te use of fertility drugs that may cause alterations in endogenous hormones and multiple ovulations has raised concerns about the long-term safety of such medications. A lot of attention has focused on whether the use of fertility enhancing drugs can have an effect on malignancies associated with breast cancer, endometrial carcinoma, ovarian cancer, and cervical cancer. Several studies have investigated the relationship between the use of fertility drugs and thyroid cancer; however, their results have been contradictory. Terefore, we conducted a meta-analysis based on the current literature, and the results are reported in this study. To investigate the clinical signifcance of fertility drugs used for the treatment of female infertility and the risk associated with thyroid cancer, we performed a literature search using PubMed, MEDLINE, the Cochrane Library, the Web of Science, and EBSCOHOST for comparative studies published any time prior to July 21, 2017. The studies included women who were treated for infertility with fertility drugs, such as clomiphene citrate, gonadotropins, or other unspecifed fertility agents, which reported the incidence of thyroid cancer as the main outcome. Eight studies were included in the meta-analyses. Among women with infertility, there was a signifcant positive association between thyroid cancer risk and the use of fertility drugs (relative risk [RR] = 1.35;95% confdence interval [CI] 1.12–1.64;P = 0.002). Additionally, among women with infertility, the use of clomiphene citrate was associated with an increased risk of thyroid cancer compared to women who did not use fertility drugs (RR = 1.45; 95% CI 1.12–1.88;P = 0.005). Afer pooling results, we found that the parity status of infertile women using fertility drugs was not associated with thyroid cancer risk (RR = 0.99; 95% CI 0.61–1.58, P = 0.95). In summary, clomiphene citrate (the most commonly used fertility drug) and other fertility drugs are associated with an increased risk of thyroid cancer.
Thyroid Cancer Thursday Poster Clinical
Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. PTC is prone to metastasize to the cervical lymph nodes (LNs), especially to the central LNs; the incidence of cervical lymph node metastasis is 20–90%. Cervical lymph node metastasis, a common cause of relapse following surgical treatment, is associated with suboptimal surgical removal of these lymph nodes at the time of initial surgery. Although it is important to standardize the surgical removal of cervical lymph nodes, there is no clear consensus on this topic or regarding the indications for surgery. Clinicopathologic data from 829 patients (104 men and 725 women) with PTC, operated on by the same thyroid surgery team at the First Afliated Hospital of Harbin Medical University from January 2013 to May 2017, were analyzed.
Overall, 309 patients underwent total thyroidectomy with bilateral lymph node dissection, 488 underwent right thyroid lobe and isthmic resection with right central compartment lymph node dissection, and 32 underwent near-total thyroidectomy (ipsilateral thyroid lobectomy with contralateral near-total lobectomy) with bilateral lymph node dissection. The overall rate of central compartment lymph node metastasis was 43.5% (361/829), with right central compartment lymph node and RPELN metastasis rates of 35.5% (294/829) and 19.1% (158/829), respectively. Tumor size, number, invasion, and location, lymph node metastasis, right central compartment lymph node metastasis, and right lateral compartment lymph node metastasis were associated with RPELN in the univariate analysis, whereas age and sex were not. Multivariate analysis identifed tumors with a diameter ≥1 cm, multiple tumors, tumors located in the right lobe, right central compartment lymph node metastasis, and right lateral compartment lymph node metastasis as independent risk factors for RPELN metastasis. Lymph node dissection, including RPELN dissection, should be performed for patients with PTC with a tumor diameter ≥1 cm, multiple tumors, right-lobe tumors, right central compartment lymph node metastasis, or suspected lateral compartment lymph node metastasis.
Thyroid Cancer Thursday Poster Clinical
Bone metastases (BM) are diagnosed clinically in 5-25% of patients with differentiated thyroid cancer (DTC). The objective of this study was to evaluate overall and disease-related survival of patients with differentiated thyroid cancer (DTC) and bone metastases (BM) attending a single medical center and to investigate variables predictive of better long-term outcomes. The Rabin Medical Center Thyroid Cancer Registry was searched for patients with BM from DTC. The cohort included 64 patients (48.4% female) diagnosed at mean age 62.1 ± 14.3 years. Mean primary tumor size was 41 ± 30 mm. Most patients (63%) were stage T3/T4; 45.5% had extrathyroidal extension; 38% had lymph node metastases. Histopathology yielded papillary and follicular thyroid carcinoma in 40.6% and 32.8%, respectively, and intermediate/poorly differentiated carcinoma in 26.5%. Radioactive iodine was administered to 62 (96.9%) after thyroidectomy. BM were synchronous in 67.2%. Mean follow-up was 11 ± 9.6 (median 8) years from detection of DTC. The common sites of BM were spine (46.9% of patients), pelvis (37.5%), ribs (21.9%) and limbs (12.5%). After initial treatment 62/64 of patients (96.7%) had structural persistent DTC. At the last follow-up, structurally-progressive disease was documented in 57.8% of patients. Overall, 55.6% of patients had died, 71.43% of DTC. Improved outcomes in terms of survival and disease progression were associated with younger age, lower tumor stage, non-extra-thyroid extension, bone-only distant metastases, and non-spinal BM. Selected patients with DTC and BM may achieve fair long-term outcomes. Novel therapies might be necessary in a significant proportion of these patients, and the reported prognostic factors can aid in their identification.
Thyroid Cancer Thursday Poster Clinical
The response to therapy assessment tool is well validated for patients with differentiated thyroid cancer (DTC) following total thyroidectomy and radioiodine, but limited data is available for patients treated with lobectomy. The main limiting factor is thyroglobulin (Tg) produced by the remaining lobe, and the lack of data on normal ranges of thyroglobulin in this scenario. Our objective was to define normal range of Tg after lobectomy, with subgroup analysis for Hashimoto's thyroiditis (HT), autoantibodies (TgAb), and contralateral nodules. We included patients from the Rabin Medical Center Thyroid Cancer Registry who had lobectomy for DTC, followed for >1 year without completion thyroidectomy, and who had sufficient data on Tg and TgAb levels. One-hundred seventeen patients met inclusion criteria. Age at diagnosis was 49.6 ± 15 year, and 86% were women. Lobectomy was performed for classic papillary thyroid cancer (PTC) in 68% and for follicular variant PTC in 32%, with tumor size of 9.1 ± 5mm. Following thyroidectomy, Tg levels were 10.8 ± 13ng/ml (median 8.6ng/ml), excluding one patient with Tg of 1,041ng/ml (found benign after completion). Of 36 patients with HT, 50% had positive TgAb with titers of 285 ± 410IU/mL, and 50% had no TgAb, with Tg levels of 9.9 ± 5 ng/ml. In 19 patients with contralateral nodule ≥1cm, Tg was 17.7 ± 23 ng/ml. During the first two years of follow up, Tg declined ≥1 ng/ml in 40% of patients (by 7 ± 6.7 ng/ml), remained stable in 20%, and increased in 40% (by 8 ± 8.9 ng/ml). During 71 ± 41.1 months of follow-up, 10 patients had completion thyroidectomy and five were diagnosed with contralateral cancer (n = 3) or lymph node metastases (n = 2). All recurrent disease was diagnosed using ultrasound. Of these five cases, there was a steady rise in Tg in two cases, Tg was stable in two cases, and in one case TgAb decreased from 1534 to 276 in the presence of a new LN metastasis. Analyzing the whole cohort, basal Tg and Tg change did not predict disease recurrence. Thyroglobulin used independently is of limited value to predict or detect locoregional recurrence following lobectomy. Other potential roles of Tg, such as exclusion of distant metastases following lobectomy should be further studied.
Thyroid Cancer Thursday Poster Clinical
Cervical lymph node (CLN) metastases (mets) from differentiated thyroid cancer (DTC) do not always correlate with specific clinical or pathological features of the primary tumor. In a retrospective study, we examined clinical and pathological features of patients (pts) with DTC diagnosed at Houston Methodist Hospital between 2006 and 2018. Based on existing literature, we hypothesized that the presence of CLN mets would correlate with tumor size and multicentricity. We compared three groups: patients with pathologically confirmed CLN mets (N1); patients with no mets in CLN (N0); and patients in whom no lymph nodes were resected (Nx). There were 72 pts in N1; 85 pts in N0; and 74 pts in Nx. Mean age (yr +/-SD) for pts in N1 (44.0 + 16.7) was significantly lower than that in N0 (47.9 + 14.6) or Nx (50.6 + 13.9). 92% were papillary thyroid carcinoma; 8% were follicular thyroid carcinoma.N1 pts were significantly younger than Nx pts but N0 was not different than N1 or Nx. ANOVA analysis did not find any differences among the groups in gender or tumor type. Significant differences among groups were present for tumor size (p < 0.001), multicentricity (p < 0.004), AJCC Stage (p < 0.001), and the presence of thyroglobulin autoantibodies (TgAb) (p < 0.003). N1 pts had a higher incidence of TgAb compared to N0 and Nx, but there was no difference between N0 and Nx. N1 pts had significantly larger tumors compared to N0 and Nx, but there was no difference between N0 and Nx. Finally, N1 pts had a significantly higher incidence of multicentricity than N0 or Nx with no difference between N0 and Nx. There is a high correlation of clinical features between the N0 and Nx groups. We conclude that larger or multiple primary tumors increase the likelihood of CLN mets. We suggest that increased vigilance for CLN mets is appropriate in larger tumors, in multicentric tumors, and in patients with elevated TgAb. Furthermore, Nx pts are very similar to N0 pts and could be managed as if they were N0.
Disorders of Thyroid Function Thursday Poster Case Report
Thyrotoxic Periodic Paralysis (TPP) is an alarming complication of hyperthyroidism characterized by muscle paralysis and hypokalemia due to intracellular shift of potassium. TPP mainly affects male patients of Asian descent. Some TPP patients do not have obvious symptoms or signs of hyperthyroidism. We describe here a case of TPP in the setting of Graves' disease.
This is a 39-year-old Vietnamese male who presented with palpitations and weight loss despite good appetite in the setting of tachycardia, lid lag and tremors. His brother had Graves' and his mother had hyperthyroidism. He had a suppressed TSH <0.01 uIU/ml, elevated fT4 and fT3 at 3.5 ng/dL and 4.4 ng/dL respectively as well as an elevated TSI at 168%, normal <140%, confirming Graves' disease. He was started on propranolol. He refused methimazole and RAI ablation. Five months after his diagnosis, the patient reported an episode, upon awakening, of total body paralysis more severe in the lower extremities and lasted three hours in the setting of persistent hyperthyroidism. Serum potassium was 3.7 mEq/L down from 4.7 about one month ago. He was diagnosed with TPP and advised to increase potassium in his diet and avoid carbohydrate rich food. No further episodes were reported.
Patients with TPP often experience the paralytic attack a few hours after a carbohydrate rich meal or in the early morning upon waking up. Paralysis after strenuous exercise is also a common presentation. TPP occurs only in the presence of hyperthyroidism and is abolished when thyroid hormone levels are normalized. TPP is characterized by hypokalemia which occurs due to a massive shift of potassium into muscle cells. Moreover, thyroid hormones can increase Na/K-ATPase activity in skeletal muscle, liver, and kidney to induce an influx of potassium into the intracellular space. Catecholamines and insulin can also increase Na/K-ATPase activity playing a role in the potassium shift. The mainstay of treatment includes replacing potassium carefully, beta blockade and, ultimately, definitive treatment of the hyperthyroidism.
In short, increased awareness among Physicians about TPP will result in early diagnosis, appropriate treatment, and the prevention of sequelae of this disorder.
Thyroid Cancer Thursday Poster Clinical
Intra-operative frozen sections (FS) are often utilized on indeterminate thyroid nodules to determine if a lobectomy should be converted to a total thyroidectomy. We seek to examine how intra-operative FS affects surgical decision making, and its correlation to ultra sound guided fine needle aspiration (USFNA) results in the age of molecular testing and the updated 2015 ATA Guidelines on Differentiated Thyroid Cancer. This was a retrospective review of all thyroid FS from 2012 - 2017 at a single tertiary care center. Patient demographics, complications, USFNA results, molecular testing results, FS diagnosis, and final diagnosis were recorded. Fisher's Exact tests were used for analysis.738 total patients had an intra-operative FS performed. Intra-operative management was affected by the FS 53 times (7.2%). An USFNA diagnosis of “suspicious for malignancy” significantly correlated with FS altering the operation (n = 17 out of 55, p = 0.0001). Molecular testing was sent on 92 USFNA specimens, 80 of which were deemed “suspicious.” Of those 80 patients FS affected the type of surgery performed 6 times (7.5%, p = 0.82). Of the 53 patients whose management was altered intra-operatively based on FS, 27 (51%) would not necessitate a completion thyroidectomy under the 2015 ATA guidelines based on final pathology. Intra-operative frozen sections rarely alter the pre-surgical plan. Molecular testing of indeterminate USFNA results does not appear to predict meaningful intra-operative FS results. Consistent with prior studies, an USFNA result of “suspicious for malignancy” did correlate with altered management and represents cases where FS can still be useful. Furthermore, the most recent 2015 ATA guidelines on differentiated thyroid cancer a reflect of a shift towards less aggressive surgical interventions to reduce morbidity. In approximately half of our historical cases where a lobectomy was converted to a total thyroidectomy based on the intra-op FS, the need for the completion thyroidectomy would now not necessarily be recommended.
Thyroid Cancer Thursday Poster Clinical
The ultimate goal of thyroid nodule evaluation is to detect thyroid cancer. Clinical risk assessment, ultrasound (US) and US-guided fine needle aspiration biopsy (US-FNA) represent the primary tools for evaluation. Using the largest of its kind prospective cohort analysis of consecutive nodules, we sought to analyze the clinical landscape of nodule assessment and determine the relative impact of variables upon malignancy. From 1995-2017, demographic, sonographic, cytologic and histopathologic data were prospectively collected for all patients evaluated with US-FNA for a thyroid nodule ≥1cm. Descriptive statistics and malignancy risks were calculated. Mixed effect logistic regression was performed for all nodules, and also for those with atypical (AUS) or follicular neoplasm (SFN) cytology. We analyzed 20,001 nodules from 9,967 patients. Median age was 53 yrs (18-95 yrs), 8,372 (84%) patients were female, and median nodule size was 17mm (10-128 mm). Thyroid cancer was confirmed in 1,974 nodules (9.9%) from 1624 subjects (16.3%), of whom 87.4% had papillary thyroid carcinoma. For all nodules, multivariate regression analysis showed odds of cancer were increase for male sex (OR: 1.71 [1.48-1.98], p < 0.0001) and larger nodule size (OR: 1.30 [1.14-1.49] for 20-29mm, OR: 1.59 [1.34-1.88] for 30-39mm, OR: 1.72 [1.43-2.06] for ≥40mm, p < 0.0001 for all). In contrast, the risk of cancer was lower with increasing age (OR: 0.98 [0.97-0.98], p < 0.0001), >75% cystic component (OR: 0.20 [0.15-0.28], p < 0.0001), and when there were ≥4 nodules ≥10mm (OR: 0.19 [0.16-0.23], p < 0.0001). Thus, for example, cancer risk in a solitary solid ≥40mm nodule in a male <50 years old was 14/31 (45%) compared to 1/218 (0.46%) for a 10-19mm >75% cystic nodule in a multinodular gland (≥4 nodules) from a woman >50 years old (p < 0.0001). For nodules with AUS or SFN cytology that underwent resection, only younger age (OR: 0.99 [0.98-0.99], p = 0.03) and multinodularity (≥4 nodules; OR: 0.64 [0.43-0.95], p = 0.03) were significant predictors of malignancy. In this extensive analysis, we convey the landscape of thyroid nodular disease, and demonstrate the precise impact of clinical and US risk factors for predicting thyroid cancer.
Thyroid Cancer Thursday Poster Clinical
Thyroidectomy is an accepted same day procedure. While risks of airway hematoma, hypocalcemia, and recurrent nerve injury cannot be eliminated, advances in monitoring and technique provide for an increasingly safe patient experience. The ATA Statement on Outpatient Thyroidectomy suggests guidelines for same day surgery which take into account eligibility criteria, patient risk factors, and discharge criteria; these can be adapted to create institution-specific guidelines. We retrospectively reviewed thyroidectomies performed by a single surgeon to determine eligible thyroidectomy patients for same day discharge. Currently, all patients at our institution stay overnight. Eighty-nine sequential adult patients undergoing hemi-thyroidectomy, total thyroidectomy, or completion thyroidectomy were reviewed from September 2017-February 2018, after a two-hour post-operative PTH lab draw was implemented for total and completion thyroidectomy patients. Charts were reviewed for demographic characteristics, comorbidities, as well as surgical sequelae of hematoma, hypocalcemia, and RLN injury. ATA pre-operative, peri-operative, and post-operative discharge criteria were used to determine patients fit for same day discharge, with a PTH value set at 15. Of the 89 patients reviewed in this time period, 76 (85%) met criteria for same day discharge. This included 48 total thyroidectomies and six completion thyroidectomies. No patients experienced hematoma, post-operative stridor, or need for return to the OR. Two RLNs were purposefully sacrificed for tumor invasion. Two patients (2%) had post-operative PTH values <15. Medical comorbidities determined ineligibility for same day discharge for nine additional patients: one had known RLN injury from prior anterior cervical discectomy and fusion, six patients had sleep apnea; one had liver failure and was on the liver transplant list; one was on Plavix. Thyroidectomy is a safe outpatient procedure. Risks of hematoma, hypocalcemia, and RLN injury are not higher with same day surgery. Approximately 85% of our patients who currently stay overnight are eligible for same day discharge. Now we aim to prospectively discharge patients according to our outlined criteria.
Thyroid Cancer Thursday Poster Clinical
Bilateral axillo-breast approach (BABA) robotic thyroidectomy is a novel “scar-less” techniques in the US. Its efficacy for large goiter as well as advanced or metastatic thyroid cancers has been demonstrated in the literature. This study evaluates the initial experience of BABA technique for benign and malignant thyroid disease in the US. From June 2015 to October of 2017, BABA technique was performed in selected patients who were either prone to forming an undesirable scar or with a personal preference for avoiding a neck scar. Four 8mm remote incisions were utilized (periareolar and axillary skin fold). Endoscopic subplatysmal flap dissections were performed. Thyroidectomy and lymph node dissections were performed using the robotic platform. Intraoperative nerve monitoring was performed throughout the surgery. Patients were followed in 1 week and 4-6 months after the surgery. A series of 50 cases (26 hemithyroidectomies, 21 total thyroidectomies with central neck dissections when indicated, 1 lateral neck dissection, and 2 completion thyroidectomies) were performed. All patients were female with an average age of 37.8 (range 17-68) and median BMI of 25 (range 19-49). Indications for surgery were cancer (N = 11; 22%), Graves' disease (N = 9, 18%), toxic goiter (N = 5, 10%), symptomatic goiter or indeterminate nodule (N = 21, 42%). On pathology, average tumor size was 3.4cm (range 0.7-6.5), and chronic lymphocytic thyroiditis was present in 15 cases (30%). Average specimen weight for Graves' disease was 54.6gm (range 25-101). The median operative time was 250 minutes (range 192-420), and the median estimated blood loss was 20 ml (range 10-300). Mean length of stay was 0.5 days (Median 0; Range 0-3). Complications included transient vocal cord paresis with spontaneous recovery in <2 months (N = 2, 4%), transient hypoparathyroidism (N = 2, 1%), and neck seroma requiring needle aspiration (N = 2, 4%). There were no mortalities, postop hematomas, open conversions, infections, permanent hypoparathyroidism, or permanent recurrent nerve injury. BABA robotic thyroidectomy can be safely implemented in the US with excellent surgical and cosmetic outcomes in a selective group of patients with benign and malignant thyroid diseases.
Thyroid Cancer Thursday Poster Clinical
Radioiodine refractory (RAI-R) thyroid cancer is uncommon, with an estimated incidence of 5% of patients with differentiated thyroid cancer (DTC). Outcomes vary among patients with RAI-R disease. In clinical trials of kinase inhibitors, more than half of refractory patients in the placebo arm showed disease progression, however, there were still 30-50% showed control disease, which means, without progression. The aim of this study is to evaluate the prognostic value of 18F-FDG PET/CT in the disease progression of patients with RAI-R thyroid cancer. We retrospectively reviewed 2329 DTC patients treated at our hospital from 1986 to 2014. About 10% (235 patients) of them had distant metastases in the initial diagnosis or during follow-up. Patients with distant metastases who had PET scan and confirmed having RAI-R disease were included into this study. Finally, 49 patients were included. Prognostic factor analysis included age, sex, histology, disease stage, initial ATA risk, lesion 18F-FDG avidity, lesion size, etc. The primary end-point was progression free survival less than 2 years after the 18F-FDG PET scan according to RECIST criteria. The average age at refractory disease confirmed was about 56 of age. The average interval from diagnosis of cancer to refractory disease were 7.2 years. Mean follow-up after 18F-FDG PET were 5.2 years. About 60 percents (22/49) of patients experienced disease progression less than 2 years after 18F-FDG PET.
Univariate analysis showed that initial advanced stage (stage III-IV), serum Tg level higher than 13.5ng/ml, lesion 18F-FDG uptake higher than SUVmax 4.5, age at refractory older than 55 of years were predictive factors of progression free survival less than 2 years. In multivariate analysis, only the lesion 18F-FDG uptake was independent factor to predict progression free survival less than 2 years. The 18F-FDG uptake of structural lesion is an independent prognostic factor to predict short-term disease progression. The results of this study may improve the selection of candidates for kinase inhibitors in patients with refractory thyroid cacner.
Thyroid Cancer Thursday Poster Clinical
Laryngeal recurrent nerve and parathyroid gland injury are major complications following thyroidectomy. The bifurcation of laryngeal recurrent nerve and location of parathyroid gland may variate between individual patients. We seek to investigate the relationship of these anatomical variations and post-operative complications. A cohort of 50 consecutive patients planned for thyroidectomy were enrolled in this study. All surgeries were operated by an experienced endocrine surgeons. Recurrent laryngeal nerves were carefully dissected and exposed for the entire length. Parathyroid glands were carefully identified and preserved in situ if possible (otherwise we would perform auto-transplantation). Short term and long term post-operative complications such as harsh voice, muscle cramps and paresthesia were observed. Follow-up time was 6 months after surgery. A total of 84 recurrent laryngeal nerves were dissected (36 left and 48 right). 42 (50%) nerves bifurcated into at least 2 branches. No patients experienced post-operative complications related to recurrent laryngeal nerve injury. 168 parathyroid gland sites were explored and 152 glands (80 superior and 72 inferior) were successfully identified. Among them, superior parathyroid glands has a significantly higher rate of identification during surgery (95.2% vs 85.7%, p = 0.035), and a significantly lower rate of auto-transplantation (2.5% vs 20.8%, p < 0.01). However, short term post-operative complication rate was not different between the in situ preservation group and auto-tranplantation group (20.0% vs 22.2%, p = 0.84) and no patients suffered from long-term complications due to parathyroid gland injury at follow-up. Anatomical variations of recurrent laryngeal nerves and parathyroid glands are common and special attentions should be paid during thyroidectomy. However, post-operative complications were not increased due to nerve bifurcation or parathyroid gland auto-transplantation acording to our results. Novel techniques that help localizing and preserving the inferior parathyroid glands should be investigated.
Thyroid Cancer Thursday Poster Clinical
ATC has poor prognosis with median OS of approximately 6 months. We previously reported high PD-1/PDL-1 staining in anaplastic thyroid cancer (ATC), raising the possibility of the productive application of the immunotherapeutic pembrolizumab in ATC. However, having found pembrolizumab to anecdotally have limited single-agent activity in ATC, we sought to alternatively define whether pembrolizumab might synergistically combine with chemoradiotherapy as initial ATC therapy. An investigator-initiated therapeutic phase 2 trial of pembrolizumab, 200 mg IV every 3 weeks, combined with chemoradiotherapy [docetaxel/doxorubicin, 15 mg/m2 each IV weekly plus (neck/tumor bed) intensity modulated radiation therapy (IMRT)] was initiated as front-line therapy in ATC to assess efficacy and toxicities. Six-month overall survival (OS) was selected as the primary endpoint using a Simon's optimal design with interim analysis (target accrual 25 patients; Cohort A: prior resection Cohort B: no resection). Based upon historical patient cohort treated similarly, but without pembrolizumab, the design was such that, if 6 month true survival is 75%, the probability of declaring the trial worthy of further pursuit would be 91%. Three patients were enrolled; two with rapidly enlarging neck masses. Initial tumor response was favorable in all three, and all three satisfactorily completed: intended radiotherapy, preceding and radiotherapy-concurrent pembrolizumab, and concurrent chemoradiotherapy. However, all three patients died <6 months following therapy initiation - one from tumor progression, and two experiencing infectious complications leading to their death. An unscheduled meeting with the involved Data Safety and Monitoring Board was undertaken, and study closure was recommended and implemented. Although initially well tolerated and effective in terms of locoregional control, disappointing survival outcomes compared to historical control and the unexpected occurrence of two deaths from complications other than tumor progression, limit our enthusiasm for study reactivation.
Thyroid Cancer Thursday Poster Clinical
Differentiated thyroid cancer (DTC) has the fastest rising cancer incidence in the U.S., yet remains vastly underexplored in terms of quality of life and survivorship experiences. Favorable outcomes after diagnosis of high-risk DTC may be partly due to use of radioactive iodine (RAI) therapy. The range and impact of post-RAI side effects are not well documented. The purpose of this study was to identify the range of symptoms experienced by patients after RAI and use this information to develop a survey targeting this patient population. We used a mixed methods approach. First we conducted focus groups with patients diagnosed with DTC treated with RAI within the past 10 years. Trained facilitators guided participants' discussion. We audiotaped and transcribed discussions. Trained raters coded transcripts and identified themes for survey development. Then we conducted a pilot of the survey with patients diagnosed with DTC following RAI therapy. From the focus groups, we identified several themes that most impacted quality of life following RAI. These included salivary symptoms such as dry mouth, nasal symptoms such as burning, and eye symptoms such as tearing. Psychosocial factors such as uncertainty regarding the thyroid cancer diagnosis and unpreparedness for treatment were also prevalent. The pilot survey (n = 59) revealed that in this mostly female population (83.1%), the most frequently experienced symptoms were dental cavities (81.4%), dysgeusia (42.4%), dry eyes (35.6%), and salivary gland obstruction (30.5%). Other identified factors affecting quality of life included decreased sex drive (45.8%) and feeling uninformed regarding the side effects of RAI (61%). Patients with DTC treated with RAI reported a wide range of symptoms after treatment. Symptoms ranged from mild to burdensome. As most participants reported that they were unprepared for the range, type, or severity of symptoms, study findings have implications for patient-physician communication and treatment decision-making. Our targeted survey can be used to guide physicians and patients through the treatment process and will be prospectively observed and validated through objective measures in phase II of our study.
Thyroid Cancer Thursday Poster Clinical
Thyroid nodules and thyroid cancer are among the extraintestinal manifestations of familial adenomatous polyposis (FAP), with prevalence of 35-80% and 3-12% respectively. Predominantly seen in females before age 28. The incidence of thyroid cancer, mainly the cribriform-morular variant of papillary carcinoma is higher in FAP patients than in the general population, however, routine thyroid cancer screening is not consistently performed by most providers for them.
Of the 49 patients with FAP syndrome, 24 (49%) were female with mean age of 38 ± 16years. Only 12 patients (24.5%) had thyroid ultrasound performed, 8 of whom had thyroid nodules, size ranging from 0.3-2.0 cm, and all were female. 6 patients had fine needle aspiration and 1 patient had thyroid cancer. With limited data, our study showed decreased prevalence of thyroid cancer of 8%, when compared to some prior studies. Most adult FAP patients do not receive thyroid cancer screening. This may be due to lack of awareness of their medical providers on the increased incidence of thyroid cancer in FAP. Another reason may be lack of patient education on the importance of screening, as several patients had the study ordered but not completed. Every clinician managing FAP patients should be educated on the increased risk of thyroid cancer in FAP and the role of thyroid ultrasound screening for early detection of thyroid cancer.
Thyroid Cancer Thursday Poster Clinical
Thyroid cancer screening is not recommended for asymptomatic adults by the US Preventive Task Force. However, the role of screening in selected populations, such as individuals with family history of thyroid cancer, remains to be elucidated. Starting from 2009, neck sonography screening was offered to the first-grade relatives of all patients with differentiated thyroid cancer (DTC) followed at the Thyroid Cancer Unit of Sapienza University of Rome. Cytology was performed in suspicious nodules according to the available guidelines. The rate of newly-diagnosed thyroid cancers (primary endpoint) and thyroid nodules (secondary endpoint) were stratified according to the number of DTC affected members in the kindred. Among 2287 individuals eligible for the screening, 1176 from 473 kindreds accepted the examination (age 41.7 [26.0-55.6] years, 652 females, 55.4%). Patients refusing the screening were older (54.2 [38.6-70.0], p < 0.0001) and more frequently males (54.7%, p < 0.0001).
Overall, 500 individuals with nodules were detected (42.5%) and 95 (19%) underwent fine-needle aspiration cytology. Twelve (1%) new cases of DTC were diagnosed: 7 in 346 kindreds with 1 known DTC case (2%), 2 in 103 kindreds with 2 DTC cases (1.9%), and 3 in 24 kindreds with ≥3 cases (12.5%). The OR for detection of DTC in kindreds with ≥3 cases was 6.98 (95%CI 1.76 – 27.71, p < 0.001). Younger age (<45 years) and/or multifocality in the index case did not increase the likelihood of new thyroid cancer detection. Thyroid nodule detection rate in the families with 1, 2, and ≥3 cases, was 62%, 75%, and 66.7%, respectively. In conclusion, the thyroid cancer detection rate is significantly higher in kindreds with at least 3 DTC cases, making this specific subgroup potentially eligible for a screening program. Whether such an approach improves health outcomes remains to be evaluated. Moreover, screening is likely to detect a large number of benign thyroid nodules, requiring long-term follow-up and additional diagnostic procedures.
Thyroid Cancer Thursday Poster Clinical
Large population-based analyses of squamous-cell thyroid cancer (SCTC) are few. In this study, we investigated the prognosis of this rare neoplasm as compared to the common subtypes, papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC). Information regarding patients with a diagnosis of PTC, FTC, or SCTC, between 2004 and 2013, was acquired from the Surveillance, Epidemiology, and End Results (SEER) database. Patient survival curves were assessed by Cox proportional hazards regression analyses, Kaplan-Meier analyses, and log-rank tests. On Kaplan-Meier analysis of the entire cohort of thyroid cancer patients, cancer-specific survival declined modestly in patients with PTC and FTC, but declined sharply in patients with SCTC. Unadjusted Cox regression analysis and Kaplan Meier curve analysis showed that SCTC had a poorer prognosis compared to PTC and FTC. Similar results were obtained after adjustments for different confounding factors. Our study, comprising a large cohort, assessed the prognosis of SCTC as compared to that of PTC and FTC, and found relatively accurate hazard ratios for the death rate due to SCTC as compared to PTC and FTC. This could aid in the development of evidence-based recommendations for informed clinical decision-making in the management of SCTC. Based on these findings, an aggressive treatment modality may be recommended for this rare subtype of thyroid cancer.
Thyroid Cancer Thursday Poster Clinical
Insular thyroid cancer (ITC) is a relatively rare thyroid malignancy that has an unclear prognosis. Recent studies have indicated that watchful waiting is sufficient for younger patients with more differentiated thyroid lesions such as papillary thyroid microcarcinoma (PTMC). In this study, we investigated the prognosis of younger patients (<45 and <55 years old) with ITC and compared their outcomes to patients with PTMC and follicular thyroid microcarcinoma (FTMC). We hypothesized that ITC, like PTMC and FTMC, can be managed with active surveillance in younger patients with this disease. We investigated a large cohort of younger patients with ITC, PTMC, or FTMC who were listed in the Surveillance, Epidemiology, and End Results database between 2004 and 2013. Patient mortality was examined by Kaplan-Meier analyses with log-rank tests and Cox proportional hazards regression analyses. In the study cohort, the rate of cancer-specific mortality per 1000 person-years for younger ITC patients (<45 and <55 years) was lower than that for PTMC and FTMC. Kaplan-Meier analyses revealed that the cancer-specific and all-cause mortality rates in younger ITC patients were similar to those of PTMC and FTMC. Similar results were obtained when cases with tumor extension were excluded from the analysis. The unanticipated excellent prognosis of younger patients with ITC challenges the current clinical practice of automatically treating this disease, and offers new implications for management such as pursuing active surveillance instead.
Thyroid Cancer Thursday Poster Clinical
According to the surveillance, new cases of thyroid cancers in the young population have increased. The thyroid ultrasound screening for children aged 0-18 was performed in Fukushima after the accident at the Fukushima Daiichi Nuclear Power Plant. As a result, many thyroid cancer cases in the young population have been found. To explore the carcinogenic mechanisms of the cancers, we analyzed their clinicopathological and genetic features. We analyzed 145 patients (53 males and 92 females) operated between 2013 and 2016 at Fukushima Medical University. The mean age at operation was 17.8 years old. The mean size of the tumors was 14.9mm. The majority of the patients (90%) were diagnosed as papillary thyroid cancer (classical type). We analyzed BRAF(V600E) mutation by direct DNA sequencing in 123 cases. The BRAF(V600E) mutation was observed in 71.5% of the thyroid cancers. On the contrary, the RET/PTC3 rearrangement was observed in 0.8%. The RET/PTC3 rearrangement has been found in pediatric post-Chernobyl thyroid cancer. However, the RET/PTC3 rearrangement with PTC was detected only 0.8% in our cases. The prevalence of the BRAF(V600E) mutation was comparable to Japanese adult sporadic cases, implying that the carcinogenesis mechanism may be similar between young population and adult papillary thyroid cancers.
Thyroid Cancer Thursday Poster Clinical
Recently, the concept of natural orifice transluminal endoscopic surgery (NOTES) has been introduced to thyroid surgery. With this approach, an endoscope is passed through a natural orifice (e.g., the mouth) into an internal organ (e.g., the thyroid).We reviewed the medical records of 63 consecutive cases who underwent transoral endoscopic thyroidectomy via a trivestibular approach between July 2016 and May 2018 in our hospital. We performed 63 transoral endoscopic thyroid surgeries in 62 patients. The average tumor diameter was 1.23 cm (range: 0.3–7.5 cm). Postoperative pathology revealed PTC in 52 cases (82.5%), nodular hyperplasia in seven (11.1%), follicular carcinomas in two (3.2%), a follicular adenoma in one (1.6%) and a hyalinizing trabeculae tumor in one (1.6%). All surgical margins were negative. Two patients exhibited transient vocal cord palsy and recovered within 2 months. One patient who developed vocal cord palsy has not yet recovered for more than 3months. Five patients who underwent total thyroidectomy developed transient hypocalcemia, but recovered within 3 months. Four patients without drain developed seroma, but resolved after aspiration. No sensory change or facial weakness around the lower lip was reported by any patient. No patient developed a wound infection or fistula between the oral incision and anterior neck. The transoral endoscopic approach provides a short, direct route to the thyroid gland and seems to be safe and feasible. It is important to further develop and refine the surgical techniques. The approach is optimal, and will become widely used for thyroid surgery in the near future.
Thyroid Cancer Thursday Poster Clinical
TORT through oral vestibule draws attention recently because it requires minimal flap dissection and postoperative scar disappears in several weeks. In this study, we evaluated surgical outcomes of TORT and compared them with those of bilateral axillo-breast approach robotic thyroidectomy (BABA RT) after propensity score matching. The medical reports were retrospectively reviewed. A propensity score matching analysis was done with seven covariates including age, gender, tumor size, extrathyroidal invasion, pathologic diagnosis, multiplicity and thyroiditis. Propensity score matching identified 92 pairs of patients. There were 87 and 85 females in BABA RT and TORT group, respectively. The mean tumor size was 1.1 and 1.0 cm for BABA RT and TORT group, respectively. Operation time for total thyroidectomy was shorter in TORT than BABA RT group (220.3 vs. 301.9 min, p = 0.023). Mean postoperative pain scores at operation day 0 and 1, and analgesic requirement were lower in TORT group. Hospital stay was shorter in TORT than BABA RT group. There were no significant differences between TORT and BABA RT group in transient vocal cord palsy rate (0% vs. 4.0%) and transient hypoparathyroidism rate (0% vs. 18.1%). TORT could be performed safely and showed comparable outcomes with BABA RT in selected patients. TORT might be an alternative approach for the patients who want scarless thyroidectomy.
Thyroid Cancer Thursday Poster Clinical
Right paraesophageal lymph nodes are rare metastatic foci and are likely to be overlooked during first operation. This study aimed to determine the incidence, to identify the predictable factor of right paraesophageal lymph nodes metastasis. We conducted a retrospective review of 415 patients with papillary thyroid cancer who were dissected right paraesophageal lymph nodes in primary thyroidectomy from March 2007 to December 2017. The clinicopathologic results were analyzed for comparison between paraesophageal lymph nodes positive and negative groups. The incidence of right paraesophageal lymph nodes metastasis was 21.2%. Patients with right paraesophageal lymph nodes positive groups were associated with male, large tumor size, extrathyroid extension, lymphovascular invasion, perineural invasion, more than T3 stage and presence of metastatic lymph nodes in the right paratracheal lymph nodes in univariate analysis. A multivariate analysis revealed that the presence of metastatic lymph nodes in the right paratracheal lymph nodes was the only predictive factor for the presence of right paraesophageal lymph nodes metastasis. In more than three lymph node metastases in right paratracheal lymph nodes, the presence of metastasis in right paraesophageal lymph nodes metastasis was 46.2%. The metastases in right paraesophageal lymph nodes were not so rare for papillary thyroid cancer patient and skip metastasis can be occurred. Careful right paraesophageal lymph node dissection should be considered for patients who have presence of more than three metastatic nodes in right paratracheal lymph node.
Thyroid Cancer Thursday Poster Clinical
In an ongoing multicenter prospective cohort study of active surveillance on low risk papillary thyroid microcarcinoma (PTMC), we aimed to compare the quality of life (QOL) of participants according to the choice of treatments; active surveillance (AS) and immediate surgery (OP).QOL was evaluated using validated Korean version of thyroid-specific QOL questionnaire at initial diagnosis and during follow-up in 203 participants with AS and 192 with OP. Score was 10-point scale, with 0 representing the worst possible and 10 representing the best possible QOL. Mean age was 47.3 ± 11.7 and 45.6 ± 10.5 years, and a mean tumor size was 5.7 ± 1.6 and 6.5 ± 2.1 mm in AS and OP group, respectively. Baseline psychological health was significantly better in AS than in OP group (7.1 ± 1.3 vs., 6.8 ± 1.7, respectively, p = 0.022), while physical and spiritual health scores were similar. During a mean follow-up period of 8.2 ± 4.6 months, change of average physical, psychological, and spiritual health was similar between AS and OP group. However, OP group experienced more fatigue, had more changed voice and appearance, felt less satisfied, while less fearful of recurrence than AS group. Self-assessed financial burden was similar at baseline and follow-up in both groups. In correlation analysis, the choice of treatment (AS or OP), age, sex, tumor size, and thyroid function was not related to the average scores of QOL. In OP group, there was positive correlation between psychological health and follow-up duration (r = 0.158, p = <0.001). In patients with low risk PTMC, baseline psychological health was better in AS than in OP group. However, overall changes of QOL was similar, except for QOL related to postoperative changes. Therefore, it is important to give patients detailed and precise information about their treatment options, because psychological health status at their diagnosis could affect decision making.
Thyroid Cancer Thursday Poster Clinical
The 2015 American Thyroid Association (ATA) guidelines recommended that low-risk, differentiated thyroid cancers (DTC) between 1-4 cm may be treated with lobectomy alone, a departure from the previous recommendation for total thyroidectomy. We sought to determine the effect of these guideline changes on the rate of completion thyroidectomy for low-risk DTC identified on initial lobectomy, and factors influencing surgical decision-making.
All patients from 2014-2017 who received an initial thyroid lobectomy at our institution with final pathology demonstrating DTC were included in the study. Microcarcinomas <1 cm were excluded as updated guideline recommendations did not change for this group. Patients were divided into pre- and post-guideline cohorts (2014-2015 and 2016-2017, respectively). The rate of completion thyroidectomy was compared between the two cohorts. Patient demographics and tumor characteristics in each time period were examined for association with completion thyroidectomy.
A total of 226 underwent thyroid lobectomy for malignancy during the time period, and 130 patients met study criteria: 63 patients in the 2014-2015 (“pre”) and 67 in the 2016-2017 (“post”) group. In the “pre” period, 41 (65.1%) patients received completion thyroidectomy, compared to 35 (52.2%) in the “post” period (p = 0.157). In the “post” period, aggressive histology, lymphovascular invasion, extrathyroidal extension, and multifocality were associated with completion thyroidectomy (p < 0.05 for all). Gender, race, age, and tumor size did not affect decision to undergo completion thyroidectomy. Of low-risk patients with DTC between 1-4 cm in size, 17/35 (48.6%) received completion thyroidectomy in the “pre” period, compared to 12/41 (29.3%) in the post period, resulting in a 40% drop in the rate of completion surgery for this group (p = 0.10). The rate of completion thyroidectomy decreased by 40% for low-risk patients with DTC between 1-4 cm, demonstrating gradual adherence to the 2015 ATA guidelines. However, nearly one-third of these patients underwent completion thyroidectomy, suggesting additional factors influencing the decision for further treatment.
Thyroid Cancer Thursday Poster Clinical
The prognostic effect of central compartment neck dissection (CCND) is still controversial in papillary thyroid carcinoma patients. In this study, we evaluated the prognostic value of central lymph node yield (LNY) and metastatic lymph node ratio (LNR) during CCND on the recurrence rate in papillary thyroid carcinoma patients. We retrospectively reviewed 1820 papillary thyroid carcinoma patients who underwent thyroidectomy with CCND between 2009 and 2012 at Seoul St. Mary's Hospital. The central LNY was separated into three groups (low: 1–5 nodes; medium: 6–15 nodes; high: 16+ nodes). The metastatic LNR was divided three groups (low: <0.3, medium: 0.3≤ <0.6, high: ≥0.6). We analyzed the correlation of central LNY, LNR and the recurrence rate. Of 1820 patients, 1498 patients were female and median age was 46 years. The median follow up period was 77 months [0-110]. The mean central LNY were 8.6 ± 6.2 per patient and mean LNR was 0.15 ± 0.24. The recurrent diseases were observed in 35(1.92%) cases. In multivariable analysis, patient's age, central LNY and LNR were associated with recurrence. In patients with high central LNY, the risk of recurrence was 1.21 times higher than that of patients with low central LNY (P = 0.009). Patients with high LNR showed 2.01 fold higher risk of recurrence than those with low LNR (P < 0.0001). The high central LNY and LNR is an independent predictive factor on the recurrence following thyroidectomy and CCND for papillary thyroid carcinoma.
Thyroid Cancer Thursday Poster Clinical
Thyroid Cancer Thursday Poster Clinical
Thyroid cancer is the most common type of endocrine malignancy adn papillary thyroid carcinoma comprises eighty percent of all thyroid cancer. Recent researches have explored controversial functions of PRDM16 gene in solid cancers. The study was performed retrospectively to investigate the role of positive regulatory domain containing 16 (PRDM16) in papillary thyroid cancer (PTC). Patients (n = 11 0) who underwent surgery and was pathologically confirmed as PTC at Fudan University Shanghai Cancer Center (FUSCC) were enrolled, and data from The Cancer Genome Atlas (TCGA) was identified as a validation cohort. We investigated PRDM16 mRNA expression in PTC tumor tissues and the adjacent normal tissues using real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR). We compared PRDM16 expression level of tumor tissue and paired normal tissue and analyzed the correlation of PRDM16 with clinicopathological features and BRAFV600E mutation status. Human-derived normal thyroid epithelial cell line Nthy-ori 3-1 and human papillary thyroid cancer cell lines K1 and BCPAP were used to verify our findings. PRDM16 was significantly downregulated in PTC tumor tissues compared with the adjacent normal tissues (P < 0.001), as well as in K1 and BCPAP compared to Nthy-ori 3-1. Low PRDM16 expression level had a significant correlation with lymph node metastasis (LNM) and extrathyroidal extension (ETE) in both the FUSCC and TCGA cohorts. PRDM16 low expression was an independent risk factor for ETE in multivariate analysis. Besides, PRDM16 low expression was also associated with BRAFV600E mutation status in the TCGA cohort. In conclusion, PRDM16 low expression was identified as a potential biomarker for aggressive behavior, especially for ETE in PTC and poor prognosis of PTC.
Thyroid Cancer Thursday Poster Clinical
Implementation of survivorship care plans (SCPs) is in direct response to the Institute of Medicine's (2006) report From Cancer Patient to Cancer Survivor: Lost in Transition and accreditation requirements by the Commission on Cancer (CoC, 2016) for cancer centers to provide SCPs to 75% of eligible patients by 2018, with accreditation criteria revised December 2017 down to 50%. The primary objective of this study was to identify a systematic process for distributing SCPs to well-differentiated thyroid cancer patients through a nurse practitioner (NP) led survivorship clinic. The study setting was an ambulatory endocrinology practice at a tertiary care center in the Midwest. A quantitative convenience sample took place over six months (April 1-October 1, 2017). Eligibility criteria included patients ≥18 years with well-differentiated thyroid cancer and had completed curative intent therapy. Patients <18 years, non-English speaking, medullary/anaplastic thyroid cancer, or active/persistent disease were excluded. Of eligible patients (N = 174), 84% received a SCP at six months compared to 0% at baseline. As time has been noted to be a barrier in completing SCPs, time data was analyzed. Time to complete SCPs by a registered nurse/licensed practical nurse (n = 125) ranged from 7-45 minutes (M = 17.50, SD = 7.93, 95% CI [16.10, 18.91]), and by the NP (n = 48) ranged from 2-35 minutes (M = 12.16, SD = 8.41, 95% CI [9.72, 14.61]). Survivorship visits (n = 146) ranged from 25-90 minutes (M = 48.84, SD = 11.50, 95% CI [46.96, 50.72]). Patients further from diagnosis/last intervention spent shorter time in visits whereas patients closer to diagnosis/last intervention had longer visits (p = 0.0025). This study reinforces the need to deliver SCPs early on following a cancer diagnosis and suggests an NP-led survivorship clinic is one model able to deliver SCPs and meet CoC accreditation standards.
Thyroid Cancer Thursday Poster Clinical
Classic and Follicular Variant are the most common types of papillary thyroid cancer (PTC). Recent evidence has emerged suggesting to rename a subset of non-invasive encapsulated FVPTC (EFVPTC) as Non-Invasive Follicular Thyroid neoplasm with Papillary-like nuclear features (NIFTP) given low reported risk of adverse outcomes. This shift in nomenclature and re-classification of this entity as “non-cancer” is thought to reduce the clinical consequences and psychological burden of a cancer diagnosis on people afflicted by it. Our study aimed to evaluate clinicopathological characteristics in patients with EFVPTC, assess sonographic features of these tumors, and quantify the morbidity associated with previously established treatment modalities. A retrospective chart review was performed on all patients with FVPTC from 01/2010 to 03/2014 at the Cleveland Clinic with approval by the Institutional Review Board. Data were collected to look for specific variables pertaining to clinical outcomes and morbidity with a minimum follow up of 3 years. Of 201 patients, 27 (13.4%) had non-invasive EFVPTC, 27 (13.4%) had EFVPTC with invasion of the capsule (IEFVPTC) and 148 (73.2%) had infiltrative FVPTC. Among patients with EFVPTC, malignant nodules could be assessed by US in 77% of cases. Compared to IEFVPTC, EFVPTC were less likely to have nodules with microcalcifications (7.4% vs 33%; p = 0.018), irregular contour (14.3% vs 47%; p = 0.019) and nodules taller than wide (16.75% vs 42.8%; p = 0.024). After excluding patients with concomitant thyroid cancers, 20 EFVPTC and 15 IEFVPTC cases remained. One patient with IEFVPTC (6%) had lymph node involvement compared to none in the other group. All cases of EFVPTC were stage I vs 80% in IEFVPTC. None of EFVPTC cases had disease recurrence vs 20% for IEFVPTC. 15% had surgical complications vs 13% for IEFVPTC (p = 0.89). 60% of EFVPTC received radioactive iodine therapy vs 73% for IEFVPTC (p = 0.37). EVPTC is less likely to have suspicious features on US compared to IEVPTC. Based on the clinicopathological characteristics, it is not associated with high risk disease characteristics. The risk of recurrence seems to be lower than in other subsets, with a higher rate of surgical complications.
Thyroid Cancer Thursday Poster Clinical
The detection of incidental or small thyroid nodules has increased. Although the 2015 ATA guidelines for adults stated that fine needle aspiration (FNA) was not recommended for nodules <1cm, establishment of an appropriate size cutoff has been problematic in children. We reviewed surgically resected pediatric thyroid specimens with microcarcinomas to investigate associated clinicopathological features. All surgically resected thyroid carcinomas in patients age ≤18 years old from 2000-2017 were retrospectively reviewed. All microcarcinomas (size <1 cm) were examined for clinical and pathological findings. Of 94 thyroid carcinomas, 15 (16%) were microcarcinomas (mean 0.6, range 0.1-0.9 cm). The average patient age was 14.7 years (range 0.9-18.4 years) and most were female (73%). The final histological diagnoses were papillary (13, 87%) and medullary (2, 13%). There was a pre-operative FNA in 12 (80%) targeting the small nodule in 11 (73%), with a diagnosis of papillary thyroid carcinoma (PTC) (2, 17%), suspicious for PTC (1, 8%), suspicious for follicular or oncocytic neoplasm (6, 50%), and atypia of undetermined significance (2, 17%). One negative FNA (1, 8%) occurred in a case of a 0.1cm papillary thyroid carcinoma that was not targeted by the FNA. Three (20%) were in patients' with a history of genetic syndromes (NF1, MEN2, and Gardner). Nine had molecular testing (60%) with 6 (67%) testing positive for a mutation (3 NRAS, 2 RET/PTC1, 1 RET) using a 7-gene panel or ThyroSeq 1 or 2. All are alive with no evidence of disease with a mean follow-up of 3.8 years. Thyroid microcarcinomas are diagnosed in approximately 15% of pediatric thyroid cancer patients, which is lower than that reported in adults. Although small nodules can be challenging to target, size alone should not guide clinical management without consideration of sonographic and clinical findings. When appropriately sampled with FNA, the findings can be helpful in triaging small thyroid carcinomas for early treatment.
Thyroid Cancer Thursday Poster Clinical
The prevalence of thyroid cancer is rapidly increasing worldwide. Though emphasis has been placed on recurrence in risk stratification, the concept of persistent disease as a separate entity is rarely addressed. This study explores the relationship between lymph node yield and ratio in neck dissections for well-differentiated thyroid cancer as they pertain to risk for persistence following surgery. A retrospective review was conducted of patients undergoing central or lateral neck dissection for well-differentiated thyroid cancer at the authors' institution from 1994 to 2016. Based on inclusion criteria, patients were divided into a persistent disease group, or a control group with no disease at 2 years post-treatment. Demographic characteristics, adjuvant therapy, and tumor and lymph node features were extracted. Total lymph nodes removed as well as the ratio of positive nodes to total yield were compared based on Wilcoxon rank sum analysis. Location of disease persistence and need for additional therapy were also reported.175 patients were included in the control group while 49 were determined to have disease persistence. The nodal yield of patients with central neck persistence was significantly less than those who had no recurrence/persistence (4.8 vs. 11.9 p < .0001). The yield in lateral neck persistence was also lower than those in the control group (14.8 vs. 31.0; p < .0001). Positive node ratio was higher in patients with persistence in both the central and lateral neck (29.4% vs. 74.2%, p < .0001 and 19.8% vs. 54.2%, p < .0001, respectively). Disease persisted in the lateral neck in 40.6% of patients, in the central neck in 36.7%, and both locations in 22.4%. Lower lymph node yield and higher node ratio from neck dissection are associated with greater risk of persistent disease in thyroid cancer. Suboptimal initial surgery results in additional intervention and carries significant implications for risk stratification, adjuvant therapy, and follow up.
Thyroid Cancer Thursday Poster Clinical
Ewing sarcomas represent only 1 percent of all the thyroid malignancies. We describe the case of a 31 y female with a primary Ewing sarcoma of the thyroid. This 31 y female presented with an asymptomatic enlarging neck mass 11 months prior to evaluation. On physical exam she had a mobile, painless nodule in the right thyroid lobe measuring 5 cm with no palpable lympadenopathy. Ultrasound revealed a right thyroid hypoechoic nodule with microcalcifications, irregular borders and a vascular flow grade 2. FNA biopsy demonstrated a markedly cellular specimen with single and clusters of round to oval cells with salt and pepper chromatin and occasional nuclear inclusions. Fixed smear showed focal positive staining for chromogranin. These findings were consistent with medullary thyroid carcinoma. CT scan of the neck did not showed lymphadenopathy. The patient underwent total thyroidectomy. Pathology described sheets of small round blue cells with scant cytoplasm and high N/C ratio. Immunohistochemical stains were positive for CD99, AE1-3, PanCK, GATA3, chromogranin and InI-1. FISH and EWSR1 translocation were positive. These findings were consistent with Ewing sarcoma. PET/CT was negative for any evidence of distant metastases. Post-operative, she began adjuvant chemotherapy with alternative cycles of vincristin, doxorubicin, cyclophosphamide, alternating with ifosfamide and etoposide with mesna given days 1-5. Plan is for a minimum of 8 cycles, followed by radiation therapy to the primary tumor siteEwing sarcoma of the thyroid is extremely rare. Kabata et al described eight cases in ten years. Most patients are male ranging from 9 to 67 years. Most present as a fast-growing mass in the neck with normal thyroid function test. Usual diagnostic methods like FNA failed to give the correct diagnosis and only after surgery was the diagnosis made by the presence of EWSR1 mutation. Given the high rate or recurrent disease, treatment of Ewings sarcoma involves a systemic combination chemotherapy in the neoadjuvant and adjuvant setting.
Primary Ewing sarcoma of the thyroid is a very rare thyroid malignancy and diagnostic challenge. It should be suspected in any patient with a rapidly growing thyroid mass.
Thyroid Cancer Thursday Poster Clinical
Despite an increasing number of thyroid cancer survivors, worry about recurrence and death in these patients remains understudied.
Patients diagnosed with differentiated thyroid cancer in 2014-2015 from the Surveillance, Epidemiology and End Results Program (SEER) registries of Georgia and Los Angeles County were surveyed two to three years after diagnosis. After excluding 188 (9%) patients with persistent or recurrent thyroid cancer and 111 (5%) patients with missing data, multivariable logistic regression was used to identify correlates of worry about recurrence and death in the 1,798 patients who reported that their cancer was gone after initial treatment. Of the 1,798 patients in the sample, 1,398 (78%) were female, 1,077 (60%) were white and 836 (46%) had a college degree or higher. At diagnosis, 1,555 (86%) patients reported that worrying about their thyroid cancer made them feel upset, 1,086 (60%) that it made it difficult to carry out their daily activities, and 764 (42%) that it made them feel distant from family and friends. After two to three years, 676 (38%), 428 (24%) and 345 (19%) patients reported these concerns respectively. However, 1,088 (61%) patients reported worry about recurrence and 714 (40%) reported worry about death two to three years after diagnosis. In multivariable analyses with separate models for recurrence and death, worry about both outcomes was significantly higher in younger patients (≤40 years: p < 0.001, p = 0.002; 41-55 years: p < 0.001, p = 0.004, respectively; reference 56-70 years), patients with lower education (some college: p = 0.003, p = 0.003; high school and below: p < 0.001, p < 0.001, respectively), and patients with higher stage (T2: p = 0.003, p < 0.001; T3/T4: p = 0.005, p = 0.042; N1: p = 0.002, p = 0.008, respectively). Worry about death was also significantly associated with being Asian (p = 0.025), Hispanic (p = 0.030) or Black (p = 0.047).
Although thyroid cancer-related worry affecting day-to-day life decreased two to three years after diagnosis, worry about recurrence and death remained common in this group of patients. Younger age, lower education and higher stage were associated with worry about recurrence and death. Physicians may use these findings to identify patients at risk.
Thyroid Cancer Thursday Poster Clinical
According to increasing the concern about cosmesis, patients are distressful to the neck scar after thyroidectomy. Various attempts have been adopted to reduce those scars. Recently, it has been reported that botulinum toxin type A (Botox), which has been used for a long time due to cosmetic effects such as wrinkle improvement, suppress scar enlargement at the incision site. The aim of this study was to evaluate the effect of Botox administration on postoperative neck scar during thyroid surgery. A prospective randomized double-blind clinical trial was performed for the patients undergoing conventional thyroidectomy at Haeundae Paik Hospital from January to July 2016. The patients with previous neck operation, neck irradiation, or planning radical neck dissection or operation avoiding neck scar were excluded. Conventional thyroidectomy was performed after 5 cm low collar incision. The wound was closed with absorbable synthetic material after injecting 50 U Botox mixed with 1 mL normal saline or 1 mL of saline into subplatysmal muscle at 1 cm interval. Skin scars were assessed using SBSES (Modified Stony Brook Scale Evaluation Scale) and MSS (Manchester Scar Scale) at 1 week, 3 months, and 6 months postoperatively in all patients. Demographic data and operative results will be analyzed statistically using student t-test, chi-square test and repeated ANOVA. Forty patients who underwent conventional thyroidectomy were enrolled and 20 patients in the experimental group and 20 patients in the control group were randomly assigned. At now, skin scarring was assessed up to 3 months and statistical analysis will be performed if follow-up results are added for the next 6 months. The purpose of this study is to investigate the effect of Botox on cervical incision scar after conventional thyroidectomy. Based on the results of this study evaluating the usefulness of Botox, it is expected that the new modality of cervical scar management will be presented.
Thyroid Cancer Thursday Poster Clinical
Recommendation 59 in the 2015 American Thyroid Association (ATA) states that “[f]or low-risk patients who have undergone lobectomy, TSH may be maintained in the mid to lower reference range (0.5–2mU/L) while surveillance for recurrence is continued. Thyroid hormone therapy may not be needed if patients can maintain their serum TSH in this target range.” Studies published prior to 2015 addressed this question and estimated that anywhere from 5-49%3-12 of patients need thyroid hormone supplementation after thyroid lobectomy, with the majority of these studies ranging between 15-30%. However, this data was not based on the new ATA TSH suppression guidelines. Therefore, we sought to evaluate the percentage of patients that need to be on thyroid hormone therapy after thyroid lobectomy to stay in accord with the new guidelines. Retrospective chart review of patients that underwent a thyroid lobectomy from 1/1/2010 to 12/31/2017 for any cause. Head and Neck cancer patients and patients that underwent completion thyroidectomies were excluded. We collected pre/post-operative TSH numbers and the number of patients prescribed Synthroid pre and post-operatively. We performed 339 thyroid lobectomies; 59 head and neck cancer and 100 completion thyroidectomy patients were excluded. Final patient cohort was 180 patients; 20 had WDTC. Mean/median pre-operative TSH for the entire cohort was 1.49/1.26. 6 week, 6 month, and one year mean/median TSH was 6.0/2.79, 2.75/2.56, and 3.19/2.23 respectively. 14% and 42% were on Synthroid pre-operatively/post-operatively. WDTC patients had pre-operative mean/median TSH was 1.265/1.22. 6 week, 6 month, and one year mean/median TSH was 7.345/3.045, 2.254/2.0, and 1.93/1.82 respectively. 20% of these patients were on synthroid pre-operatively, 60% were on synthroid post-operatively, and 75% of people met 2015 ATA guidelines for post-operative thyroid hormone supplementation. Quoting historical data citing rate of Synthroid supplementation rates of 15-30% is likely not accurate for WDTC to stay in congruence with 2015 ATA guidlines. Our study indicates need for thyroid hormone supplementation in WDTC patients to be 75%.
Thyroid Cancer Thursday Poster Clinical
The optimal management for papillary thyroid microcarcinoma (PTMC) remains controversial. Therefore, the purpose of this study is to explore clinicopathologic factors predictive of regional lymph node metastasis in conventional PTMC and to improve perioperative decision making for those harboring regional lymph node metastasis. We retrospectively reviewed 2,404 PTMC patients who underwent lobectomy or total thyroidectomy with central neck dissection and/or lateral neck dissection between January 2010 to December 2017 in a university hospital in China. In overall conventional PTMC patients, 915(38.1%) and 184(7.7%) cases were found to have central lymph node metastasis (CLNM) and lateral lymph node metastasis (LLNM), respectively. Multivariate regression analysis found male (adjusted odds ratio [OR] = 1.977, p < 0.001), age less than 45 (adjusted OR = 1.579, p < 0.001), tumor size greater than 5mm (adjusted OR = 1.963, p < 0.001), extrathyroidal extension (ETE) (adjusted OR = 1.679, p < 0.001), multifocality (adjusted OR = 1.420, p < 0.001), and intrathyroid spreading (adjusted OR = 3.355, p < 0.001) were independent predictors for CLNM. Chronic lymphocytic thyroiditis (CLT) was significantly associated with decreased risk of CLNM (adjusted OR = 0.726, p < 0.01). In a smaller cohort of PTMC patients with BRAF V600E tested (n = 644), 548 (85.1%) harbored BRAF V600E mutation, 43.6% (239/548) and 39.6% (38/96) had CLNM in cases detected with and without BRAF V600E mutation, respectively (p = 0.462). In the subgroup analysis focusing only on PTMC patients, undergoing lateral neck dissection (n = 248), multifocality (adjusted OR = 1.75, p = 0.083) and intrathyroid spreading (adjusted OR = 6.75, p < 0.066) had a statistical trend towards significance, while other clinicopathologic features (sex, age, tumor size, ETE, lymphovascular invasion, CLT, and BRAF V600E mutation) were not significantly associated with LLNM. In the patients undergoing prophylactic central neck dissection, male, age, tumor size, ETE, multifocality, and intrathyroid spreading were found to be predictive of CLNM. No association was observed between BRAF V600E mutation and regional lymph node metastasis in Chinese PTMC patients.
Thyroid Cancer Thursday Poster Clinical
After the Fukushima Daiichi Nuclear Power Plant accident that followed the Great East Japan Earthquake and tsunami on March 11, 2011, a large-scale thyroid ultrasound examination (TUE) survey began for people aged 18 years or younger at the time of the disaster. We would like to report the thyroid cancers screenedd from this survey.
In the first round survey, 300,476 subjects were screened by March 31, 2016. Among them, 116 subjects were diagnosed with malignancy or suspected malignancy by fine needle aspiration cytology (FNAC) A second and third round survey were completed with 270,511 and 120,596 subjects, among whom 71 and 4 were also diagnosed with malignancy by FNAC.
Among the 191 subjects diagnosed with malignancy or suspected malignancy by FNAC, 153 underwent surgery, and one benign nodule and 152 thyroid cancers were confirmed. Of the 152 operated thyroid cancer cases, 145 underwent surgery at our department. We analyzed clinicopathological findings of our operated 145 thyroid cancer.
Among these 145 subjects, 143 papillary thyroid carcinomas, one poorly differentiated thyroid carcinomas, and one other thyroid carcinoma were postoperatively confirmed. Mean age at diagnosis was 17.8 years, and mean tumor size was 14.9 mm. Postoperative lymph node metastasis, extra-thyroidal invasion, and pulmonary metastasis were positive in 79%, 45%, and 2.1% of all cases, respectively. Total thyroidectomy was performed in only 12 cases (8.3%) and hemi-thyroidectomy was performed in the remaining cases.
We are aware of the high prevalence of thyroid cancer detected by sophisticated and large-scale ultrasound screenings following the accident. However, there are no choice which don't carry out TUE in the current Fukushima residents who were exposed radiation after the accident.
Thyroid Cancer Thursday Poster Clinical
Analysis of the integrity of plasma circulating cell-free DNA (ccfDNA) has emerged as a promising tool in diagnosis of malignant vs benign breast and prostate tumors. The goal of this study was to analyze if ccfDNA could serve as a biomarker of malignancy in patients with thyroid nodules with indeterminate cytology. Sixty-eight patients with indeterminate thyroid nodules (Bethesda III), who underwent hemi- or total-thyroidectomy were enrolled in this study. All patients underwent plasma collection within 24-72h before the surgery. Additionally, nine patients had samples collected from the vein draining the nodule and peripheral vein during the surgery. The ccfDNA was extracted from plasma using Thermo Fisher Scientific King Fisher Duo Prime Purification System. The isolated ccfDNA was subjected to quantitative real time PCR, which utilized two different primer sets to amplify both shorter (ALU115) and longer fragments (ALU247) of consensus ALU sequences. Human genomic DNA was used as a standard to determine ccfDNA concentration in the samples. ccfDNA integrity index (cDI) was calculated as the ratio of ALU247 to ALU115. The average age of thyroid nodule diagnosis was 46 ± 15 years, tumor size 1.9 ± 1.8 cm, and 80.9% (55/68) of the patients were women. Women were characterized by lower cDI than men (0.42 ± 0.14 vs.0.51 ± 0.17, p = 0.049). There was no difference in cDI between patients with benign (n = 29) and malignant (n = 39) lesions (0.46 ± 0.16 vs 0.42 ± 0.14, p = 0.31, respectively). There were no differences in cDI in samples derived from vein draining the nodules and peripheral vein (0.35 ± 0.19 vs. 0.39 ± 0.18, p = 0.43). Patients with T1 tumors (<2 cm) were characterized by lower cDI than patients with tumors exceeding 2 cm (0.42 ± 0.13 vs 0.50 ± 0.14, p = 0.02, respectively). There was a weak inverse correlation between cDI and age (r = -0.3). Patients older than 45 years were characterized by lower cDI than younger patients (0.39 ± 0.15 vs 0.47 ± 0.14, p = 0.03). Integrity of plasma circulating cell-free DNA is associated with patient's age, gender and tumor size, but has limited utility as a biomarker differentiating between benign and malignant thyroid nodules with indeterminate cytology.
Thyroid Cancer Thursday Poster Clinical
A low iodine diet (LID) limiting iodine content to <50 ug daily has been recommended as a method of preparation for radioactive iodine (RAI) therapy in patients with differentiated thyroid cancer (DTC). The 24h urinary iodine excretion (UIE) is routinely utilized to confirm an iodine-deplete status. There are no data on the optimal UIE cutoff associated with beneficial progression free survival (PFS). Seventy-one patients with intermediate- and high-risk DTC, who underwent total-thyroidectomy ± central/lateral lymph node dissection and RAI therapy were enrolled in this study. All patients were recommended to adhere to two weeks of LID and underwent 24h urine collection before RAI therapy. UIE was categorized as <50 ug/24h, 50-99 ug/24h, 100-250 ug/24h and >250 ug/24h. Kaplan-Meier analyses were performed to compare PFS between the groups. A Cox proportional hazards regression model was performed to study the contribution of age, tumor size, presence of metastases on PFS. The study group was characterized by a median age at diagnosis of 42 [IQR 32.5, 54.5] years, tumor size 2.8 [IQR 1.8-4.5] cm, presence of central neck lymph node metastases in 64.8% (46/71), lateral neck in 33.3% (24/71) and distant metastases in 24% (17/71) of patients. Patients were treated with 1 to 5 RAI dosages with median cumulative activity of 150 [IQR 104-325] mCi. During the follow-up of 45 [IQR 17.5-78] months, 22.5% (17/71) of patients had disease progression. While there was no difference in PFS between the patients with UIE <50 ug/24h, 50-99 ug/24h, and 100-250 ug/24h, patients with UIE >250 ug/24 were characterized by higher risk of progression (HR 22.5, CI 3-170.9, p = 0.03) and shorter time to progression (HR 11.7, CI 2.0-67.4, p = 0.01). However, a multivariate model revealed that only tumor size was a significant factor affecting PFS (HR1.9 1.03-3.7, p = 0.03), while UIE was of borderline significance (p = 0.05). A UIE exceeding 250 ug/24h is associated with a higher likelihood of progression in intermediate and high-risk thyroid cancer patients treated with RAI. These data suggest that a simplified, rather than stringent LID might be sufficient for appropriate preparation for RAI.
Thyroid Cancer Thursday Poster Clinical
Papillary Thyroid Cancer (PTC) measuring ≤1 cm is known as Papillary Thyroid Microcarcinoma (PTMC). This definition does not depend on the presence or absence of high risk features such as lymph node metastasis and/or distant metastasis. Although apparently small thyroid carcinomas frequently are present in otherwise healthy adult people, most of them are considered harmless to their hosts. Active surveillance (AS) of low risk PTMC was adopted by the American Thyroid Association guidelines since 2015. However, in our center all diagnosed PTMC underwent surgery. Observational, cross-sectional, retrospective study of 867 patients that underwent total thyroidectomy between 2012 and 2017, in CEDIMAT, Dominican Republic. From those, 205 (23.4%) were diagnosed as Differentiated Thyroid Cancer (DTC), of which 82 (40%) were confirmed as PTMC. For studying purposes this group was subclassified in ≥5 mm and <5 mms. From the 82 PTMC, 68 (83%) presented ≥5 mm and 14 (17%) < 5 mms. Metastasis was reported in 5 patients (6.09%) with >5mm. PTMC diagnosis was incidental in 4 patients operated from Primary Hyperparathyroidism (PHPT), 3 of them (80%) presenting adenomas and 1 (20%) parathyroid carcinoma. Almost half of our DTC cases were PTMC of which only 6% were of high risk. Active surveillance of PTMC is not a common practice in Dominican Republic, sociocultural factors may be related to this behavior. Would active surveillance in our context translate into delayed surgical intervention? Are there genetic factors that increase the incidence of PTMC?
Thyroid Cancer Thursday Poster Clinical
Genetic testing for mutations in the RET gene, which cause the Multiple Endocrine Neoplasia Type 2 (NEM2) syndrome, has become crucial in the management of patients with medullary thyroid carcinoma (MTC). With rare exceptions, mutations in the RET gene occur in heterozygosis in an autosomal dominant inheritance, so that the offspring of a MEN2 patient can present 2 genotypes (with corresponding phenotype): wild/wild (not affected) and wild/mutated (affected). Double germline mutations in different codons of the RET gene in the same patient have been described, but mosaicism has never been reported. We report the case of a patient who died at age 41 years from locally advanced MTC and whose mother had also died from MTC. Due to MEN2A hypothesis, her siblings went through genetic RET investigation. We surprisingly found that they had inherited three different genotypes: homozygous wild type, heterozygous p.C634G mutation or heterozygous p.C634R mutation.Ten out of 11 proband's siblings and her father had the RET gene analyzed in blood samples. Three had wild-type RET gene, 4 had a heterozygous mutation in codon 634 – p.Cys634Gly (c.1900T>G) - and 2 had a different heterozygous RET mutation in the same codon- p.Cy634Arg (c.1900 T>C). Her older brother was deceased from gastric cancer. Their parents were first-grade cousins, but the father was 80-years-old at the time of the evaluation and had no RETmutation. As the patient's mother was deceased many years before, the mutated alleles, which were less frequent, could not be identified in paraffin-embedded thyroid tissue through Sanger sequencing. Exome sequencing succeeded in detecting the three nucleotides in the same position. Therefore, we hypothesized that a germline mutation followed by early somatic mutation during embryogenesis leading to mosaicism in the proband's mother's RET gene might have caused this rare occurrence. We describe for the first time the occurrence of a mosaicism affecting the RET gene in a MEN2A family. This case also reinforces that, when genotype and phenotype do not match, one should consider the possibility of mutations or diverse inheritance patterns that could have been overlooked through direct sequencing.
Thyroid Cancer Thursday Poster Clinical
Lateral lymph node metastasis (LNM) is not uncommon in papillary thyroid microcarcinoma (PTMC). Our present study aimed to determine the incidence and patterns of and to investigate the risk factors associated with lateral LNM in PTMC. From January 2014 to July 2015, a retrospective review was performed of 215 patients with PTMC who underwent total thyroidectomy and central lymph node dissection (CND) with lateral CND. The clinicopathologic results were reviewed, and the incidence and patterns of lateral LNM were analyzed. Among the aforementioned cases, 163 cases(75.814%) were PTMC with the presence of Lateral LNM. The most commonly metastatic site of Lateral LNM was level III (82.219%), followed by level IV (65.644%), level II (38.037%) and level V (10.429%). Then the most commonly model of distribution was two levels (41.104%) and single 1evel (33.742%) followed by three levels (20.245%) and four levels (4.908%). Lateral LNM without central LNM was observed in 14 (8.589%) cases of PTMC. A multivariate analysis revealed that the predictive factors for the presence of lateral LNM were central LNM (OR = 8.280, 95% CI, 3.430–19.988) and upper portion location of primary tumor (OR = 2.856, 95% CI, 1.339–6.089). The lateral LNM of PTMC was often involved in level III and level IV, most found in two levels and single 1evel models. Patients with central LNM or upper pole location should be paid more attention to the status of lateral lymph node.
Thyroid Cancer Thursday Poster Clinical
External beam radiotherapy (EBRT) is an important adjunct to surgery and radioactive iodine (RAI) in the treatment in locally advanced differentiated carcinoma of thyroid (LATC). Second primary tumour (SPT), particularly those developed inside radiation portal, represents an uncommon yet dreaded long-term complication that significantly impacts cancer survivorship. For LATC, epidemiology for in-field SPT after adjuvant EBRT is uncertain. We have conducted a retrospective cohort study, including 60 consecutive patients who received adjvant EBRT for locally advanced, surgically resected thyroid cancer from 2005 to 2007 in a tertiary oncology center in Hong Kong. All patients received total thyroidectomy, central and lateral compartment lymph node dissection as indicated, followed by adjuvant radioactive iodine. Adjuvant EBRT was delivered mostly with intensity-modulated radiotherapy (IMRT) technique at a dose from 60-66Gy to planning target volume covering thyroid bed and bilateral cervical lymph nodes. Median follow up was 10.89 years. We observed no SPT within radiation field and 4 SPTs out of radiation field.
We compared the incidence of SPTs with a cohort of 759 patients who received definitive EBRT with or without chemotherapy for nasopharyngeal carcinoma (NPC). Between two groups, the median age was similar (p = 0.331, mann-whitney U test), smoking was more prevalent for patients with NPC (OR 2.54, Chi-square test, p = 0.004) and median follow up was longer in LATC group (10.89 years vs 6.40 years). We noted a significantly lower risk of in-field SPT for LATC patients (0 in 1000 person-years vs 4.6 in 1000 person-years, p = 0.013, log rank test), while risk of out-field SPT is similar (6.18 in 1000 person-years for LATC vs 6.07 in 1000 person-years in NPC, p = 0.0612, log rank test). There is still a trend for lower risk of SPT (HR 0.34, 95% confidence interval 0.103-1.133) for patients with LATC after adjustment for smoking in multivariate analysis, though the statistical significance was marginal. This study shows that the risk of in-field SPT for patients receiving adjuvant EBRT for LATC is lower than those receiving EBRT for definitive treatment of NPC. Further study with larger cohort is warranted.
Thyroid Cancer Thursday Poster Clinical
Current guidelines suggest that metastatic disease from papillary thyroid microcarcinoma (PTMC) is rare. Active surveillance has been recommended for these patients as an alternative to immediate surgery. Periodic ultrasonography (US) is used to identify unfavorable features such as lymphadenopathy, extrathyroidal invasion and location adjacent to the trachea, at which point surgery is recommended. However, it is well documented that cervical US has variable accuracy depending on the ultrasonographer's experience. Inability to identify unfavorable features on US can impact the management of these patients. This study aims to analyze the reliability of preoperative radiology and surgeon-performed US (SUS) in identifying nodal disease in patients with PTMC who underwent thyroidectomy. Retrospective chart review of 249 consecutive patients with PTMC (≤1cm) who underwent thyroidectomy at a single tertiary referral institution over a period of 10 years was performed. Clinical information and preoperative SUS and radiology performed US were analyzed and compared with operative and pathology findingsOf the 249 patients with PTMC, 38 (15%) had lymph node metastasis on final pathology. Thirty –five (14%) had central and 6 (2%) had lateral node metastasis. Ninety-seven (39%) patients were found to have multifocal PTMC and 7 (3%) had extrathyroidal extension. The classic subtype was predominant in 182 (73%) and the follicular variant in 65 (26%) patients. Of the 38 patients with loco-regional metastasis, preoperative SUS visualized 18 (47%) of the central and 6/6 (100%) of the lateral neck disease, whereas radiology performed US identified none of the central neck lymphadenopathy and only 1/6 (17%) lateral metastasis. This study suggests that nodal metastasis from PTMC is not as rare as previously believed and is often not recognized on preoperative US. Although nodal metastasis may not affect patient survival, active surveillance and determination of patients who can be treated non-operatively may be compromised by unreliable US findings, particularly when performed by non-dedicated radiologists. We suggest caution when recommending observation for patients with PTMC if a specialized ultrasonographer is unavailable.
Thyroid Cancer Thursday Poster Case Report
Primary hyperparathyroidism with concomitant occurrence of nonmedullary thyroid carcinoma is rare, occurring less than 4%. Concurrence of papillary thyroid carcinoma and parathyroid adenoma is extremely rare. To our knowledge, this is the first described case of Hobnail variant papillary thyroid carcinoma (HVPTC) and intrathyroidal parathyroid adenoma (IPTA) within same thyroid lobe. Herein, we report a case of a 61-year-old woman presented to our endocrine clinic with generalized ache, bone pain and polyuria for few months. This was associated with right neck swelling. She underwent fine needle aspiration (FNA) followed by right lobectomy. Further radiological investigation found 4.6 cm complex nodule within right thyroid lobe and Sestamibi scan was suggestive of parathyroid adenoma and cold nodule in the right thyroid lobe. Laboratory findings revealed hypercalcemia and hyperparathyroidism. FNA revealed atypical follicular lesion of undetermined significance (FLUS). Right thyroid lobectomy was performed, which resulted in normalization of intraoperative rapid parathyroid hormone levels. Final pathology demonstrated 2.0 cm HVPTC and 2.0 cm IPTA with supportive immunohistochemical stains in addition, BRAF V600 mutation was positive within the HVPTC. To our knowledge, this is the first reported case of concurrence of HPTC and IPA. This report is a reminder that the presence of parathyroid adenoma should not exclude the diagnosis of thyroid carcinoma; therefore, careful thyroid evaluation should be considered for all patients with primary hyperparathyroidism to prevent missing concurrent thyroid cancers. Furthermore, describing the cytomorphologic features to distinguish thyroid from parathyroid cells on FNA cytology samples and the utilization of ancillary study of immunohistochemical stains will be discussed.
Thyroid Cancer Thursday Poster Case Report
Anaplastic thyroid carcinoma (ATC) arises de novo or through a process of de-differentiation of a pre-existing well-differentiated thyroid carcinoma. Such transformation has been most commonly described to occur within the thyroid gland primary tumor. Here, we describe a case where ATC was found in the lateral neck lymph nodes without evidence of de-differentiation of the primary thyroid cancer.
A 58-year-old female with Hashimoto's thyroiditis presented with a one-year history of worsening subjective central neck fullness in the setting of clinical thyromegaly. Over 4 months, consecutive ultrasounds demonstrated a stable heterogenous gland with no discrete nodules; however, on ultrasound just prior to referral to endocrine surgery, new pathologic right lateral neck lymphadenopathy was noted. Ultrasound guided fine needle aspiration of the right thyroid and a right lateral neck lymph node were consistent with papillary thyroid carcinoma (PTC). The patient underwent a total thyroidectomy with bilateral central and right modified radical neck dissection. Pathology demonstrated a right lobe 3.1cm T3 PTC, Warthin-like variant with peripheral tall cell features. Margins were uninvolved, and no lymphovascular invasion was present. All level VI lymph nodes were benign; however, 2/35 right lateral neck lymph nodes demonstrated ATC. The patient was further treated with 100mCi radioactive iodine, external beam radiation totaling 66cGy, and 5 weeks of cisplatin therapy. She has been in remission for 30 months.
In this case, the primary cancer was a Warthin-like variant of PTC, which is rare, and typically has an excellent prognosis with metastases uncommon. ATC is a highly aggressive cancer with a median survival of approximately six months and a disease-specific mortality nearing 100%. Here, ATC was found within lateral neck lymph nodes without evidence of de-differentiation or ATC within the primary tumor. This is uncommon with few similar cases reported in the literature.
Having ATC isolated to lymph nodes and not within the thyroid increased the resectability of the anaplastic disease in this patient. This, combined with adjuvant chemoradiation, resulted in prolonged survival.
Thyroid Cancer Thursday Poster Case Report
A nonrecurrent laryngeal nerve (NLN) is a rare entity encountered in less than 1% of the population. Given the unique embryology of NLNs, patterns of lymphatic spread may vary in these patients. Surgeons should be aware of these variations to prevent iatrogenic injury to the nerve as well as for oncologic clearance of disease. A 54-year-old female presented with an incidentally noted right lower cervical cystic lesion, found on a thoracic spine MRI ordered for back pain. A CT and MRI of the neck were performed for further evaluation, revealing a 2cm cystic mass surrounded by clear fat planes lateral to the thyroid and posterior to the carotid artery. Ultrasound-guided biopsy revealed cells of thyroid origin. Formal ultrasound of the thyroid and neck was within the normal limits without any concerning cysts or nodules greater than 4mm or any pathologic lymphadenopathy in the central or lateral necks. The patient was taken to the operating room and found to have a NLN on the right side. There was a cystic mass noted within the right carotid sheath- posterior to the carotid and deep to the vagus nerve. The mass was carefully excised, preserving the vagus and nonrecurrent inferior laryngeal nerve, and sent for frozen pathological analysis. Frozen section pathology returned as papillary thyroid cancer in a cystic node. Total thyroidectomy and central compartment neck dissection were performed. Final pathology revealed 4 micro papillary thyroid carcinomas within the thyroid gland: 1mm and 5mm in the left lobe (classical type), 3mm and 2mm in the right lobe (infiltrative follicular variant). There were 4 metastatic nodes within the right cystic mass located within the carotid sheath but no positive metastatic nodes in the central compartment. We present an extremely unusual case of an isolated papillary thyroid carcinoma metastasis within the carotid sheath in a patient with a NLN. To our knowledge, such a case has not been reported in the literature. We suspect that the unusual lymphatic spread may be associated with the NLN. Surgeons should be aware of the potential for highly unusual metastatic patterns in papillary thyroid cancer, particularly in patients with a NLN.
Thyroid Cancer Thursday Poster Case Report
Mucoepidermoid carcinoma (MEC) of the thyroid gland is a rare entity first described in 1977 by Rhatigan et al. Since then, two distinct subtypes have been identified. The first displays invasive tumor nests with squamous and glandular differentiation, often associated with conventional papillary thyroid carcinoma (PTC). The second, termed sclerosing mucoepidermoid carcinoma with eosinophilia (SMECE), occurs in a background of severe lymphocytic thyroiditis and shows tumor cells in a dense fibrocollagenous stroma with abundant eosinophils. We present two cases to show the distinct histologic and molecular features of these lesions. Case 1: 74 y.o. F presented with a lateral neck mass and a thyroid nodule. The surgically resected thyroid revealed areas of papillary thyroid carcinoma, tall cell variant, with adjacent nests of atypical cells with mucin. The neck mass showed metastatic mucoepidermoid carcinoma, similar in appearance to the mucoepidermoid component in the thyroid, along with poorly-differentiated areas. Gene sequencing of the neck mass revealed mutations in BRAF (V600E), PIK3CA, and TP53. The patient died within months with multiple lung and liver metastases. Case 2: 60 y.o. F presented with “goiter.” She underwent thyroidectomy and a diagnosis of Hashimoto thyroiditis was made. 20 years later she developed “recurrent goiter.” Excised tissue showed a tumor diagnosed as SMECE. Review showed that the tumor had been present in the original slides. MEC of the thyroid gland is a rare entity with uncertain origin. Previous authors have suggested SMECE may originate from ultimobranchial rests. The lateral location of SMECE in the thyroid and the association of severe lymphocytic thyroiditis with hyperplasia of the ultimobranchial remnants support this idea. Molecular analysis has shown no signatures of follicular, C cell or salivary type epithelium present in SMECE. The histologic origin of conventional MEC in the thyroid gland is also unclear. However, we suggest the association of MEC with conventional forms of thyroid carcinoma and the lack of background thyroiditis support transdifferentiation from existing PTC. In our case, this is further supported by the BRAF V600E mutation in the metastatic MEC.
Thyroid Cancer Thursday Poster Case Report
NGS increasingly allows tumor profiling for targeted therapies in recurrent or metastatic disease. Here we present a case report of sporadic PDTC arising within a longstanding benign multinodular goiter.71 year old female presented to ED with enlarging thyroid mass, neck pain, weight loss and worsening dysphagia. FNA showed malignant cells strongly positive for PAX-8 and TTF-1. A palpable right neck mass corresponded with CT findings of IJV thrombus. Flexible laryngoscopy confirmed right vocal cord paralysis. MRI confirmed invasion into the internal jugular vein and tracheal narrowing, and PET/CT revealed possible pulmonary metastases as well as a sternal bone metastasis. Therefore she was scheduled for total thyroidectomy and bilateral neck dissection.
Tumor pathology was consistent with poorly differentiated thyroid carcinoma with extensive LVI and intravascular tumor thrombi, however 112 lymph nodes were negative for carcinoma. She subsequently underwent RAI 250 mCi, followed by CyberKnife treatments to the sternum; local recurrence at the cricothyroid joint, with extension into the subglottic airway required tracheostomy and EBRT. Next generation sequencing found TP53, p.R248q, a missense variant, which leads to loss of tumor suppressor activity. TP53 mutations are found in 14% of malignant thyroid tumors, more often in poorly differentiated tumors. This particular variant has been previously reported in other cancer types but not in thyroid cancer. There are currently no FDA approved targeted therapies for patients with this mutation.
TP53 mutations with derangement of a fundamental apoptotic/cell senescence pathways are found in 50% of human cancers, however there are no targeted therapies approved as monotherapy. Strategies to reverse the effects of mutated p53 within the tumor microenvironment include viral transfection to restore wild-type p53, use of mutated p53 as antigen in vaccine trials, and regulation of inhibitor molecules MDM2/MDM4. Even more promising has been combined approaches with immunotherapy, possibly with tumor debulking and/or palliative radiotherapy to stimulate the primed host immune system. NGS in advanced PDTC can help guide treatment strategies.
Thyroid Cancer Thursday Poster Case Report
A 68-year-old man presented with painless swelling and a hematoma on his right ring finger. Symptoms started one month ago and there was no associated trauma. Radiography showed an osteolytic lesion involving the terminal phalanx. A biopsy revealed a malignant tumor with infiltration of the epidermis. The immunohistochemistry revealed a strong expression of thyroglobulin, corresponding to a metastasis of a thyroid carcinoma. Lab tests found a thyroglobulin >2500 μg/l. Sonography of the right lobe (37 ml) showed an inhomogeneous, hypoechoic, borderline calcified nodule of 23 × 32 mm, but no further clear malignancy criteria were noted. The left lobe exhibited only small cystic lesions. A thyroid scan showed a cold nodule, and fine-needle aspiration revealed a follicular lesion. In addition, a chest CT revealed pathological lymph nodes in the mediastinum (dorsal to the superior vena cava) measuring up to 56 mm and small intrapulmonary secondary lesions. Therapeutically, the amputation of the right terminal phalanx of the fourth finger was performed first. 3 weeks later, the patient underwent a combined procedure: thyroidectomy with neck dissection and thoracoscopic metastasis removal via VATS. A rapid section revealed the diagnosis of a multifocal solid papillary thyroid carcinoma with a transition into a poorly differentiated form pT3 (m), N1(12/24), L1, V0, RX, M1. Six weeks postoperatively, the patient underwent radioiodine treatment with 3,7 GBq J131. Under thyrogen stimulation, the whole body scan revealed uptake on the neck, in the mediastinum on both sides and in the left scapula. Further imaging with 18F-FDG-PET/CT showed lytic secondary blastomatous lesions along L2-L3, showing no iodine uptake. Thus a palliative radiotherapy was performed by single shot therapy with a total dose of 8 Gy. The patient was adjusted for thyroid hormone substitution in TSH-suppressive doses and Denosumab. Thyroglobulin decreased to 500 μg/l. A re-evaluation is planned for the coming weeks.
Conclusively, this case shows that patients with thyroid cancer may remain asymptomatic for a long time, underlining the question whether sonographic and laboratory thyroid screenings should be included in screening programs.
Thyroid Cancer Thursday Poster Case Report
Autonomous thyroid nodules in children are generally benign. Fine-needle aspiration is rarely required, and treatment consists of surgical resection or antithyroid drug as a bridge to radioiodine ablation. Hyperfunctioning thyroid carcinoma is a rare cause of thyrotoxicosis. We report the case of a 15-year-old with thyrotoxicosis caused by a hyperfunctioning, metastatic, differentiated thyroid carcinoma harboring a somatic mutation in the TSH receptor. A 15-year-old girl presented with a neck mass and right cervical lymphadenopathy. Laboratories showed thyrotoxicosis with suppressed TSH <0.005 mIU/L (0.7-5.7) and high free T4 2.96 ng/dL (0.8-1.9) and total T3 261 ng/dL (80-260). TPO antibodies were elevated, but Tg Ab, TSI, and TBII were negative. Ultrasound demonstrated bilateral thyroid nodules and two abnormal right sided lymph nodes (2.6 cm, 3.1 cm) that were round and showed loss of the normal hilum, intranodal necrosis and calcifications. FNA cytology yielded atypical cells of uncertain significance in a 1.8 cm right lobe nodule and both lymph nodes. I-123 SPECT-CT revealed autonomy of the right nodules (24hr uptake 26%), negligible uptake in the left lobe, and abnormal uptake in the lymph nodes. Patient underwent right hemithyroidectomy and lateral neck dissection. Histology showed differentiated thyroid carcinoma throughout the right thyroid lobe and in the two lymph nodes with features of papillary, follicular and Hürthle cell carcinoma. Completion thyroidectomy was performed, and histology was benign. Mutational analysis of the tumor revealed an activating mutation of the TSHR gene (c.1358T>C, p.M453T) in 38% of cells. Due to tumor size, metastatic and functional nature, thyroid hormone withdrawal and dosimetry will be pursued to calculate I-131 therapeutic dose. Hyperfunctioning thyroid carcinoma in children is rare. While autonomous nodules are generally benign, careful evaluation with ultrasound and scintigraphy are necessary. Suspicious findings such as sonographically abnormal lymph nodes and radioiodine uptake outside the thyroid bed should prompt further evaluation for possible malignancy. Like many benign autonomous nodules, hyperfunctioning cancers may contain activating mutations in TSHR.
Thyroid Cancer Thursday Poster Case Report
Anaplastic thyroid carcinoma (ATC) is a rare malignancy of the thyroid with a high mortality rate. The most common sites of metastases related to ATC are: lungs, pleura, adrenal glands, liver, brain, heart, and intrathoracic, neck and retroperitoneal lymph nodes. Skin represents only 2.8 – 10.4% of all ATC metastases. A 66-years-old female patient was admitted to outpatient clinic due to skins lesions (figure 1). The symptoms began 6 moths prior to admission with intense pain at the level of the cervical spine associated with the presence of a rapidly growing nodulation at the level of the thyroid gland currently associated with dysphagia to solids. During the physical examination, multiple indurated nodular skin lesions in scalp were found, the biggest of approximately 3 centimeters of diameter, and clinical data of root compression in higher and lower limbs. A fine-needle aspiration biopsy reported anaplastic thyroid carcinoma. A PET-CT (figure 2) showed left thyroid tumor with metastatic disease of bone, lymph nodes, muscle, adrenal, pancreatic, pulmonary, splenic, cutaneous, cerebral, and renal. The vertebral metastases in C3 and L3 present intraspinal extension conditioning the narrow channel, and finally brain metastasis without data of associated hypertensive skull. ATC is still an extremely rare kind of thyroid carcinoma in which high mortality is related to its aggressive behavior. In this case, despite the lack of an early diagnose, the metastases were a poor prognosis predictor. Cutaneous metastases of anaplastic carcinoma of the thyroid are very rare, because this tumor has a rapid growth that leads to death, although it has a relatively high potential to develop metastases in other organs, usually lung and bone.
Thyroid Cancer Thursday Poster Case Report
Differentiated thyroid cancers causing malignant pleural effusions are rare. We present the case of a 57 year-old Caucasian woman with a history of follicular variant papillary thyroid carcinoma who presented with one week of shortness of breath and cough. She was found to have a large left pleural effusion on imaging. Thoracentesis was performed with pleural fluid cytology consistent with malignant papillary thyroid carcinoma. Thyroglobulin level in the pleural fluid 468 ng/ml while the serum thyroglobulin returned at 9.5 ng/ml (TSH 35 mIU/L). A subsequent pleural biopsy confirmed the diagnosis of PTC. Two years prior, patient had been diagnosed with unencapsulated follicular variant papillary thyroid carcinoma. She initially presented with a right neck mass, subsequently underwent fine needle aspiration biopsy with pathology revealing papillary thyroid carcinoma. She then underwent total thyroidectomy, central and right neck dissection. Surgical pathology revealed papillary thyroid carcinoma, follicular variant with lymph node involvement (13/31 involved with extranodal extension). Subsequently the patient received 78.9mCI of radioactive iodine ablation. Her post ablation whole body scan was negative for any distant metastatic disease. Her thyroglobulin level one year after her diagnosis was 0.7 ng/ml. She was then lost to follow up until one year later when she presented to our hospital as above. FDG PET scan demonstrated multiple tiny bilateral pulmonary nodules with FDG avid (SUV 5.7) pleural thickening on the left. A left sided pleural effusion was also noted to be faintly FDG avid. The patient required chest tube drainage and was started on lenvatinib for RAI-refractory PTC.
A review of the literature shows less than twenty cases of papillary thyroid cancer-related pleural effusions. Our case is also unusual in that the stimulated serum thyroglobulin level was not significantly elevated (9.5 ng/ml) and one year prior, a post RAI whole body scan was negative for metastatic disease to the lungs. The speed of recurrence is very unusual for most cases of papillary thyroid carcinoma. Although PTC rarely leads to death, a malignant pleural effusion unfortunately portends a poor prognosis and survival rate.NA
Thyroid Cancer Thursday Poster Case Report
Metastases to the thyroid gland are not commonly encountered in clinical practice. Literature review of postmortem examination studies suggests that as many as 2 - 24% of patients who die of non-thyroid malignancies have metastases to the thyroid gland. In autopsy series, the most common primary site with metastasis to the thyroid is the lung, whereas in clinical series the most common primary tumor with metastasis to the thyroid is renal cell carcinoma (RCC). Only 2% of reported metastatic cancers to the thyroid are sarcomas. We present the case of a 35 year old female with past medical history of right tibia osteosarcoma diagnosed in 2010. She received neoadjuvant chemotherapy with doxorubicin/cisplatin/methotrexate/ifosfamide followed by right extremity above the knee amputation in 2011.
On follow up in 2014, she was found to have an enlarged suspicious left thyroid mass for which she underwent left thyroidectomy. Pathology confirmed the diagnosis of metastatic osteosarcoma to the thyroid with a 6.0 cm lesion removed. Furthermore, in 2014 she was found to have several lung micronodules suspicious for metastases which showed slow progression in size during surveillance. In 2016 she underwent stereotactic body radiotherapy (48Gy in 4 fractions) to 3 lung nodules.
On follow up in January 2018, she was found to have a right thyroid lobe nodule (measuring 3.0 × 1.8 × 2.8 cm), left superior neck lesion (measuring 2.5 cm) and a posterior scalp mass (measuring 2.0 × 3.2 × 3.1 cm). She underwent surgical resection of these lesions, for all of which pathology report was positive for metastatic high-grade osteosarcoma.N/ASarcomas metastatic to the thyroid are very rare as the majority of thyroid metastases, as reported in clinical series, are caused by tumors of the kidneys (25%), lungs (22%), GI tract (13%), mammary glands (13%) and melanomas (4%).
This is the first reported case of osteosarcoma with metastasis recurring to the thyroid gland. Other sites of osteosarcoma metastases in this patient were lungs and scalp.
Thyroid Cancer Thursday Poster Case Report
Myasthenia gravis (MG) is a neuromuscular junction disease characterized by muscular weakness and fatigability caused by antibodies against the acetylcholine receptor (AChR). We present a rare case of paraneoplastic MG in the context of papillary thyroid carcinoma (PTC). A 59-year-old Filipino man presented to his family physician with progressive dysphagia in the spring of 2017. Neck ultrasound and fine needle aspiration biopsy of a right-sided thyroid nodule disclosed an underlying PTC. The patient underwent a two-stage total thyroidectomy in July and October 2017. Pathology reported a dominant right-sided 2.8 cm classical PTC with extrathyroidal extension. The patient's dysphagia worsened after surgery and he was eventually sent to the emergency room by his family physician with a suspicion of impending myasthenic crisis. In retrospect, the patient began experiencing intermittent droopy eyelids, diplopia worse in the evenings and progressive dysphagia since April 2017. The combination of clinical muscular fatigability and impaired neuromuscular transmission on repetitive nerve stimulation led to the diagnosis of MG in November 2017, five months after the onset of symptoms. Anti-AChR antibody levels are pending, and chest imaging showed no thymic enlargement. The patient was promptly treated with prednisone 30 mg daily and pyridostigmine 60 mg QID, with rapid improvement of his symptoms after one week of treatment. MG associated with thyroid carcinoma is rare but can be life-threatening if unrecognized. Undiagnosed MG can also pose a higher surgical risk for thyroid cancer patients. Awareness of this combination may help with early identification, prompt intervention, and timely prevention of myasthenic crisis.
Thyroid Cancer Thursday Poster Case Report
Ectopic bone formation (EBF) can occur in a wide variety of soft tissues. However, EBF developing in a thyroid cancer is quite rare. Over-expression of bone morphogenic proteins and a variety of bone growth factors, such as FGF, have been reported in thyroid cancers. These could foster the development of osseous tissues. We report a case of EBF in a papillary thyroid carcinoma (PTC) that also demonstrated extramedullary hematopoiesis (EMH). A 74 y male underwent resection of a PTC that was discovered incidentally while having a FDG-PET scan to monitor status of recurrent plasmacytomas. Histology revealed classical PTC that was multicentric with 3 of 7 lymph nodes positive for PTC (T2; N1a; M0 – Stage II AJCC 8th edition). In addition, he has metaplastic ossification within the tumor showing mature bone with osteoblasts and osteoclasts. Further, he had normal bone marrow elements adjacent to the bone within the tumor. A whole body scan after 100 mCi of 131-Iodine did not reveal any metastatic uptake. His serum thyroglobulin is currently <0.1 ng/ml. PTC often contains calcifications (up to 53%) and psammoma bodies. In several series from Asia, EBF has been reported in 16-23% of all PTC. EBF can also occur in benign nodular goiters. The impact of EBF on local recurrence and prognosis, however is not well defined. The co-occurrence of EBF and EMH has only been reported rarely in the medical literature. It has been suggested that EBF with EMH is more common in patients with hematologic malignancies, as in our patient. At this time, the most common proposed theory for these rare occurrences involves the role of bone morphogenetic proteins, VEGF, and fibroblast growth factors. This gentleman recently had a recurrences of his plasmacytoma but has no evidence of residual thyroid cancer. In older patients with EBF in a thyroid cancer, clinicians should be aware that occult lymphoid malignancies appear to be more common.
Thyroid Hormone Action Thursday Poster Basic
The anterior pituitary regulates the function of several glands including the thyroid gland. Pituitary secretion of thyroid-stimulating hormone (TSH) is subject to feedback inhibition by thyroid hormone (TH), a fundamental mechanism for maintaining thyroid hormone homeostasis. The THRBgene encoding TRb is expressed in the anterior pituitary and is mutated in the syndrome of resistance to thyroid hormone. However, the genome wide regulation of pituitary gene expression by TH and the role of TRb in this regulation is poorly defined. Hypothyroidism was produced in wild type and TRbKO male mice groups by administration of methimazole (MMI) in drinking water for 4 weeks. Hyperthyroid groups were additionally treated with T3 in the drinking water for the 4th week. Pituitaries were isolated for RNA-sequencing (RNA-seq) to identify genome-wide gene expression patterns. Expression changes for selected genes were confirmed by quantitative real time PCR (qRT-PCR). Epigenetic changes were investigated by determining histone modifications (chromatin-immunoprecipitation-sequencing) and open chromatin analysis (ATAC-seq). Transcriptome analysis revealed that known TH responsive genes such as Tshb and Cga were down regulated whereas Hr and Gh were upregulated in hyperthyroid versus hypothyroid groups. Several hundred genes displayed statistically different expression between these two treated groups. However, in TRbKO mice, expression of most of these genes was impaired. Specific histone acetylation marks were dynamically regulated in enhancer regions of many genes. We report a comprehensive analysis of pituitary responses to TH at the level of the transcriptome, histone modification and chromatin accessibility status. A majority of TH response genes depend to some extent upon TRb suggesting a major role for TRb in pituitary regulation. Chromatin modification in enhancer regions of target genes is associated with TH-dependent regulation in the pituitary.
Thyroid Hormone Action Thursday Poster Basic
We have recently reported using TRH knockout mice that TRH acts as a strong stimulant of NR4A1 (Nurr 77) in pituitary thyrotrophs, which then stimulates expression of the TSH gene (PLoS One. 2012;7(7):e40437.). Mechanisms underlying negative regulation of the TSHb gene by thyroid hormones remains unclear. We therefore hypothesized that pituitary NR4A1 levels may be regulated by thyroid hormone and affect expression of the TSHβ gene.
We examined Ithe effects of the thyroid status on pituitary NR4A1 mRNA levels in vivo.
We investigated whether thyroid hormone stimulated the promoter activity of the NR4A1 gene in vitro using CV-1 cells.
To identify the region responsible for the T3-mediated suppression of the promoter activity of the NR4A1 gene, we generated a series of deletion mutants of the NR4A1 promoter and examined the effects of T3.
We determined whether TRβ binds to the region responsible for the T3-induced suppression of the promoter activity of the NR4A1 gene using EMSA and Chip assay. We demonstrated here the significant negative regulation of the pituitary NR4A1 by thyroid hormone in vivo and in vitro. Pituitary NR4A1 mRNA levels were decreased to 51 ± 9% of control levels 24 hr after a single peritoneal injection of T4 in mice. An in vitro study revealed that the NR4A1 promoter activity was increased by the overexpression of TRβs, and an addition of T3 completely depressed its activity. Series of the deletion studies demonstrated the region -27 ∼ +152 bp of the gene to be responsible for these effects. An EMSA study showed no binding of TRβs on the gene, and a ChIP assay demonstrated the recruitment of both TRβs and NCoR into the region -147∼+148 bp in the absence of T3, whereas T3 induced their release. Furthermore, experiments with overexpression and knockdown of NCoR, and with mutant TRs further supported the involvement of NCoR in the TR-induced stimulation of the gene. In conclusion, these findings demonstrated that NR4A1 appeared to be a factor for negative regulation of the TSHb gene by thyroid hormone in the pituitary thyrotrophs.
Thyroid Hormone Action Thursday Poster Basic
It has been postulated that triiodothyronine (T3), a thyroid hormone, is involved in breast cancer (BC) progression, as T3 was shown to modulate the expression of various genes, including amphiregulin (AREG). AREG is an oncogene overexpressed in various types of cancers, and it is related to poor prognosis and tumorigenesis. The effect of interplay between T3 and AREG on BC cells remains largely unclear. The present study aimed to examine the modulatory effects of T3 on AREG expression, and the involvement of extra nuclear signaling pathways in MCF-7 human BC cell line. Cells were treated with 10 nM T3 for 1 h, in the presence or absence of the (i) phosphatidylinositol 3-kinase pathway inhibitor, LY294002; (ii) targeting ligand for integrin αvβ3 peptide, RGD; or (iii) MAP/ERK pathway inhibitor, PD98059. AREG mRNA expression and protein synthesis were analyzed by RT-qPCR and western blotting, respectively. T3 increased the expression of AREG in MCF-7 cells, and this effect was inhibited by all compounds tested. Western blotting analysis confirmed these results, indicating the dependency of AREG expression on the PI3K, MAP/ERK, and integrin pathways. These results demonstrate that activation of the PI3K, MAP/ERK, and integrin signaling pathways is necessary for the T3-mediated effects on AREG expression in MCF-7 cells, highlighting the non-genomic action of T3. In this study, we demonstrate that T3 increases AREG expression through extranuclear pathways. The data obtained present a great potential for application, since the identification of new signaling pathways and other mecanisms by which thyroid hormones act can lead to the development of specific drugs, to activate or block such pathways, promoting desirable effects and blocking undesirable ones.
Thyroid Hormone Metabolism & Regulation Thursday Poster Basic
Monocarboxylate transporter 8 (MCT8), is a membrane-spanning protein that specifically transports iodothyronines. MCT8 shares its 3D topology with other major facilitator superfamily members, whith two 6 TMH-bundles, an N-terminal bundle linked by an extended linker peptide to a C-terminal bundle. Each of its 6 TMH-domain surrounds the translocation pore, which could be depicted through the translocation process as extracellular opened, extracellular partly occluded and intracellular opened conformations. Several residues inside the pore have been identified to participate on the translocation process by alanine scanning and molecular docking simulations, nevertheless; this method does not describe the substrate diffusion in proteins, required to define the roles of specific amino acids at atomic level. In this work, we use microsecond molecular dynamics (MD) to describe the T4 and T3 interactions inside MCT8 substrate–translocation pore at different conformations, and to provide insight into MCT8 dynamics beyond the docking models. Extracellular opened, extracellular partly occluded and intracellular opened conformations MCT8 homology models as described by Protze et al. were embedded into an explicit POPC, hydrated and ionized by 0.15 M NaCl. Starting initial conformation of each T4, T3 and MCT8 complex were produced by docking. MD were conducted in AMBER18 package. Each MD included a minimization, heating and equilibration by 50 ns, then, 1 us production NPT MD simulation was conducted with periodic boundary conditions at 310 K and 1Bar. We characterized the interactions between iodothyronines and several residues of TMH 7 and TMH10 as example L492, G495, D498, F50, L512 and His415 and Lys418. As described by docking models, Arg445 and Asp498 interaction with T3 is observed in all MCT8 states. Also, Lys418 participate on T3 binding and attracting other charged sidechains at the pore. Other residues and interaction partners will be further described, as molecular simulations are currently underway. Molecular dynamics Simulations were conducted to describe T4 and T3 diffusion inside MCT8, revealing key interactions of the different conformations that guide these substrate through the pore
Thyroid Hormone Metabolism & Regulation Thursday Poster Basic
Hyperthyroidism remains as one of the endocrinology disorders that have a broad effect on the patient's body system. Recent evidence shows that hyperthyroidism could lead to impairment of insulin activity. This mini systematic review addresses the correlation between overt hyperthyroidism that could lead to insulin resistance state.
Literature searching through four databases, which are PubMed®, Cochrane Library®, PROQUEST®, and SCOPUS® was performed. Articles were appraised for validity, importance, and applicability. There were five studies met the criteria before the critical appraisal is conducted. Four of five studies showed a significant linear correlation between overt hyperthyroidism and insulin resistance. Two studies also showed that overt hyperthyroidism altered insulin sensitivity in the post-prandial state. Each of studies also studied any components which suggestively contributed to insulin resistance developing, i.e. glucagon and ghrelin hormone, glucose intolerance (as performed by OGTT). Insulin resistance is commonly developed in patients with overt hyperthyroidism, either in fasting or postprandial state. Pathogenesis-related to development of insulin resistance as a consequence of overt hyperthyroidism should be determined briefly as there are many pathways have their role contributed to this condition.
Thyroid Hormone Metabolism & Regulation Thursday Poster Clinical
The changes of thyroid hormone levels during pregnancy vary greatly among different racial and geographic groups. It is recommended to establish population-based reference range more representative of the local population being treated. Our aim was to establish the reference values for serum TSH, fT3 and fT4 during the first trimester of pregnancy in a healthy Canadian population. We conducted a cross-sectional study at the CIUSSSE-CHUS academic hospital in Sherbrooke, Quebec. We recruited a convenient sample of healthy pregnant women at their first antenatal visit, before 13 weeks of gestational age (determined by sonography). We excluded women with past/actual history of thyroid disease, past/actual use of interfering drugs (levothyroxine, anti-thyroid drugs, amiodarone), recent exposure to high dose iodine, past head and neck irradiation/surgery, twin pregnancy and features of hyperemesis gravidarum. Women with positive thyroid peroxidase antibody results were subsequently excluded. Reference ranges were established as the 2.5thand 97.5thpercentiles. We recruited 121 women aged between 19 and 38 years (mean of 28). Gestational age ranged between 7.4 and 13 weeks (median 12.3). Reference ranges during the first trimester in our population were: 0.17-3.16 mUI/L for TSH, 4.01-6.29 pmol/L for fT3 and 11.40-19.12 pmol/L for fT4. We found no statistical difference in TSH values between age subgroups (<30 y.o vs >30 y.o), even though our study was not powered for this analysis. We observed a trend towards lower TSH values at the end of the first trimester (12-13 vs 7.4-12 weeks subgroups), seemingly reflective of the peaking hCG values; however, the number of patients in those subgroups were too small to draw firm conclusions. We established reference values for TSH, fT3 and fT4 during the first trimester of pregnancy in our center, in a well-characterized population, as recommended by various medical associations. The results of the TSH values are slightly under the normal non-pregnant reference range in our center (0.35-3.50 mUI/L); this is consistent with the latest 2017 ATA guidelines that suggest a reduction in the non-pregnant TSH upper reference limit of ∼0.5 mUI/L.
Thyroid Nodules & Goiter Thursday Poster Case Report
Many features of thyroid nodules increase the risk of malignancy. Focal FDG-PET uptake in a thyroid nodule confers a risk of cancer of 30% to 50%, depending on the series. The risk is also significantly increased with higher SUV uptake.
We here report two cases of highly suspicious thyroid nodules, with significant FDG-PET focal thyroid uptake with final benign histology.
Case 1: A 71 yo man, without significant medical history and no exposure to radiation, was referred for a left thyroid nodule, measuring 30x30x40 mm, solid and hypoechoic on ultrasound (US). His TSH was normal at 2,41 mUI/L. A FDG-PET done to investigate pulmonary nodules showed a very high focal uptake of the thyroid nodule, with a SUV of 112. The pulmonary nodules were metabolically inactive. The fine needle aspiration (FNA) showed a follicular neoplasm. His McGill thyroid nodule score (MTNS) was 17 pts, confering a risk of malignancy of 93%. On the final pathology report after total thyroidectomy, the left nodule was a benign follicular adenoma, with no capsular or vascular invasion. An inframillimetric papillary carcinoma was found in the right lobe, away from the surgical margins.
Case 2: A 87 yo man treated for renal cancer, was found with a pulmonary nodule on control imaging. On FDG-PET, the pulmonary nodule was mildly active with a SUV of 2,5, and a highly metabolically active right thyroid nodule was found with a SUV of 53. There was no renal uptake. His TSH was normal at 2,08 mUI/L. On US, a multinodular goiter was seen, and the highly active nodule was solid, hypoechoic and measured 21x18x34mm. The FNA showed a follicular neoplasm. The MTNS was 16 pts, with a risk of malignancy of 93%. He had a total thyroidectomy and the final pathology reported a multinodular hyperplasia. There was no sign of vascular or capsular invasion. These two patients had thyroid nodules with many suspicious features: male sex, age, size, hypoechogenicity on US, and very high focal FDG-PET uptake. There was no molecular testing done because of their limited access in our clinical setting. They both underwent surgery, and fortunately, had benign lesions. Even in highly active suspicious thyroid nodules, malignancy is not necessarly the explanation.
Thyroid Hormone Metabolism & Regulation Thursday Poster Clinical
Whether recombinant human growth hormone (rhGH) therapy in adults alters thyroid function is controversial because results of previous reports were inconsistent. Here, we show a representative case and results of our retrospective study. A 53 year-old female with primary hypothyroidism was suffered from fatigue. We diagnosed as isolated GH deficiency: serum IGF-1 level was 30 ng/mL and peak serum GH levels were 7.45 ng/mL in GHRP-2 stimulating test and 0.25 ng/mL in arginine test. 0.25 mg/day of rhGH therapy improved her symptoms and increased IGF-1 to 116 ng/mL. Interestingly, her serum fT3 level increased from 2.53 to 3.13 pg/mL, fT4 decreased from 1.940 to 1.880 ng/dL, and TSH decreased 0.823 to 0.280 μIU/mL. In addition, her serum levels of total-cholesterol, LDL-cholesterol, and creatinine were decreased (254 to 219, 161 to 126, and 0.82 to 0.69, respectively). Then, we performed a retrospective study focused on 20 consecutive patients with severe adult GH deficiency who received rhGH therapy in our institution. After 3 months of rhGH therapy, median serum fT3 level increased from 2.38 to 2.78 pg/mL (p < 0.001), fT4 decreased from 1.115 to 1.065 ng/dL (p = 0.081), and TSH decreased from 0.834 to 0.624 μIU/mL (p = 0.029). Considering an increase in serum fT3 level and decreases in serum levels of cholesterols and creatinine, rhGH therapy might augment thyroid hormone action. We hypothesize that rhGH therapy is more effective for patients with adult GH deficiency who present low serum fT3 level. We verified that rhGH therapy increased serum fT3 level and decreased fT4 and TSH in the patients with severe adult GH deficiency. Data on thyroid function might be useful in the management of adult GH deficiency.
Thyroid Hormone Metabolism & Regulation Thursday Poster Case Report
Management of hypothyroidism may be challenging due to malabsorption or non-adherence. Replacement of enteral dose is 1.6-1.8mcg/kg with intestinal absorption of 70-80%. Some patients require higher doses of levothyroxine (LT4 > 1.9mcg/kg). Various gastrointestinal disorders that lead to malabsorption or loss of intestinal secretions may result in higher requirement. We present a case of refractory hypothyroidism despite large doses of oral levothyroxine due to malabsorption of oral LT4. A 60-year old, 130 kg female presented with fatigue and intermittent diarrhea, with TSH 206 uIU/ml (0.45-5.33 uIU/ml) and FT4 < 0.25 ng/dl (0.61-1.44 ng/dl). She had had total thyroidectomy and radioiodine treatment at outside institution for papillary thyroid microcarcinoma and had normal thyroid function tests on standard doses of LT4 until she underwent cholecystectomy. She reported intermittent diarrhea and abnormal thyroid function tests (TSH 206 uIU/ml) following cholecystectomy. Her doses were increased gradually and she was taking LT4 1200 mcg and lliothyronine 25mcg orally daily on an empty stomach without missed doses when she presented. Extensive gastrointestinal evaluation failed to reveal any evidence of malabsorption. She was hospitalized multiple times for severe symptomatic hypothyroidism. LT4 absorption tests revealed poor enteral absorption. Subcutaneously administered LT4 did not result in a rise in FT4 or TT4. She responded to twice weekly intravenous 300mcg LT4 and daily 600 mcg LT4 soft gel capsules, with TSH improving to 18uIU/ml and FT4 0.68ng/dl. Hypothyroidism in our patient was refractory to large doses of oral LT4 and responded to intravenous but not subcutaneous LT4. Studies indicate possible hypotheses including intestinal malabsorption of LT4 due reduction in bile salts after cholecystectomy, type 3-deiodinase overexpression and altered intestinal microbiota. About 10-20% of hypothyroid patients require greater than weight based amounts of LT4 for unknown reasons. We recommend early initiation of parenteral LT4 therapy to reduce morbidity. More studies are needed to evaluate mechanism of enteral LT4 malabsorption in such refractory cases.
Thyroid Imaging Thursday Poster Basic
Our objective was to assess to comparison of clinicopathologic features of thyroid nodules according to the thickness of hypoechoic rim on ultrasonographyFrom January 2016 to December 2016, 235 thyroid nodules were having hypoechoic rim on ultrasonography were included. All patients underwent preoperative thyroid ultrasonography and thyroid surgery. The thickness of hypoehoic rim of each thyroid nodule were retrospectively reviewed according to the clinicopatholgic features. Thick group was defined as a thickness of hypoechoic rim of ≥1mm. Of the 235 thyroid nodules (mean size, 2.01 ± 1.6cm; mean thickness, 0.86mm), 81 were thick group and 154 were thin group. A statistically significant difference was found between thick and thin group regarding the malignant nodules (p = .0.04) and extrathyroidal tumor extension (p = .0.04), while no significant differences were observed in the tumor size, age, sex, op method, status of lymph node metastasis, the number of metastatic lymph node, or lymphovascular tumor extension of the lesion (p > 0.05) The thickness of hypoechoic rim of thyroid nodules on preoperative ultrasonography were helpful for predicting malignancy and extrathyroidal tumor extension.
Thyroid Imaging Thursday Poster Translational
While hypocalcemia remains the most common complication associated with thyroid surgery, technological developments have focused on lowering morbidity associated with bleeding, vocal cord palsy and scar burden. Optical coherence tomography (OCT) is a portable imaging modality that uses near-infrared light interferometry to reproduce in real-time the microarchitecture of tissues. Given its properties, several groups have proposed that OCT could serve as an adjunct tool to differentiate neck tissues and identify parathyroid glands during thyroid surgery. In fact, preliminary studies have demonstrated that OCT imaging characteristics correlate closely with histopathologic findings for each tissue type. Previously, our group described the feasibility of obtaining high-quality, 3D OCT imaging of tissue in an in vitro and in vivo setting. The objective of this study is to determine the sensitivity, specificity and reliability of OCT in differentiating parathyroid glands, thyroid, lymph nodes and fat during thyroid surgery.
Thirty-two patients undergoing thyroidectomy, parathyroidectomy and/or neck dissection were prospectively recruited. Surgical specimens of parathyroid, thyroid, lymph nodes and fat were imaged with a commercial grade OCT system prior to histopathological evaluation and diagnosis. Two blinded reviewers examined all images and independently classified them by tissue type based on OCT characteristics. The same reviewers were asked to review the same images 4 weeks later to calculate inter-rater and test-retest reliability with Cohen's kappa. Fourteen pathology-proven specimens of parathyroid were imaged, 27 of thyroid, 26 of lymph node, and 19 of fat. The sensitivity and specificity of OCT in identifying each of these tissue types were respectively: 92.9% and 100%, 96.3% and 98.3%, 100% and 98.5%, and 92.9% and 98.3%. Inter-rater and test-retest reliability were 0.952 and 0.968. This proof-of-concept study suggests that OCT is an innovative imaging modality with excellent sentivity, specifity, inter-rater and intra-rater reliability. It has the potential to assist surgeons in parathyroid identification and preservation during thyroid surgery and central neck dissections.
Thyroid Imaging Thursday Poster Clinical
Both radioiodine FDG PET/CT and WBS scans play an important role in the management of higher-risk differentiated thyroid cancer (DTC). For several years our institution has offered a combined protocol in which both of these scans are performed sequentially. Following stimulation with either thyroid hormone withdrawal or the use of recombinant human Thyroid Stimulating Hormone, the patient undergoes a PET/CT followed by a dedicated PET/CT of the neck. Following this scan, the patient is administered radioiodine (RAI), and returns 24-48 hours later to receive a WBS. Baseline and stimulated thyroglobulin (Tg) levels are also obtained. Thirty randomly selected studies were analyzed. Collected data included demographic information, PET/CT and WBS results, Tg levels, additional radiographic data, and clinical information. The patients were predominantly female (22/30), aged from 20 to 78 years (mean 49.4). All had DTC, with 27 diagnosed with papillary thyroid cancer, two with follicular thyroid cancer, and one with components of both. Most were TNM stage 1 (20/30) at initial diagnosis, five stage 2, one stage 3, and four stage 4. The primary indication for the combination of studies was aggressive features; time from diagnosis to scan ranged from 0.3 to 18 years (mean 6.9). All but two had been treated with 131I.
Residual or recurrent disease was diagnosed in 11 patients. PET/CT proved sensitive, detecting all of these cases, but relatively nonspecific. WBS proved less sensitive, detecting only four of those with disease, although only three false positives were noted. WBS demonstrated a benefit accurately showing a good response to therapy and predicting RAI distribution following therapy. Stimulated Tg levels accurately detected six patients with disease; three of the patients not detected in this manner had Tg antibodies, although one patient with PTC demonstrated no Tg stimulation. Combined stimulated PET/CT and WBS provides a valuable tool at our institution for efficiently evaluating higher-risk DTC patients. PET/CT proved sensitive, although unspecific. WBS was relatively insensitive, although did demonstrate other clinical benefits. Tg levels were relatively specific, but complicated by antibodies.
Thyroid Nodules & Goiter Thursday Poster Clinical
To validate a new risk stratification system for thyroid nodule, K-TIRADS was proposed by Korean Society of Thyroid Radiology. Despite the high diagnostic performance, 30 ∼ 80% of biopsied nodules turned out benign. To reduce unnecessary biopsy, other assessment methods were evaluated, i.e.elastography, which measures the stiffness of nodule. Here, we present the prospective study of US elastography to evaluate the role of elastography in differentiating indeterminate thyroid nodules by ultrasonography in order to decrease the number of tissue biopsies. From May 2015 to Jan. 2017, we recruited subjects who were referred to perform FNA from primary physician. During the period, elastography was performed on 145 nodules from 127 subjects before FNA. Among them, 11 nodules were not biopsied. Among 134 nodules, 4 nodules showed unsatisfactory and 1 nodule came out as a follicular neoplasm but didn't undergo surgery. Finally, 129 nodules from 116 subjects were enrolled in the analysis. The mean maximum diameter of nodule was 13.7 ± 7.3 mm. Incidence of malignant nodule proven by cytology with/without pathologic report was 32.1% of total. The diagnostic performances in category 4 and 5 of K-TIRADS showed 97.6% sensitivity, 39.1% specificity, 43.6% positive predictive value, 97.1% negative predictive value (NPV) and 58.1% accuracy. There's no benefit of additional diagnostic yield of combining ECI value of elastography in whole patients. Among indeterminate nodule by K-TIRADS (category 4), applying cut off value determined by ROC curve (2.255), the overall NPV was slightly better, 100% compared to 97.1% respectively. Elastography should not replace US, but it may be used as a complementary tool for assessing nodules for FNA in indeterminate nodules, especially due to its high NPV.
Thyroid Nodules & Goiter Thursday Poster Clinical
Bilateral axillobreast approach (BABA) endoscopic thyroidectomy can be a good option for huge benign thyroid goiter larger than 5 cm. This study aimed to describe the effectiveness and technical aspects for Bilateral axillobreast approach (BABA) endoscopic thyroidectomy in detail. Between January 2008 and October 2017, 30 patients with a benign thyroid goiter larger than 5 cm or Graves' disease underwent BABA endoscopic thyroidectomy. Parathyroid hormone was measured at postoperative day 1 in all patients. The bilateral axillo-breast approach endoscopic thyroidectomy was successful in all patients, was performed by a single surgeon, and none required conversion to open surgery. The operation types were lobectomy (n = 20), subtotal thyroidectomy (n = 2), near total thyroidectomy (n = 3), and total thyroidectomy (n = 5). There were no postoperative vocal cord paralysis or postoperative bleeding. Postoperative transient hypocalcemia occurred in 3 patients (10.0%), but permanent hypocalcemia occurred in only 1 patient (3.3%). BABA endoscopic thyroidectomy can be safely performed in patients with a thyroid goiter larger than 5 cm, and it showed excellent clinical and cosmetic outcomes.
Thyroid Nodules & Goiter Thursday Poster Clinical
Lipodystrophy (LD) and insulin receptor mutation (INSR) syndromes are characterized by severe insulin resistance (IR) and hyperinsulinemia. High-dose insulin and leptin are common treatments and both have the potential to increase cell growth and proliferation via MAPK signaling, which may be enhanced as IRS/PI3K signaling is impaired. There is evidence that milder IR in type 2 diabetes may lead to increased thyroid volume (TV) and thyroid nodules/cancer.
The aim was to analyze thyroid abnormalities in severe IR and to determine if leptin therapy is associated with thyroid structural changes.81 patients with LD and 11 with INSR (mean age 32 ± 18 and 18 ± 12y (p = .0002) with available thyroid ultrasound (US) were analyzed. 60 were on leptin therapy. TV was similar in LD and INSR (10.6 ± 6.5 and 9.3 ± 7ml, p > .05). Echotexture was heterogenous in 61% and 73% with normal vascularity in 96% and 91%, in LD and INSR (p > .05). Thyroid cysts were present in 60% and 73% of LD and INSR patients (p > .05). Thyroid nodules (TN) were present in 36.3% of LD patients (55 TN in 29 patients; mean size 1.1 ± 1.5cm). 40% of TN were solid; 11% hyperechoic and 81.8% hypoechoic with ill-defined or lobulated/irregular margins in 22% and 3.6%. Macro/peripheral calcifications were found in 23.6% of TN (13/55). In patients <18y, there was no difference between LD and INSR groups for gender, TV and prevalence of TN.
In LD, there was no difference in TV, cysts, or TN between patients on leptin vs those never treated with leptin. INSR patients on leptin had greater TV (15.4 ± 8.6) vs those never treated with leptin (6 ± 3ml, p = .04). However, all leptin-treated patients were homozygous while those never treated with leptin were all heterozygous for INSR mutation.
3.2% of patients (2 LD, 1 INSR, mean age 25 ± 12y) were diagnosed with low risk papillary thyroid cancer. 1 LD patient never treated with leptin and other 2 patients were on leptin. Patients with severe IR have a high prevalence of TN and thyroid cancer at young age, which occurred in both leptin-treated and never treated patients. Further studies are needed to determine the etiology of thyroid abnormalities in patients with severe IR, and whether leptin treatment increases risk of PTC.
Thyroid Nodules & Goiter Thursday Poster Clinical
The purpose of this study was to evaluate the results of radionuclide therapy with iodine-131 (I-131) in patients (pts) with autonomously functioning thyroid nodules (AFTNs) and a normal thyroid stimulating hormone (TSH) blood level. Up to our knowledge, this is the first study which has scintigraphically evaluated the effect of I-131 therapy in patients with AFTNs and normal TSH blood level.
In this study 76 cytological benign AFTNs in 67 pts (58 female and 9 male) with normal TSH level have been treated with a fixed I-131 doses (370 MBq). Clinical exam, ultrasonography with color Doppler (US), fine needle aspiration biopsy (FNAB), TSH, FT4, FT3, anti-TPO, anti-Tg and thyroid scan (scintigraphy) have been performed in all pts before and 6 months after I-131 therapy. The median age of the pts was 57 (range 35 – 83) years. AFTNs were located more frequently in the right thyroid lobe (44 nodules) than in the left lobe (32 nodules). In 11 pts a solitary AFTN has been found on ultrasonography and the other 56 patients had AFTNs in multinodular goiter. Nine pts had two AFTNs. On post I-131 therapy thyroid scan in 52 AFTNs complete therapy effect has been observed, but in 24 AFTNs a scintigraphycally partial effect has been noted. Statistical analysis showed a significant reduction in the thyroid (p = 1.1815E-18) and AFTNs (p = 0.00049) volume after J-131 therapy. TSH value significantly increased (p = 0.00225) and FT4 value significantly decreased (p = 0.00054) after I-131 therapy. FT3 (p = 0.3616), anti-TPO (p = 0.9387) and anti-Tg (p = 0.2713) values did not change significantly.
This study shows that radionuclide therapy with I-131 in pts with AFTN and normal TSH blood level is a simple, cheap and very effective modality. The effect of the I-131 therapy on AFTNs can be evaluated with a thyroid scan 6 months after I-131 therapy.
Thyroid Nodules & Goiter Thursday Poster Clinical
Following thyroidectomy, transient hypocalcemia is a common and well recognized complication. Whether a low preoperative vitamin D level increases the risk of this complication continues to be a topic of debate. The aim of this study was to determine whether 25-hydroxyvitamin D (25[OH]D) level predicts postoperative hypocalcemia in patients undergoing total or completion thyroidectomy. A single center retrospective study was conducted including all patients receiving total or completion thyroidectomy between January 2007 and March 2017. 25-hydroxyvitamin D (25[OH]D) levels were measured within 42 days of surgery or one day post operatively. Hypocalcemia was defined as an adjusted calcium (based on albumin levels) of <8.0mg/dL or symptomatic hypocalcemia with a positive Chvostek's sign. Univariate analysis was performed using a two-sample t-test and chi-squared test while multivariate analysis was performed using logistic regression analysis to determine whether preoperative 25-hydroxyvitamin D (25[OH]D) level is a predictor of postoperative hypocalcemia. Significance was determined with an alpha level of 0.05. A total of 517 subjects were included in the study. 15.67% (n = 81) of subjects experienced postoperative hypocalcemia with an average serum calcium level of 7.64 ± 0.48mg/dL compared to 8.92 ± 0.51mg/dL in the normocalcemic population (p ≤ 0.0001). The mean 25-hydroxyvitamin D (25[OH]D) level for hypocalcemic patients was 24.43 ± 11.97 ng/mL compared to 27.49 ± 12.21 ng/mL in normocalcemic patients (p = 0.0382). Subjects who were hypocalcemic experienced a significantly longer hospital stay (2.93 ± 2.47 vs. 1.37 ± 1.08; p < 0.0001). After adjusting for preoperative calcium, 25-hydroxyvitamin D (25[OH]D) levels was a significant predictor of postoperative hypocalcemia (OR = 1.023; p = 0.0420; 95% CI (1.001, 1.045). We have demonstrated that 25-hydroxyvitamin D (25[OH]D) level is a significant predictor of postoperative hypocalcemia after thyroidectomy.
Thyroid Nodules & Goiter Thursday Poster Clinical
Solitary toxic adenomas (TA) have been traditionally treated by surgical resection. In surgical high risk patients or if surgery is not desired, radioactive iodine ablation is an alternative. Besides the obvious risks of surgery, RAI can induce partial or complete hypothyroidism due to higher RAI dose that is required to treat TA and the variable degree of RAI exposure to the contralateral lobe. Percutaneous ethanol injection (PEI) under sonographic guidance has been utilized effectively in Europe as an alternate therapeutic intervention for TA. However, in the United States, many centers do not have the expertise to conduct this treatment modality. A retrospective review of all patients presenting to our institution with a toxic adenoma who underwent PEI from 2010 to 2018 was conducted. Eight adults (7♀ / 1 ♂ mean age 42 ± 14 years) presenting with hyperthyroidism due to a toxic adenoma were ablated with alcohol percutaneously as outpatients. Thyroid uptake and scan was utilized for confirmation of diagnosis prior to the procedure. Pre-ablation median thyroid stimulating hormone (TSH) was 0.01 mU/L (IQR <0.01–0.02 mU/L; normal 0.35–4.94 mU/L), free thyroxine (FT4) 1.4 ng/dL (IQR 1.3–1.5 ng/dL; normal 0.8-1.7 ng/dL) and total tri-iodothyronine (TT3) 144 ng/dL (IQR 131–160 ng/dL; normal 80–200 ng/dL). Nodules were described as isoechoic in 88% (n = 7), hypoechoic in 12% (n = 1), highly vascular in 75% (n = 6) with a median volume of 6.0 cm3 (IQR 4.7–7.5 cm3). 3 nodules underwent one injection, 3 underwent 2 injections and 2 underwent >2 injections. Follow up thyroid function showed normalization of TSH in 63% (n = 5), low but increased TSH from baseline in 25% (n = 2) and lost to follow up in 12% (n = 1). Other than self-limiting pain on the day of injection no adverse events were reported. PEI under sonographic guidance is an effective treatment modality of toxic adenomas once such expertise is available. Endocrinologists should be trained in administering this treatment modality in the United States.
Thyroid Nodules & Goiter Thursday Poster Case Report
Selecting a nodule for FNA in a multinodular thyroid poses a diagnostic challenge. We present a case of benign FNA of the largest thyroid nodule in a female with MNG who presented 6 months later with a neck mass, which was positive for Papillary Thyroid Cancer (PTC). A 60 y/o female was referred for a left thyroid nodule. She had no associated signs and symptoms. Her sister had PTC. Physical exam revealed a left thyroid nodule. TSH and FT4 levels were normal. Thyroid ultrasound showed multinodular thyroid; largest was a left lobe, complex, hypoechoic nodule measuring 2.4 × 1.7 × 2 cm with increased peripheral vascularity. There was also a hypodense, irregular nodule in the right lobe, measuring 1.1 × 0.7 × 1.1 cm. FNA of the complex 2.4 cm nodule was performed; cytology revealed colloid nodule with cystic degeneration. She refused biopsy of the right lobe nodule.
Patient presented 6 months later for an enlarging neck mass and a firm 2 cm left neck node was felt on exam. FNA was consistent with PTC.
CT neck showed non-enhancing 5.6 cm cystic nodule in the left thyroid lobe with cervical lymphadenopathy including multiple necrotic lymph nodes at level II and IV, with the largest one measuring 2.1 cm at level II. Patient underwent total thyroidectomy, central neck and left lateral neck dissection.
Pathology reported bilateral follicular variant PTC, multifocal, the largest focus measuring 1.2 cm, with minimal extra-thyroid extension, angiolymphatic and perineural invasion, and positive margins. 13 of 28 lymph nodes were involved. Extra-nodal extension was reported. This case illustrates that in a multinodular thyroid, sonographic features are an important factor in selecting a nodule for FNA. Individual risk factors for thyroid cancer warrant close monitoring, even in the presence of benign cytology. Ultrasound features and not size alone (as previously known) are important in nodule selection for FNA to correctly identify the pathology. Multiple thyroid nodules have the same risk of malignancy as a solitary nodule.
A benign result of FNA of a thyroid nodule in a patient with risk factors for malignancy should be interpreted cautiously.
Thyroid Nodules & Goiter Thursday Poster Case Report
Posterior mediastinal extension of retrosternal goiters is uncommon. We report a case of right sided multinodular goiter with an additional ectopic posterior mediastinal component mimicking a large confluent retrosternal goiter that was excised by a combined cervical and thoracoscopic approach. Under general anaesthesia with double lumen endotracheal tube, thyroid mobilization in the neck was performed as usual via skin crease collar incision after ligating the superior, middle and inferior vascular pedicles and safeguarding the external branch of the superior laryngeal and the recurrent laryngeal nerves. On completion of the cervical mobilization, the intrathoracic mediastinal component was noted to be separate from the cervical portion and could not be visualised from the neck. Single portal access was created over the right chest and after collapsing right lung, the mediastinal pleura was dissected and the mediastinal component was excised with a combination of diathermy and ultrasonic dissection while preserving the phrenic and recurrent laryngeal nerve. The reported incidence of retrosternal goiters vary over a wide range from 1-20% due to multiple definitions on its extent. Most retrosternal goiters can be excised via cervical approach alone while an extracervical approach is required in up to 11% of cases (sternotomy 2/3 rd, thoracotomy 1/3 rd). Most mediastinal goiters are secondary to growth and descent. Anterior mediastinal goiters are approached by sternotomy, while posterior mediastinal goiters usually require posterolateral thoracotomy or a thoracoscopic approach. Thoracoscopic planning is required for posterior mediastinal extension beyond T4. The goiter can be delivered via the neck after adequate division of ligaments in the sternal notch. Anterior mediastinal extension is twice as common on the left while posterior mediastinal extension is seen predominantly on the right side. Multinodular goiters with confluent ectopic mediastinal component are extremely rare and mandate a combined approachThoracoscopic planning is required for all posterior mediastinal goiters. Ectopic component of mediastinal goiters can rarely mimic a retrosternal extension presenting as a confluent goiter.
Thyroid Nodules & Goiter Thursday Poster Case Report
Metastases to the thyroid gland are rare, accounting for 2-3% of thyroid malignancies (1,2). Thyroid metastases are often occult in nature and difficult to distinguish from primary thyroid malignancy. While molecular marker testing is used to determine thyroid cancer risk in indeterminate thyroid nodules, their role in determining nonthyroid malignancies is still undetermined (3). A 76-year-old-male with a history of renal cell carcinoma (RCC) presented with a 2.9 cm hypoechoic left thyroid nodule with internal vascularity on ultrasound in November 2016. He underwent a right nephrectomy in 2011 and surgery for a local recurrence in 2012. Surveillance imaging showed no evidence of recurrence. Initial (12/2016) and repeat (3/2017) fine needle aspiration biopsy (FNAB) of the thyroid nodule showed atypia of undetermined significance. Molecular marker testing for the initial FNAB was negative using the ThryoSeq Next-Generation Sequencing and was suspicious for the repeat FNAB using the Afirma gene expression classifier. He underwent a left hemithyroidectomy in December 2017. Pathology revealed metastatic RCC, clear cell type. Immunohistochemistry was positive for pan-keratin (AE1/AE3), PAX-8, CA9 and CD10 and negative for thyroglobulin, TTF-1, synaptophysin, chromogranin A, PTH, calcitonin, pCEA, and CK7. 18F-FDG PET-CT one month later showed no new metastases. Metastatic disease should be considered when faced with suspicious thyroid nodules in patients with a history of non-thyroid malignancy, especially RCC, melanoma, breast carcinoma, and lung carcinoma (4). However, there is a 38.7% false negative rate for detection of metastases on FNAB (5) and neither ThyroSeq Next-Generation Sequencing nor the Afirma gene expression classifier have been validated for detection of non-thyroid malignancy in thyroid nodules. Therefore, it is important to maintain suspicion for metastatic disease in patients with prior non-thyroid malignancy and a suspicious thyroid nodule, regardless of the results of FNAB or molecular marker testing. Thyroid surgery should be considered in these cases. The role of molecular marker testing in the detection of non-thyroid malignancy in thyroid nodules warrants further investigation.
Friday, October 5, 2018
Thyroid Cancer Friday Oral Basic
The tumor tropism of mesenchymal stem cells (MSCs) provides the basis for a “Trojan Horse”-like therapy approach, in which genetically modified MSCs deliver a therapeutic gene into the microenvironment of growing tumors. Due to its dual role as reporter and therapy gene, the sodium iodide symporter (NIS) allows detailed noninvasive imaging of transgene expression and effective application of therapeutic radionuclides. To improve the effectiveness and tumor selectivity of MSC-mediated gene therapy, we established MSCs that express the NIS gene driven by heat-inducible HSP70B promoter (HSP70B-NIS-MSCs) to control activation of the NIS gene locally as well as temporally. MSCs were heat-treated in a water bath for 60 min at temperatures ranging from 39 to 42°C, followed by incubation at 37°C for 0-24h. NIS mRNA was analysed by RT-PCR and protein levels by Western blot and immunofluorescence staining. In a s.c. HCC xenograft mouse model HSP70B-NIS-MSCs were injected three times i.v. and hyperthermia was applied locally to the tumor for 1h at 41°C or as control at 37°C. 6-36h after thermostimulation radioiodine uptake was assessed by 123I-scintigraphy. The HSP70B promoter showed low basal activity in vitro, but could be induced significantly in response to heat. The strongest radioiodine accumulation was detected at 41°C, the induction occurred very rapidly and maximum levels were reached as early as 4h after heat exposure. NIS mRNA and protein levels confirmed heat-induced NIS expression. The highest tumoral iodine accumulation was seen when radioiodine was applied 12h after hyperthermia. Immunohistochemistry confirmed tumor-selective recruitment of MSCs. In summary, we have established a stable MSC line armed with a heat-inducible NIS construct. We observed an increased tumor-selective, temperature-dependent accumulation of radioiodine in heat treated tumors compared to control animals. As a next step, we will evaluate potential additive or synergistic therapeutic effects of hyperthermic treatment on NIS-mediated radioiodine therapy in vivo based on its own anticancer effects and its well characterized radio- and chemosensitizing effect.
Thyroid Cancer Friday Oral Basic
Poorly differentiated (PDTC) and anaplastic (ATC) thyroid cancers have high mortality due to rapid growth and poor response to therapy. Animal models of these cancers are needed for better understanding of the mechanisms of cancer dedifferentiation and preclinical studies of targeted therapies. ALK fusions, most commonly STRN-ALK, are found in human papillary thyroid carcinoma (PTC), PDTC and ATC. We have recently generated mice with thyroid-specific expression of STRN-ALK which showed the development of PDTC. However, these tumors did not have a complete loss of differentiation characteristic to ATC. To investigate the effect of TP53 loss on the the progression of STRN-ALK driven tumors, we generated Tg-STRN-ALK+/-;Tg-Cre+/-;trp53Loxp/LoxP (ALK-p53KO) triple transgenic mice. To determine the contribution of TSH stimulation, mice were treated with goitrogen. Ultrasound imaging was used to screen for development and progression of thyroid tumors. Animals were sacrificed at 6 months of age or when life-threatening symptoms developed. Microscopic and immunohistochemical analysis was performed. In a pilot experiment, the ALK inhibitor Crizotinib (100mg/kg) or vehicle were administered for 10 days by oral gavage. The ALK-p53KO mice developed thyroid tumors starting at 5-7 months of age. The tumors were advanced, well-differentiated PTC with morphological and immunohistochemical evidence of progression to PDTC and ATC, and had frequent vascular/muscle invasion and lung metastasis. Among 18 animals on goitrogen that were sacrificed, 17% had PTC, 11% PDTC, 5% ATC. Among the 19 animals without goitrogen, 16% had PTC, 10% PDTC, and 16% ATC. By ultrasound, the expected frequency of thyroid tumors by 12 months of age is >25% without goitrogen and 50% with goitrogen. Treatment of two mice with Crizotinib led to shrinkage of tumors by ∼40%, while two mice treated with vehicle had the tumors grew by ∼60%. Whereas STRN-ALK can drive the development of murine PDTC, we report here that combination of STRN-ALK and TP53 inactivation results in full anaplastic transformation. These mouse models will allow studying multistep tumor dedifferentiation and testing targeted therapies for dedifferentiated thyroid cancer.
Thyroid Cancer Friday Oral Basic
Thyroid cancer is the most common endocrine malignancy. Compelling epidemiologic studies have shown a strong positive correlation of obesity with thyroid cancer, but a cause-effect relationship at the molecular level has yet to be established. We used ThrbPV/PVPten+/- mice as a preclinical mouse model, which expresses a dominant negative thyroid hormone receptor beta (denoted as PV) and deficiency in one allele of the Ptengene, exhibiting aggressive follicular thyroid cancer. We showed that high-fat-diet induced obesity promotes aggressive thyroid cancer by aberrantly activating leptin-JAK2-STAT3 signaling in ThrbPV/PVPten+/- mice. We showed that metformin, a widely used antidiabetic drug, markedlyblocked invasion and metastasis, but not thyroid tumor growth inthese mice. Our results suggested that tumor growth and invasion/metastasis could be regulated by different signaling pathways. Accordingly, we searched for another potential therapeutic that could inhibit thyroid tumor growth. We chose JQ1, a potent inhibitor of the activity of the bromodomain and extraterminal domain (BET) family, for combined treatment with metformin. We found that such treatment synergistically increased overall survival rate and suppressed obesity-activated thyroid tumor growth. Pathohistological analyses showed that JQ1 together with metformin blocked invasion and decreased lung metastasis. Additional molecular analyses showed that combined treatment synergistically suppressed thyroid tumor growth by attenuating STAT3 and ERK signaling, resulting in decreased anti-apoptotic key regulators such as Mcl-1, Bcl-2, and survivin and increased pro-apoptotic regulators such as Bim and Bad. Combined treatment regulated cMYC levels along with EMT markers (E-cadherin, MMP9, vimentin, N-cadherin, and fibronectin) to suppress cancer invasion and lung metastasis. This decreased tumor growth by the combined treatment was mediated by elevated caspase activity to promote tumor cell apoptosis. These preclinical findings suggest that combined treatment of JQ1 with metformin can be an effective treatment modality for obesity-activated thyroid cancer and could be tested for efficacy in future clinical trials.
Thyroid Cancer Friday Oral Basic
The catalytic subunit of telomerase, telomerase reverse transcriptase (TERT), is upregulated in over 90% of malignancies by mechanisms including activating promoter mutations, alternative splicing, and promoter methylation changes. We have previously characterized TERT promoter methylation in multiple thyroid cancer cell lines and normal thyroid tissue, which revealed distinct differences in methylation between cancer and normal thyroid.
We hypothesized that the unique methylation patterns observed correspond to transcription factor (TF) binding sites, such that promoter methylation changes affect factor binding and therefore TERT activation in cancer. TFs chosen (CTCF, c-Myc, WT1, GSC2, and GABPA) have either been shown to cause TERT transcription changes in other cancer types, or were identified through binding motif analysis of focal hypomethylated sites. To investigate binding of these TFs in thyroid cancer, we conducted chromatin immunoprecipitation (ChIP) in thyroid cancer cell lines and thyroid tumor samples. We performed ChIP to characterize TF binding to the TERT promoter in five cell lines of papillary and follicular thyroid cancer origin, as well as in matched benign and malignant tissue samples. We determined the enrichment of the precipitated TF-bound DNA by q-PCR. Consistent with other telomerase positive cancers, TFs CTCF and c-Myc bind at the TERT promoter in thyroid cancer cell lines. Further, binding motif analysis identified a new c-Myc binding site in the TERT promoter, and preliminary analysis confirmed c-Myc binding. Analysis is ongoing to evaluate TF binding in FFPE patient samples. Transcriptional activation of TERT plays a significant role in telomerase upregulation in malignancy. We hypothesize that binding of TFs to the TERT promoter is altered by DNA methylation, thereby abrogating binding. We have previously catalogued the TERT methylation patterns in thyroid cancer, and are poised to interrogate TF binding that may influence TERT activation. Coupling TF information with known TERT promoter mutation status will also further our understanding of regulation of telomerase in thyroid cancer.
Thyroid Cancer Friday Oral Clinical
High resolution ultrasound (US) evaluation of the central and lateral neck is considered the gold standard in the evaluation of thyroid nodules and lymph nodes of concern for malignancy. We hypothesized that since US is an accurate predictor of complete surgical resection and long-term disease-free regional control, comprehensive US evaluation of the neck would be commonplace throughout the United States. A prospective analysis of 217 consecutive patients who provided preoperative US CDs prior to our definitive high resolution US evaluation and management of their primary thyroid malignancy at a tertiary referral center for the year 2017. Information retrieved included sonographic status of the thyroid and central and lateral neck lymph nodes, demographics, histopathologic variables, and cancer staging. There were 66 males and 151 females with a median age of 41 years (range 14-87). 68 (31%) of the US studies were from the southwest region of the United States, whereas 149 (69%) were from the remainder of the United States. Reviewed images and reports revealed 4 (2%) of US studies obtained prior to referral analyzed any lateral neck lymph nodes. There were 101 (46%) patients with T1, 39 (18%) with T2, and 77 (35%) with T3 or T4 thyroid malignancies. Our high resolution preoperative ultrasound effected the indicated surgical procedure and established lateral neck metastases in 39 (18%), central compartment lymph node disease in 60 (28%), and contralateral second primary thyroid disease in 4 (2%) of patients.
Preoperative analysis of suspicious and malignant thyroid nodules is inadequate in imaging centers throughout the United States and likely contributes to persistent thyroid malignancy, increased health care costs, and patient morbidity.
Thyroid Cancer Friday Oral Clinical
During 1977-86, post-BTLR 20-yr rates for CSM and TR were 0.7 and 6%; for ablated cases, rates were higher at 1.8 (p = 0.34) and 13% (p = 0.02). When TR rates were examined separately for N0 and N1 patients, no significant differences were found. During 1987-2016, after surgery alone, 20-yr CSM was 0% and TR was 9%; rates after PRRA were higher at 0.7% (p = 0.11) and 20.5% (p < 0.001). In N0 cases, 20-yr LRR rates were 5% after either BTLR alone or with ablation (p = 0.63). In N1 patients, 20-yr LRR rates were higher in ablated patients at 28%, compared with 16% in non-ablated (p = 0.004). In N1 patients, no significant difference existed (p = 0.96) in 20-yr risk of distant spread between the ablated and non-ablated patients.
Thyroid Cancer Friday Oral Clinical
Although well-differentiated thyroid cancers (DTC) have an excellent prognosis, their response after thyroidectomy and radioiodine (131I) therapy (RIT) can be influenced by various factors, including age, number, location of locoregional nodes (N) invasion at diagnosis, and tumor stage. Whether any of these factors impact the response to RIT in patients prepared with rhTSH vs patients prepared with THW remains unknown. The primary objective of the study was to demonstrate non-inferiority of rhTSH vs. THW in terms of disease-free status (basal ultrasensitive Tg <0.2 ng/mL and/or stimulated-Tg ≤1 ng/mL, absence of TgAb and normal neck US) at the first follow-up control performed at 6-18 months post RAI therapy in the real-life setting in N+M0DTC. Another objective was to determine the non-inferiority for eachoutcome predictor.
This was a French multicenter retrospective, matched cohort study. Groups were matched in each participating center according to age (<45 vs. ≥45 years), number (≤5 vs. >5) of metastatic locoregional (LN) and tumor stage (pT1-T2 vs. pT3), according to pTNM 2010. The cohort consisted of 404 pT1-T3 differentiated thyroid cancer patients with lymph node metastases and no evidence of distant metastasis at the time of RAI therapy, prepared with rhTSH (n = 205) or THW (n = 199). Patients and tumor characteristics were similar between the two groups. Most patients had 5 LN or less (90.7% and 91.9%, in rhTSH and THW, respectively). At the first follow-up control, disease-free rate was not inferior in the rhTSH group (75.1% [95% CI: 68.6; 80.9]) compared to the THW group (71.9% [95% CI: 65.1; 78.0]). At the last follow-up control (between 29.7 and 36.7 months), 83.5% (rhTSH group) and 81.5% (THW group) of patients achieved a complete remission status. None of the prognostic factors (gender, age, number, location (N1a, N1b) of regional lymph node invasion, tumor stage and abnormal 131I WBS…), were found to be associated with different RIT outcomes after rhTSH or THW preparations.rhTSH was non-inferior to THW for RAI therapy in our series of DTC patients staged pT1-T3/N1/M0. This result was independent from the evaluated prognostic factors.
Thyroid Nodules & Goiter Friday Oral Clinical
Benign solid thyroid nodules are good candidate for radiofrequency ablation (RFA). However, they often require RFA with high power and energy, which increase the incidence of complications. Ethanol has been used for treatment of cystic/cystic solid thyroid nodules and residual solid portion adjacent to critical structures. In this study, a new combination of RFA and ethanol, using ethanol as sensitizer, was developed to explore a safer, faster and more effective RFA. From June 2016 to February 2018, 84 cases of benign thyroid nodules were studied. They were randomly divided into ethanol sensitized RFA group and conventional RFA group. In the first group, before RFA, a small amount of ethanol was injected into different parts of the solid nodule by 21GPTC needle until the high echo covered most of the nodule before RFA. The diameter and volume of nodules, volume of ethanol, treatment time, RFA energy, volume reduction rate (VRR) and complications were analyzed and compared between the two groups. 42 nodules in 38 patients and 42 nodules in 34 patients were enrolled in ethanol sensitized group and conventional RFA group. The maximum diameters of the two groups were 5.02cm ± 0.95cm and 4.87cm ± 1.42cm (P = 0.632), the volumes were 27.9ml ± 14.8ml and 34.6ml ± 37.4ml (P = 0.301). The average dosage of ethanol was 1.92 ml ± 1.06ml per nodule and 0.08 ml ± 0.03ml per milliliter nodule. The treatment time of ethanol sensitized group (454.7s ± 234.3s) was shorter than that of conventional RFA group (796s±349.0s), and the ablation energy (3.69KJ ± 1.98KJ) was less than that of conventional RFA group (5.10KJ ± 2.15KJ), with significant difference (P < 0.01). There was no significant difference between ethanol sensitized group and conventional RFA group in ablation area (27.1ml ± 13.1ml vs 34.0ml ± 35.0ml), VRR at 1 month (0.57 ± 0.14 vs 0.48 ± 0.16), 3 months (0.62 ± 0.19 vs 0.53 ± 0.23) and 6 months (0.62 ± 0.14 vs 0.49 ± 0.36) after RFA. No complications happened in ethanol sensitized group. 2 cases of hematoma happened in conventional RFA group. RFA is an effective treatment for benign solid thyroid nodules. Ethanol can significantly improve the efficiency of RFA, reduce the time and energy of ablation, and reduce the occurrence of complications.
Autoimmunity Friday Poster Basic
TSH-Receptor blocking autoantibodies (TBAb) are prevalent in patients with autoimmune thyroid disease. The analytical performance and clinical validity of a novel TBAb bioassay was assessed. CHO cells expressing a chimeric TSH-receptor were grown for 16 hours at 37°C, 5% CO2. Samples were 1:11 diluted in TBAb Working Solution. After 3h incubation, the cells were lysed and measured as relative light units (RLU) in a luminometer. Blocking activity was defined as percentage inhibition of luciferase expression relative to induction with bovine TSH alone. Percent Inhibition (% I) was calculated as follows: % I = (Reference RLU - Sample RLU)/(Reference RLU) × 100. The analytical performance was determined with 88 serum samples from healthy euthyroid subjects to calculate the limit of blank (LoB). LoB was calculated by the 95th percentile of the blank distribution using the formula: TBAb LoB = results at position [normal blank measurements (p/100) + 0.5)] = [88*0.95 + 0.5] = 84th position at which the sample produced 13% Inhibition. The limit of detection (LoD) was calculated as LoD = LoB +1.645 standard deviation (low concentration samples) = 13%I + 1.645 × 5.6% I = 22% I. Two serum samples from healthy control subjects were spiked with two different concentrations of K1-70 TBAb (40 and 80 ng/ml) and were utilized for the precision testing. Intra-assay precision for 40 and 80 ng/ml were 45 ± 2.6% I and 71 ± 1.5% I with a very low coefficient of variation (CV %), 5.7% and 2.1%, respectively. The inter-assay precision was 45 ± 7.4% I and 71 ± 45% I with a low CV%, 16.4% and 6.3% respectively. No cross-reactivity was noted for the follicle-stimulating hormone (FSH), luteinizing hormone (LH) and for human choriongonadotropin (hCG) in the TBAb bioassay. The TBAb results remained positive when testing for interference of FSH, LH and hCG in the presence of K1-70. The assay cut-off was established with 285 serum samples from healthy control subjects and the 98% probability [mean +2.05 x SD = 7.47% + (2.05 × 12.8%)] was 34% I. This cell line accurately detects TBAb therefore enhancing the clinical utility of this novel bioassay.
Autoimmunity Friday Poster Translational
Stimulating TSH-receptor (TSHR) autoantibodies (TSAb) are specific for Graves' disease (GD). We evaluated the utility of two novel cyclic adenosine monophosphate (cAMP) assays for the detection of TSAb and compared results with a luciferase-based TSAb bioassay. CHO cell lines that express a wild-type (wt.) or chimeric (Mc4) TSHR stably transfected with the GloSensor 22F plasmid were incubated with forskolin, a TSAb monoclonal antibody (M22) and GD samples. Levels of cAMP were measured using the lytic Bridge-it cAMP Designer assay (Mediomics, USA) that is based on binding of cAMP to a DNA-binding protein and the non-lytic Glosensor cAMP assay, (Promega, USA) which uses genetically encoded biosensor variants with cAMP binding domains fused to mutant forms of Photinus pyralis luciferase. Results were compared with those obtained using FDA-cleared luciferase TSAb bioassay (Thyretain, Quidel, USA). A dose-response curve of forskolin (0.006-200 μM) was performed in wt., Mc4, and Mc4-22F cells. The linear range in the wt., Mc4, and Mc4-22F cells was 3.1-50 μM, 0.8-25 μM and, 3.1-50 μM, respectively. In forskolin-treated Mc4 and wt. cells close correlations were shown for Bridge-it® cAMP vs. luciferase (r = 0.91 and 0.84, both p < 0.001), Glosensor vs. Bridge-it (r = 0.87, p < 0.001) and Glosensor vs. luciferase (r = 0.7, p < 0.001). A dose-response curve of M22 (0.006-50 ng/ml) was measured in wt., Mc4, and Mc4-22F cells. The linear ranges for the wt., Mc4, and Mc4-22F cells were 0.8-6.3 ng/ml, 0.8-2.5 ng/ml and 0.8-12.5 ng/ml, respectively. Also in M22-treated Mc4 and wt. cells positively correlated levels of Bridge-it® cAMP vs. luciferase (r = 0.88, p < 0.001 and 0.75, p = 0.002), cAMP Glosensor vs. Bridge-it (r = 0.98, p < 0.001), and cAMP Glosensor vs. luciferase (r = 0.94, p = 0.001) were noted. Serum samples from 20 well-characterized patients with untreated GD showed comparable results in all three assays. Mean ± SD values in the cAMP Bridge-it, Glosensor and luciferase TSAb assays were 57 ± 17%, 2420 ± 250%, and 544 ± 49%. The cAMP Bridge-it® results negatively correlated with the luciferase TSAb bioassay (r = −0.83, p = 0.04). TSAb bioassays using two novel cAMP assays provide rapid TSAb results comparable to an established luciferase bioassay.
Iodine Uptake & Metabolism Friday Poster Basic
The sodium iodide symporter (NIS) represents one of the most promising reporter genes for non-invasive radionuclide-based molecular imaging and therapy. We and others have investigated the capacity of NIS to induce radioiodine accumulation in non-thyroidal tumours using various gene delivery vehicles. Based on their excellent tumour-homing capacity, mesenchymal stem cells (MSCs) are promising tumour-selective gene delivery vehicles. In the current study, we applied MSCs for tumour-targeted NIS gene delivery to glioblastoma multiforme (GBM), as a clinically highly relevant tumour with urgent need for novel therapy approaches. Brain tumours were established in C57BL/6 mice by orthotopic inoculation of the murine GBM cell line GL261. Immortalised bone marrow-derived syngeneic mouse MSCs were stably transfected with a NIS expressing plasmid driven by the constitutively active CMV-promoter (CMV-NIS-MSC) and functional NIS expression was demonstrated by 125I uptake. Four weeks after tumour implantation, CMV-NIS-MSCs were injected systemically via the tail vein and tumoural iodide uptake was monitored by 123I-scintigraphy. Injection of the NIS inhibitor perchlorate 30 min before radionuclide application served as control of NIS specificity. A strong tumoural 123I accumulation of 11.4 percent of the injected radioiodide dose (% ID) was observed after CMV-NIS-MSC administration, while only 3.2% ID were measured for the perchlorate control. Resected tumours were further analysed by ex vivo NIS immunofluorescence staining, revealing NIS-specific immunoreactivity primarily in perivascular regions. Our promising preliminary experiments demonstrate strong recruitment of MSCs into GBM tumours in a syngeneic orthotopic mouse model and establish the use of NIS as a reporter gene to track MSC homing to GBM. The fact that attempts to target therapeutically active agents to the brain are faced with the serious challenge of the blood-brain-barrier further demonstrates the potential of our strategy. In future studies, we will address the efficacy of our approach to deliver therapeutically active radionuclides, e.g. 131I, to GBM using the dual function of NIS as reporter and therapy gene.
Thyroid & Development Friday Poster Basic
Thyroid hormones (TH) are critical for mammalian brain development. In humans, low maternal serum thyroxine (T4) levels are associated with neurological deficiencies and cognitive impairment. Perfluorohexane sulfonate (PFHxS) is a widespread environmental contaminant found in human serum, tissues and milk. We have shown that PFHxS decrease serum thyroxine in pregnant rat dams and their offspring. Here, we investigate effects on the thyroid system, neurodevelopment, and combination effects of PFHxS and a mixture of environmentally relevant endocrine disruptors. Perfluorohexane sulfonate (PFHxS, 0, 0.05, 5 or 25 mg/kg/day with and without EDmix, a mixture of 12 endocrine disruptors e.g. phthalates, pesticides, UV-filters, Bisphenol A and butyl paraben) was administered (p.o.) to Wistar rat dams (n = 16-20/dose group) from gestation day (GD) 7 through postnatal day (PD) 22. Offspring were assessed in activity boxes and the radial arm maze. PFHxS not only decreased serum T4 levels in dams and offspring but in the high dose also reduced T3 to 84% of controls in both dams (PD 22) and pups (PD 16). The hypothalamic-pituitary-thyroid (HPT) axis was not activated based on lack of effect on serum TSH, thyroid gland histology, weight and thyroid gene expression levels. Developmental hypothyroxinemia did not appear to increase physical activity levels in young and adult offspring. However, the expected sex difference was absent on PD 115 in low dose PFHxS (0.05 mg/kg) and at high doses in combination with EDmix (5 mg/kg +EDmix and 25 mg/kg + EDmix). Slight effects on offspring learning and memory did not appear correlated to decreased TH levels during development. PFHxS decreased circulating levels of T3 and T4 in pregnant rat dams and their offspring without apparent compensation by the HPT axis. The thyroid hormone disruption was not associated with detectable learning and memory deficits. Rather findings suggest that PFHxS may disrupt sexual differentiation of the brain. Standard behavioral assays appear insensitive to adverse effects on brain development caused by thyroid hormone disruption. Hence, there is a need for development of sensitive assays to protect human thyroid function. Does not reflect EPA policy.
Thyroid Cancer Friday Poster Basic
Thyroid cancer is the most common cancer of the endocrine system. Overall, the prognoses for patients with thyroid cancer receiving standard therapies are good, however, outcomes for patients with resistant or recurrent disease are extremely poor. Due to the lack of effective therapies, patients with advanced or metastatic disease have a higher mortality rate than all other endocrine cancers combined. Dysregulation of the transcription factor TRβ, a member of the thyroid hormone receptor (TR) family, is characteristic of thyroid tumors. Restoration of TRβ function in malignant cells decreases tumor growth in xenograft studies. Despite a recognized role as a tumor suppressor, the mechanisms by which TRβ regulates tumor growth are not clear. At the genomic level, TRβ mediatesT3 regulation of gene expression via interaction with hormone response elements and recruitment of co-regulators and chromatin remodeling complexes to induce reorganization of chromatin and local nucleosome structures. In the present study, we have defined changes in gene expression in response to T3 treatment using an integrated analysis of genome-wide chromatin accessibility (ATAC-seq) and global gene expression (RNA-seq) data in non-malignant thyroid and anaplastic thyroid cancer cell lines. Our RNA-seq data show that treatment of non-malignant thyroid cells with T3 elicits a dynamic transcriptional response. 382 differentially expressed genes were detected. In support of a role for TRβ in this regulation, thyroid hormone response elements (TRE) were found to be enriched within ATAC-seq peaks located in promoter regions in non-malignant thyroid cells. ATAC-seq analysis also shows significant differences in chromatin accessibility between non-malignant and anaplastic thyroid cancer cells. Integration of these data sets revealed dynamic changes in chromatin remodeling and transcriptional regulatory networks and an altered response to thyroid hormone that may contribute to the aggressive nature of anaplastic thyroid cancer. These data provide key insights into anaplastic thyroid cancer growth and progression, and have identified candidate pathways as potential therapeutic options.
Thyroid Hormone Metabolism & Regulation Friday Poster Basic
TSH and TSAbs activate TSH receptor (TSHR) signaling by binding to its extracellular domain. TSHR signaling has been studied extensively in animal thyrocytes or in engineered cell lines and differences have been observed in different cell systems. We, therefore, decided to study TSHR signaling by TSH and TSAbs in human thyrocytes in primary culture. We focused on TSHR-mediated regulation of genes involved in thyroid hormonogenesis and measured the levels of mRNAs of thyroglobulin (TG), thyroid peroxidase (TPO), sodium-iodide symporter (NIS), deiodinase type 2 (DIO2) and TSHR. We measured TSHR signaling activated by TSH and two monoclonal TSAbs, KSAb1 and M22. Both TSH and the TSAbs produced sigmoidal dose-response curves with a plateau at high doses when stimulating cAMP production showing that they behaved similarly in regulating this signal transduction pathway. Unexpectedly, TSH regulation of the mRNA levels of TG, TPO, NIS, DIO2 and TSHR exhibited “inverted U-shaped” dose-response curves with a robust up-regulation of gene expression at lower doses (up to 10−7 M or 3 mIU/ml) and a decrease in mRNA levels at higher doses. In contrast, both KSAb1 and M22 showed monophasic sigmoidal dose-response curves with plateaus at high doses (beginning at 10−8 M or 2 μg/ml). In summary, TSH up-regulation of genes involved in thyroid hormonogenesis was diminished at high doses whereas regulation by the monoclonal TSAbs did not cause decreases in mRNA levels at high doses. Although KSAb1 and M22 may not be representative of all TSAbs found in patients with Graves' disease, we suggest that persistently robust stimulation of TSHRs by TSAbs may contribute to the chronic stimulation of thyroid gland function found in patients with Graves' disease. Our data indicate that stimulatory effects of TSAbs might be regulated by different mechanisms than TSH that could be due to activation of different signaling pathways or mechanisms of desensitization.
Thyroid Hormone Metabolism & Regulation Friday Poster Basic
There are evidences that the triiodothyronine (T3) induces browning of white adipose tissue (WAT) in humans, a phenomenon characterized by increased expression of uncoupling protein 1 (UCP1) that leads to the release of temperature and decrease of fat. Like T3, the myocin irisin, produced after exercise, has been reported in the significant influence of metabolism and thermogenesis of WAT. Due to the similarities in the effects of T3 and irisin, it is important to explore the potential associated and isolated action of these substances on WAT. Subcutaneous human adipocytes (HPAd-802S-05A) were differentiated into adipocytes and treated with T3 (10nM) and/or irisin (I = 20nM), the group termed T + I was administered T3 and I simultaneously, for 24 hours. Expression of UCP-1 and PPARγ were verified by Western Blot, quantification of intracellular lipid accumulation was performed with the OilRed O assay, the lipolysis product by the glycerol assay; DNA damage was assessed by quantification of 8-Hydroxyideoxyguanosine (80-OH-dG). ANOVA supplemented with the Tukey test at 5% significance was used for statistical analysis. The UCP-1 was elevated in the T3 (1.53 ± 0.08, p < 0.01), I (1.56 ± 0.25, p < 0.01) and T + I (1.57 ± 0.21, p < 0.01) in relation to the control group (C: 1 ± 0.06). PPARy showed a significant increase only in the T + I group (1.69 ± 0.13, p < 0.05) compared to C (1 ± 0.13). The lipid accumulation in the T3, I and T + I groups were decreased in 22, 26 and 37% respectively, not generating extracellular glycerol release by T3, only by irisin; all treatments diminished DNA damage. T3 alone did not alter the lipolysis process, a fact that may be associated with non-alteration of PPARγ expression, characterizing a decrease in differentiation, leading to lower lipid accumulation. The increase of UCP-1 in the TAB is reported as browning; T3 and/or irisin showed to be effective in increasing UCP-1 levels, decreasing lipid accumulation and DNA damage in human adipocytes. The browning process, as has been demonstrated by several researchers, raises thermogenesis and dissipates energy in the form of heat; therefore the thermogenic capacity of T3 and irisine in the management of obesity and metabolic diseases is quite promising.
Thyroid Cancer Friday Poster Translational
Programmed cell death ligand 1 (PD-L1) overexpression on tumour cells is associated with poor prognosis in thyroid cancer. PD-1/L1 pathway blockade has demonstrated encouraging anti-tumour activity in multiple cancers. Soluble PD-L1 (sPD-L1) has been shown to play a significant role in cancer pathogenesis. To date, there is no research evaluating the predictive capabilities of sPD-L1 in thyroid cancer. We therefore investigated the prognostic significance of serum and plasma sPD-L1 expression in papillary thyroid cancer (PTC) and evaluated the association between these levels and tumoural PD-L1 expression. Pre-treatment levels of sPD-L1 were measured by enzyme-linked immunosorbent assay (ELISA) in 101 patients with confirmed PTC. The associations between sPD-L1 with clinicopathological characteristics and disease-free survival (DFS) were analysed. Immunohistochemical (IHC) staining with an anti-PD-L1 antibody was performed on tissue microarrays constructed from patient samples. PD-L1 expression was considered positive when ≥5% of the tumour cell population was stained. The level of concordance between PD-L1 expression by IHC and sPD-L1 by ELISA was evaluated. The median serum sPD-L1 concentration in PTC patients was significantly higher when compared to healthy individuals (0.48 vs. 0.37 ng/mL; p = 0.028). An increased incidence of extrathyroidal extension was significantly associated with elevated serum sPD-L1 (p = 0.015). Kaplan Meier analysis revealed that patients with high serum sPD-L1 levels had significantly shorter median DFS compared to those with low sPD-L1 levels (14 months vs. 22 months, p = 0.011). On multivariate analysis, serum sPD-L1 was the only significant predictor for DFS. Our study is the first to confirm that elevated serum sPD-L1 expression is significantly associated with DFS in PTC. Levels of sPD-L1 may provide clinicians with a non-invasive biomarker that can lessen dependence on tissue biopsies and identify aggressive thyroid cancers at an earlier stage. Serum sPD-L1 may be used to predict favourable clinical response to PD-1/L1 checkpoint inhibitors in PTC.
Thyroid Cancer Friday Poster Translational
Medullary thyroid cancer (MTC) is a neuroendocrine (NE) tumor that accounts for 3-5% of all thyroid cancer cases. While surgery is the only potentially curative therapy for patients with MTC, almost all patients will have persistent or recurrent disease. MTC remains understudied and therefore continues to disproportionately contribute to thyroid cancer-related mortality. Compared with well-differentiated thyroid cancers, distant metastases are more commonly observed in MTC patients, which ranges from 7-23%, and contributes to a 10-year survival rate of only 10%. To address current research limitations for studying MTC, we have developed both an in vivo murine liver metastasis model to mimic disease progression and an ex vivo 3D bioreactor system to study patients' personalized responses to therapeutics. To create the liver metastasis model, nude mice were intrasplenically injected with MTC cell lines (TT, MZ) followed by a subsequent splenectomy. MicroCT imaging using Fenestra VC was used to assess tumor progression. For the ex vivo system, we used a polydimethylsiloxane bioreactor connected to a peristaltic pump to house the 3D extracellular matrix (ECM) consisting of bovine collagen I and Matrigel in several different ratios to determine the optimal growth condition. Growth of both cell lines and patient tissue was determined via non-invasive fluorescence and bioluminescence imaging using the IVIS Lumina system. After approximately 4 weeks, the murine model developed liver metastases and tumor presence was confirmed through microCT imaging with Fenestra VC. The ex vivo system for NE cancer cell growth was optimized with an ECM composition of 50% collagen I and 50% Matrigel. Imaging of human NE tumor surrogates showed growth from days 3 to 9 (1.4 fold increase) and linear growth of the cell line surrogates was observed for 14 days (7.1 fold increase compared to 0 days). We have developed two different models to enhance research for studying MTC. The combination of both an in vivo murine liver metastasis model and a patient-derived ex vivo 3D bioreactor system may provide a more holistic approach to evaluating and customizing future therapeutics to target MTC.
Thyroid Hormone Metabolism & Regulation Friday Poster Translational
Selenocysteine insertion sequence binding protein 2 (SBP2) is essential for selenoprotein synthesis. Selenoprotein deficiencies in individuals with SBP2 defects result in a multiorgan syndrome with characteristic thyroid function test abnormalities of high serum T4, rT3, TSH and low T3. Except for the latter finding, this phenotype was replicated in a mouse model of induced Sbp2 deficiency (Sbp2 iCKO). In these mice, the deiodinases' enzymatic activity or expression were decreased in tissues, and thyroid gland thyroid hormone (TH) content was increased, with a larger capacity of TH synthesis in Sbp2 iCKO compared to WT mice. This was in part due to decreased thyroidal glutathione peroxidase activity causing H202 accumulation and enhanced iodine organification. In this report we set to assess the role of the pituitary and the hypothalamus in the expression of the thyroid phenotype. We previously reported lower cerebral T3 content in Sbp2 iCKO mice, 70% of that in WT, which raised the question of central hypothyroidism. To investigate this, we measured gene expression in the pituitary glands and performed TRH stimulation test. In the pituitary of Sbp2 iCKO mice, Sbp2 mRNA level was 45% of that in WT mice, a knock down level similar to that observed in other tissues. While Tshb and Hr had normal expression, Trhr gene expression had a 1.4-fold increase in Sbp2 iCKO vs WT mice at baseline, indicative of hypothyroidism at the level of the hypothalamus. Next, in a classical TRH stimulation test, although the Sbp2 iCKO mice had a 1.8-fold higher TSH at time 0, their peak TSH level at 15 min was 70% of that in WT mice. This pattern is reminiscent of the blunt TSH response to TRH characteristic of central hypothyroidism in humans and has the potential to affect TSH bioactivity which is now being investigated. Thus, in the expression of the thyroid phenotype characteristic of SBP2 defects there are contributions not only from impaired TH metabolism due to deficiencies in the deiodinases, but also from each level of the hypothalamic-pituitary-thyroid axis.
Thyroid Hormone Metabolism & Regulation Friday Poster Clinical
Selenocysteine insertion sequence-binding protein 2 (SBP2) is an essential factor for selenoprotein synthesis. Patients with SBP2 defects have selenoprotein deficiencies that manifest as a multiorgan syndrome, and a unique pattern of thyroid function tests (TFTs) due to deficiencies in the selenoenzymes deiodinases. Less than ten families with mutations in SBP2 gene have been published. Here, we report a child with developmental delay who underwent whole exome sequencing and was found to harbor two SBP2 gene mutations and no other potentially causative genetic defects. A 3.5-year-old boy, who was conceived by in vitro fertilization using a donor egg, presented with developmental delay since the age of 4 months. At the age of 3.5, he could sit, crawl, clap his hands, and babble but was unable to stand without assistance or say meaningful words. He had failure to thrive, was less than 3rd percentile for both weight and length and had significantly delayed bone maturation with a bone age of 1.5y. His TFTs revealed high total T4 of 14.5 mcg/dL (5-12), free thyroxine index FT4I of 17.8 (6-10.5) and reverse T3 of 147 ng/dL (16-36), with low total T3 of 61 ng/dL (80-190) and normal TSH of 2.1 μIU/mL (0.4-3.6). Sequencing analysis of SBP2 gene in the proband identified a 1 nucleotide deletion in exon 3 causing frameshift and premature stop codon (c.283delT; p.Tyr95Ilefs*31) and a nonsense mutation in exon 5 (c.589C>T; p.Arg197*). His father carried only the mutation in exon 5, while the exon 3 mutation could have occurred de novo or inherited from the egg donor. Allele-specific PCR of the proband's cDNA confirmed that he was compound heterozygous for the mutations. Knowing that patients with SBP2 deficiency are unable to generate enough T3, treatment with 5 mcg of T3 BID was started and selenium supplementation was also recommended. We report a patient with novel compound heterozygous SBP2 mutations manifesting severe developmental delay, impaired coordination and failure to thrive. Clinical follow up is ongoing to determine the effect of T3 treatment on growth velocity, bone age and development.
Disorders of Thyroid Function Friday Poster Clinical
Despite the increasing attempt to individualize the levothyroxine (T4) treatment, a significant fraction of the treated patients does not reach the target TSH. Previous studies showed that several gastrointestinal (GI) disorders may increase the need for T4. This study was aimed at analyzing, in a large cohort of consecutively examined patients, the prevalence of the more relevant causes of increased need for T4 and at quantifying the impact of these disorders on the T4 requirement. A total of 2808 patients with hypothyroidism, due to inflammatory or autoimmune thyroiditis, were prospectively treated with a tight schedule and were followed up for at least 24 months. All patients agreed to take thyroxine in fasting conditions, waiting at least one hour before eating or drinking. Some 499 (17,7%) patients in pregnancy, lactating, obese, using foods and/or cosmetics and drugs known to affect T4 bioavailability, were positively excluded. The dose has been increased until the desired serum TSH (0.5-2.5 mU/l) had been obtained. Patients have been divided in responders and non-responders based on the threshold dose (1.21 μg/Kg BW/day) obtained as median requirement in 208 hypothyroid patients in whom interferences with T4 treatment, including GI disorders, had been excluded. After all, 295/2309 (12.8%) patients (268W/27M; median age = 50 years; median BMI = 25.37) failed to reach the target TSH and were classified as non responders. The median dose to attain target TSH in these patients was higher than in reference group (1.52 vs 1.21 μg/Kg BW/day; p < 0.0001). They underwent diagnostic workup for gastrointestinal disorders which revealed lactose intolerance in 38 patients (12,8%), H pilory infection and related nonatrophic gastritis in 123 patients (42%), a celiac disease in 10 patients (3.4%), a gastric atrophy in 48 patients (16.3%) and other causes in 27 patients. A definite diagnosis was not reached in 49 patients (16.6%). The median need for T4 ranged from 1.45 μg/Kg BW/day in H pylori related disorders to 1.76 μg/Kg BW/day in celiac patients. These data clearly indicate that GI disorders, mostly occult, account for a significant fraction of T4-treated patients with refractory hypothyroidism.
Disorders of Thyroid Function Friday Poster Clinical
Data on the association of ulcerative colitis (UC), a chronic inflammatory disorder of the large bowel, and thyroid disorders are scarce and whether the presence of UC may interfere with thyroxine (T4) treatment efficacy is not known. The aim of this study has been to examine, in a large cohort of consecutively examined patients with thyroid disorders, the presence of UC and its role in the pharmacologic thyroid homeostasis. A total of 8537 patients were retrospectively analyzed and 43 patients bearing an inflammatory bowel disease were recruited (0.005%). Among them, 32 patients had UC (28F/4M; median age = 59 years), and 15 of them (F/M; median age = 60 years) were in need for T4 treatment. All patients have pledged to take thyroxine in fasting conditions, abstaining from eating or drinking for at least one hour. T4 was prescribed in an increasing fashion until the target TSH (<0.8-2.5> mU/l) has been attained and maintained in at least 2 controls. To calculate the possible excess of T4 required in UC patients, the requirement of T4 has been compared to the one observed in 115, similarly treated, age- and BMI-matched patients, clearly devoid from gastrointestinal and/or pharmacological interference. The median thyroxine dose required was 1.72 μg/kg/day, significantly higher than in the reference group (+22%). An higher dose was needed in 13 out of 15 UC patients (87%). Since half of these were senior patients, we divided the sample in two groups: under 60 years (7 patients; median age = 53 years) and over 60 years (8 patients; median age = 73 years). In younger patients a dose excess has been detected in 5 out of 7 patients (median T4 increase = +26%) being the median T4 requirement 1.78 μg/kg/day, significantly increased as compared to reference patients (1.31 μg/kg/day; p = 0.003). In the elderly group an increased T4 dose was seen in all 8 patients (median T4 increase = +21%), again significantly higher than the one required by the age-matched reference group (p = 0.019). The increased need for thyroxine was therefore similar independently from the age of patients. Our findings support the hypothesis that ulcerative colitis may represent a novel cause of increased need for thyroxine.
Disorders of Thyroid Function Friday Poster Clinical
Amiodarone is an antiarrhythmic medication that can adversely affect thyroid function. The Heart Rhythm Society guidelines recommend obtaining thyroid function tests (TFTs) at amiodarone initiation and every six months thereafter in adults. The optimal screening frequency for pediatrics remains unclear, especially in young children where untreated hypothyroidism affects brain development and growth. As amiodarone is judiciously used in children, limited data exists on pediatric amiodarone-induced thyroid dysfunction. We aim to describe the patterns of amiodarone-induced thyroid dysfunction in pediatric patients. We established a retrospective cohort of 527 patients receiving amiodarone from 1997-2017. We excluded patients with abnormal newborn thyroid screens, known maternal thyroid disease, and <3 days of amiodarone exposure. We defined amiodarone therapy lasting 3-30 days as “short term” and >30 days “long term.”The final cohort (n = 150) consisted of 27 neonates (18%), 25 infants (16%), 27 toddlers (18%), and 71 children (47%). Approximately 109 patients (73%) received short term therapy, 41 patients (27%) received long term therapy. Most patients (78%) receiving long term therapy had TFTs performed. In addition, 28% of patients receiving short term therapy had TFTs performed. Neonates had the highest median peak TSH values in both short and long term groups, 23.5 mIU/L (IQR 11.4-63.1) and 28.8 mIU/L (IQR 11.4-34.4), respectively. The median peak TSH level was elevated in all children receiving long term therapy. Children receiving long term therapy had greater odds than the general population of having developmental delay (p = 0.004; OR 6.1, 95% CI 1.7-21.3), however peak TSH levels were not independently associated with abnormal development. Infants receiving amiodarone had greater thyroid dysfunction than older children. TSH elevations often occurred early, even with short term exposure. Given the concern for poor brain development and growth in hypothyroid children, our results suggest the need for more rigorous pediatric-specific thyroid monitoring guidelines.
Thyroid Cancer Friday Poster Clinical
A subset of encapsulated/circumscribed follicular variant of papillary thyroid carcinoma (fvPTC) was reclassified as “noninvasive follicular thyroid neoplasm with papillary-like nuclear features” (NIFTP) in 2016. The Boston Medical Center (BMC) Thyroid Cancer Registry (ThyroCARE) has enrolled thyroid cancer patients from 2000 to the present. BMC pathologists have historically prepared all malignant nodules using 3 sections/cm and evaluated the entire capsule. With this unique dataset and long-term follow-up, our objective was to describe epidemiology and response to therapy for NIFTP compared to fvPTC. The Registry contains 530 cases of PTC where the original operation was performed at BMC (2000-16) and 20.8% (110) of these were fvPTC (106 = thyroidectomy, 5 = lobectomy). NIFTP candidates were identified from pathology reports. Then slides of all NIFTP candidates were re-reviewed. Criteria established by Nikifurov et al (2016) were used to confirm NIFTP. Of 110 fvPTC, 15 (13%) met NIFTP criteria; 11 women and 4 men, mean age = 47.5 years. Tumors were single in 11 and multiple/bilateral in 4. Mean diameter for fvPTC = 2.3 cm and for NIFTP = 1.7 cm (p = NS). Among NIFTP patients there were no lymph node (LN) or distant metastases and no recurrences. Among fvPTC, 14.7% had positive LN at initial operation, and 4 patients (4.2%) had distant metastases. Half (8) of the NIFTP patients received post-operative RAI therapy. Mean follow-up time was 46 months for fvPTC and 69 months for NIFTP. 87 of 95 patients with fvPTC (91.6%) had an acceptable response to therapy (per 2015 ATA guidelines), and there were no recurrences. 8 patients (8.4%) did not have acceptable response: 4 with synchronous metastases and 4 others with later recurrence (1 LN and 2 distant metastases; 1 biochemical). All 6 NIFTP tested for BRAFV600E mutation were negative. Although relatively small, this dataset is unique in that all NIFTP candidates underwent complete pathologic re-review and mean follow up is >5 years. NIFTP represents a small fraction of total PTC diagnosed after strict pathology review and has low or no risk of malignant potential in our patient population, suggesting that operative treatment alone is adequate oncologic therapy.
Thyroid Cancer Friday Poster Clinical
How to accurately risk-stratify papillary thyroid microcarcinoma (PTMC), defined as <1.0 cm, particularly low-risk PTMC, remains controversial. Multicenter retrospective study of the relationship between BRAF V600E mutation and recurrence of PTMC in 743 patients (584 women and 159 men), with a median age of 49 years (interquartile range [IQR], 39-59 years) and a median follow-up time of 53 months (IQR, 25-93 months).
The overall BRAF V600E mutation prevalence was 32.4% (241/743). Tumor recurrences were 6.4% (32/502) vs 10.8% (26/241) in wild-type BRAF vs BRAF mutation patients (P = .041), with a hazard ratio (HR) of 2.39 (95% CI, 1.05-5.44) for BRAF mutation after adjusting clinicopathological risk factors. In the low-risk group, defined as having no extrathyroidal invasion (ETI), lymph node metastasis (LNM), or distant metastasis (DM), recurrences were 1.3% (5/383) vs 4.3% (6/139) in wild-type BRAF vs BRAF mutation patients (P = .076), with an HR of 6.48 (95% CI, 1.80-23.28) after adjusting medical center, sex and treatment dose of radioiodine (RAI). In low-risk patients <55 years old, adjusted HR of recurrence for BRAF mutation was 5.22 (95% CI, 0.90-30.22); in low-risk patients >55 years old, adjusted HR of recurrence for BRAF mutation was 10.02 (95% CI, 1.28-78.72). In the high-risk group, defined as having at least one of ETI, LNM and DM, recurrences were 22.7% (27/119) vs 19.6% (20/102) in wild-type BRAF vs BRAF mutation patients (P = .577), with an HR of 1.31 (95% CI, 0.71-2.41) after adjusting medical center, sex and treatment dose of RAI. In high-risk patients <55 years old, adjusted HR of recurrence for BRAF mutation was 0.74 (95% CI, 0.30-1.85); in high-risk patients >55 years old, adjusted HR of recurrence for BRAF mutation was 2.01 (95% CI, 0.79-5.10). On Kaplan-Meier analyses, BRAF mutation was associated with a significant decline in recurrence-free survival curves in low-risk PTMC.
BRAF V600E mutation can further differentiate the recurrence risk of clinically low-risk PTMC; wild-type BRAF patients have an extremely low risk whereas BRAF mutation patients, particularly those >55 years old, have a significantly increased recurrence risk.
Thyroid Cancer Friday Poster Clinical
ATC is an aggressive thyroid cancer that requires rapid diagnosis and treatment. cfDNA are double-stranded DNA fragments found within plasma, resulting from apoptosis, necrosis, or release of nuclear DNA. cfDNA can be sequenced, providing a real-time genomic signature of the tumor. Detection of cfDNA by liquid biopsy using next generation sequencing (NGS) offers a rapid, minimally-invasive method to assess mutation status. The objectives of this study were to investigate how well cfDNA results correlated with those obtained from tissue NGS (the gold standard) and to determine the prognostic significance of cfDNA mutations in ATC patients (pts).
ATC pts who underwent NGS mutation testing between Aug 2015 to March 2018 using both cfDNA (73 gene platform) and tumor tissue were included. We evaluated concordance between cfDNA and tissue NGS for individual mutations. A subset analysis of pts with a minimum of 9 months follow-up were evaluated for prognostic significance of individual genes. The median overall survival (OS) was analyzed by Kaplan-Meier method.
82 ATC pts were included. The most commonly mutated genes noted on cfDNA platform were TP53 (59.8%), BRAF (41.5%) and PIK3CA (18.3%). Treatment naïve pts (n = 26) had a higher concordance with tissue NGS than previously treated pts (n = 56). In treatment naïve pts, BRAF V600E, NRAS and PIK3CA cfDNA mutations had a specificity of 100% and positive predictive value of 100%, while BRAF V600E and TP53 had a sensitivity of 86.7% on cfDNA platform, compared with tissue NGS results. PIK3CA mutation was associated with worse OS (9.3 vs. 12.5 months; p = 0.031). Pts with BRAFV600E mutation, treated with BRAF inhibitor (BRAFi) had a longer OS when compared to BRAFV600E mutated who did not receive BRAFi (14.8 vs. 3.2 months; p < 0.001). Pts with coincident BRAFV600E and PIK3CA mutations gained less benefit from BRAFi therapy (10.5 vs. 20.2 months; p = 0.028).
Plasma cfDNA has a high concordance with tissue NGS, particularly before initiation of any treatment. Additionally, cfDNA may be used to guide treatment and provide prognostic information in ATC pts.
Thyroid Cancer Friday Poster Clinical
Extrathyroidal invasion has been well known as a risk factor for papillary thyroid cancer (PTC)-specific mortality, but its role in PTC-specific mortality with respect to the status of BRAF V600E and TERT promoter mutations, the two most prominent oncogenes in PTC, remains unknown. We investigated here the interactions of extrathyroidal invasion with BRAF V600E and TERT promoter mutatoins in the occurrence of PTC-specific mortality. A retrospective study to investigate the relationship between extrathyroidal invasion and PTC-specific mortality with respect to BRAFV600E and TERT promoter mutation status in 1051 patients (287 male and 764 female), with a median (interquatile range, IQR) age of 46 (36-57) years and a median (IQR) follow-up time of 89 (48-142) months. PTC-specific mortalities were 0.4% (2/565) in patients without extrathyroidal invasion, BRAF mutation or TERT nutation, 3.1% (2/64) in patients with extrathroidal invasion without mutation, 6.1% (2/33) in patients with mutation but without extrathyroidal invasion, and 39.4% (13/33) in patients with extrathroidal invasion and both mutations. Compared with patients with no extrathyroidal invation and mutations, HRs (95% CIs) of mortality after adjustment for clinicopathological factors were 2.189 (0.137-35.090) with extrathroidal invasion only, 2.796 (0.273-28.606) with mutation only, and 44.494 (6.638-298.264) with extrathroidal invasion and both mutations. Kaplan-Meier analyses revealed a flat PTC-specific survival curve in patients with no extrathyroidal invasion and mutation or patients with extrathroidal invasion alone, a late modest decline in the curve with mutation alone, and an early sharp decline in the curve with coexisting extrathroidal invasion and both mutations. These results demonstrate that the PTC-specific mortality risk of extrathyroidal invasion is dependent on the BRAF and TERT mutation status; extrathroidal invasion alone or mutation alone is a mild mortality risk, wheareas coexistence of extrathyroidal invasion and the two mutations is a robust mortality risk, representing a strong interaction between extrathyroidal invasion and mutation.
Thyroid Cancer Friday Poster Clinical
To determine the efficacy of low-dose radioactive iodine (RAI) therapy (30 mCi, 1110 MBq) in Chinese patients with intermediate- to high-risk papillary thyroid cancer (PTC) without distant metastasisThis large retrospective study included Chinese patients with PTC that tested negative for thyroglobulin antibodies. Patients were categorized into low-dose (30 mCi, 1110 MBq) and high-dose (>100 mCi, 3700 MBq) RAI groups. Ablation rate and long-term response were compared between groups using propensity score matching (PSM) to minimize bias and confounding. In total, we included 446 patients. No significant difference in ablation success rate was found between groups (P = 0.305) before or after PSM (N = 162; P = 0.200). Excellent response (ER) rate was not significant between groups before (P = 0.917) or after PSM (P = 0.798). Efficacy of low-dose RAI was similar to that of high-dose RAI in N0- (P = 1.000), N1a- (P = 0.981), and N1b-stage (P = 0.903) patients. Low- and high-dose RAI groups achieved similar ER rates in pre-ablative stimulated thyroglobulin level (≤1 ng/mL: P = 1.000; 1<ps-Tg ≤5 ng/mL: P = 0.444; 5<ps-Tg ≤10 ng/mL: P = 0.665; >10 ng/mL: P = 1.000) and BRAFV600E -positive (P = 0.324) subgroups. Efficacy of low-dose RAI therapy was similar to that of high-dose for ablation and achieving ER in Chinese nonmetastatic intermediate- to high-risk PTC patients. High-dose RAI could not rectify ablation failure or non-ER rates in PTC patients with BRAFV600E , lymph node metastases, or unfavorable thyroglobulin levels.
Thyroid Cancer Friday Poster Clinical
We performed this meta-analysis aimed to identify the correlation between iodine 131 treatment after thyroid carcinoma and pregnancy outcome. Electronic database the PubMed, Embase, Cochrane Library, CNKI, VIP, and Wanfang were throughly search to identify the observation studies which reported the the correlation between iodine 131 treatment after thyroid carcinoma and pregnancy outcome up to December 2017. A total of 7 observational studies were enrolled, including 14212 participants and 3106 pregnancies. The number of pregnancies in the iodine 131 treatment group was 1939 cases in the iodine 131 treatment group and 1167 in the no iodine 131 treatment group. DTC postoperative iodine 131 treatment had no significant effect on spontaneous abortion (OR = 1.05, P = 0.703); DTC postoperative iodine 131 treatment had no significant effect on induced abortion (OR = 1.05, P = 0.861); DTC postoperative iodine 131 treatment had no significant effect on premature birth (OR = 1.50, P = 0.064); DTC postoperative iodine 131 treatment had no effect on stillbirth (OR = 0.63, P = 0.406) ; DTC postoperative iodine 131 treatment had no effect on abortion (OR = 1.07, P = 0.574); The risk of the abortion in the group which interval time of last 131I treatment and pregnancy >1 year was lower than <1 year. The incidence of abortion was 0.52 times of that of the latter (OR = 0.52, P = 0.000). The postoperative iodine 131 treatment dose greater than 100mci and less than 100mci group had no effect on abortion (OR = 0.91, P = 0.526). The risk of the abortion in the group which interval time of last 131I treatment and pregnancy >1 year was lower. The postoperative 131I treatment of DTC had no significant effect on the outcome of abortion, premature birth, and 131I treatment dose had no significant effect on abortion. Recommendations DTC patients pregnancy should be avoided within 1 year after iodine 131 treatment.
Thyroid Nodules & Goiter Friday Poster Clinical
Vocal cord paralysis or paresis (VCP) is a known complication of thyroidectomy. The rates for permanent paralysis range around 0.5% to 3% with higher rates for transient paresis. Multiple studies have shown that early intervention can improve outcomes for those with VCP. There is no known literature on the timing of VCP diagnosis or referral patterns to a laryngologist. A retrospective review was conducted at a multi-institution medical system. We identified all patients who had undergone a thyroidectomy or had a diagnosis of dysphonia or had a vocal cord medialization by the use of International Classification of Diseases (ICD) and Current Procedural Terminology (CPT) codes. These lists were merged and cross referenced for analysis. Between 2002 and 2018, we identified 5980 patients who underwent a thyroidectomy, 6274 patients with a diagnosis of dysphonia and 532 patients who underwent vocal cord medialization. Of those, 142 patients had undergone a thyroidectomy and had a diagnosis of dysphonia, of whom 4 had also undergone vocal cord medialization. Of the 142 patients, 52 had a diagnosis of dysphonia predating the thyroidectomy, 68 were diagnosed with dysphonia within 1 year of the thyroidectomy and 22 were diagnosed with dysphonia over 1 year following the thyroidectomy. For the group diagnosed with dysphonia within 1 year of the thyroidectomy, mean days to dysphonia diagnosis was 97 days (SD 77; Range 4-344). Of those who had undergone vocal cord medialization, mean days to procedure was 155 (range 45-357). There is a significant delay in diagnosis of dysphonia after a thyroidectomy which delays therapy and potential recovery. Physician education of this delay is crucial to allow for timely referrals to otolaryngologist from proper evaluation and therapy.
Thyroid Hormone Metabolism & Regulation Friday Poster Clinical
Initiation of thyroid hormone replacement (THR) after a total thyroidectomy has traditionally relied on the weight of the patient, regardless of the patient's body mass index (BMI). Current literature suggests that THR in obese patients differs from non-obese patients. This can lead to over-dosing of levothyroxine (LT4) and delay in achievement of euthyroid state. This study aimed to evaluate the appropriate dosing of THR in overweight and obese patients. We retrospectively identified patients on THR after total thyroidectomy with a benign post operative diagnosis. Patients who achieved euthyroidism with THR were included in the analysis. Patient demographic and THR dosing information was collected. Regression analysis was performed to identify appropriate THR dosing at varying BMIs. Our cohort consisted of 114 patients achieving euthyroidism while on THR. Mean age was 55 years (range 28–77 years) with 84% females. Of the 114 patients, the number of patients with a BMI less than 25, 25 to 29, 30 and 34, 35 and 39, and greater than 40 were 26 (23%), 33 (29%), 23 (20%), 19 (17%) and 13 (11%), respectively. Of the entire cohort, a mean of 50 weeks elapsed after surgery to achieve euthyroidism, with no significant difference between the BMI categories (p = 0.58). In obese patients (BMI >30), 35% were over-dosed with LT4 on initial dosing. The cohort lost a mean of 3 kg until euthyroidism was achieved with no significant difference in the weight loss based on BMI category (p = 0.61). Patients with a higher BMI did require a higher dose (mcg) of LT4 to achieve euthyroidism (p < 0.01) but the dose was significantly lower in relation to their weight (mcg/kg), (p < 0.01). The LT4 dose required to achieve euthyroidism based on the previously mentioned BMI categories were 1.76 mcg/kg, 1.47 mcg/kg, 1.42 mcg/kg, 1.27 mcg/kg and 1.28 mcg/kg. A regression equation was derived for calculating initial levothyroxine dose (mcg/d = 0.97* Kg + 40). The current weight-based dosing of THR inappropriately over-doses overweight and obese patients. A more appropriate formula for THR titration should consider both the weight and BMI of the patient.
Thyroid Nodules & Goiter Friday Poster Case Report
Major cardiac symptoms caused by the thyroid gland are generally due to thyroid hormone imbalance and not the goiter size. Although a thyroid goiter can cause compressive symptoms, leading to orthopnea, dyspnea and dysphagia, there are no reports of major cardiovascular complications, such as Takesubo's cardiomyopathy. 51 year old female with a known history of multinodular goiter and worsening orthopnea developed acute shortness of breath, palpitations and symptoms of presyncope for which she presented to the emergency department. Workup showed mild elevation of troponins to 0.89 and moderate ST-T changes on electrocardiogram and an unremarkable echocardiogram. Thyroid function tests were within normal limits. Thyroid imaging showed a diffusely enlarged thyroid with multiple large nodules and mass effect on the trachea with an airway opening of 3 mm.
A cardiology consult was obtained and a cardiac catheterization was performed. The results showed basal hyperdynamic contraction and severe hypokinesis of left ventricle with ejection fraction of 35%, in the setting of normal coronary arteries. Findings were consistent with Takesubo's syndrome. This was thought to be due to stress on the body created by the airway compression.
After patient was stabilized and discharged, she underwent elective total thyroidectomy with awake intubation. Pathology showed nodular hyperplasia with no malignancy. Patient recovered well post operatively with resolution of symptoms. No further episodes of chest pain or shortness of breath have been noted. Takesubo's cardiomyopathy is a syndrome in which a patient has signs and symptoms of acute myocardial infraction without coronary artery disease. It most commonly presents after a stressful or emotional situation, hence the name “broken heart syndrome.” In our patient, the trigger was thought to be the systemic stress of orthopnea due to the airway compression. Similar to our patient, the most common symptoms on presentation are substernal chest pain, dyspnea or syncope. In euthyroid patients, a large thyroid goiter can present with orthopnea, dyspnea or dysphagia but in a minority of patients the goiter can also lead to major cardiovascular complications such as cardiomyopathy.
Autoimmunity Friday Poster Case Report
Checkpoint inhibitors can cause immune-mediated adverse events affecting virtually every organ system. We describe a patient who developed hypothyroidism, primary adrenal insufficiency, and type 1 diabetes mellitus (DM) over 4 months in the setting of Pembrolizumab therapy for non-small cell lung cancer. A 73-year-old woman with stage IV NSCLC for 10 years presented to the Emergency Department with altered mental status and severe weakness. She had been diagnosed with a new pulmonary mass 4 months before admission and received 6 cycles of Pembrolizumab. She had an 11-year history of type 2 DM on oral agents, but was admitted 2 months prior for diabetic ketoacidosis and found to have c-peptide 0.1 ng/mL (1.1-4.4 ng/mL) and GAD-65 antibody <5 U/mL (0-5 U/mL) Admission BP: 134/81, HR: 85, RR: 17, T: 103°F. Physical exam was notable for lethargy. Labs revealed severe hyponatremia114 mmol/L (135-145 mol/L). Subsequent workup included 6 am cortisol 2 mcg/dL (6.7-22.6 mcg/dL), ACTH <1.1 pg/mL (7.2-63.3 pg/mL) when already on hydrocortisone, and peak cortisol 60 min after ACTH stimulation of 8 mcg/dL (>18 mcg/dL). The remaining pituitary panel showed FSH 21.9 mIu/mL (postmenopausal: 16.7-113 mIu/mL), LH 9.7 mIu/mL (postmenopausal: 10.9-58.6 mIu/mL), prolactin 29 ng/mL (1.4-24 ng/mL), TSH 13 uIu/mL (0.4-4.2 uIU/mL), free T4 < 0.4 ng/dL (0.80-1.50 ng/dL), thyroglobulin antibody 2450 u/mL (0.0-4.1 U/mL) and TPO 41 IU/mL (<5.6 IU/mL). Aldosterone was <1 ng/dL (0-30 ng/dL) and 21OH antibody level was <1 U/mL (<1 U/mL). MRI did not show evidence of hypophysitis. She improved dramatically after replacement with hydrocortisone and levothyroxine. Pembrolizumab is a PD-1inhibitor. This class of medications can cause T-cell mediated endocrinopathies; in particular, it increases the risk of developing thyroid dysfunction 5-fold. Antibody levels may not be elevated. Our case is unique for rapid onset of 3 autoimmune endocrine disorders likely due to treatment with Pembrolizumab.
Disorders of Thyroid Function Friday Poster Case Report
Graves' disease (GD) is the most common cause of hyperthyroidism (HT) in the United States (1). Thioamide derived antithyroid drugs (ATD) are initiated in patients with HT to rapidly attain euthyroid state in preparation for radioiodine therapy or thyroidectomy (2). We report a challenging case where ATD were contraindicated in a critically ill patient and alternate medications were necessary to bridge to thyroidectomy.30 year old Hispanic man presented with weakness. He was found to have significant HT, Graves' ophthalmopathy, and thyromegaly. He was initiated on Methimazole (MMI) 20mg and propranolol 60mg every 8 hours; following clinical improvement, he was discharged. Two weeks later, he was readmitted with Influenza A along with worsening leukopenia (8.5 to 2.1 k/uL) and neutropenia (6.3-1.7k/uL). His TSH was 0.010 IU/mL, free T4 5.08 nd/dL, total T3 2.78ng/mL, TSI >500U, and TSH Receptor Ab 6.82iU/L. He was not a surgical candidate at that time. MMI was discontinued and he was placed on Filgrastim. Saturated solution potassium iodine (SSKI), high dose steroids, and cholestyramine were immediately initiated. Ultimately, lithium was added and uptitrated to achieve euthyroid state prior to total thyroidectomy. This case highlights the importance of alternate medications that can be used safely and effectively in the setting of intolerance to ATD.
Severe adverse effects of ATD include agranulocytosis, vasculitis, or hepatic failure (3). In this patient with thyrotoxicosis and agranulocytosis due to ATD, the addition of SSKI, cholesytramine, and high dose steroids provided minimal clinical and biochemical improvement. It was only with the initiation of Lithium that euthyroid state was successfully achieved. Lithium highly concentrates in thyroid follicular cells and is effective in inhibiting thyroid hormone release by altering tubulin polymerization and inhibiting action of TSH on the cAMP pathway (4). Therefore, lithium should be considered as a therapy option when more commonly used medications are contraindicated or ineffective.
This case highlights the importance of alternate therapy, most importantly, lithium that can be used safely and effectively in the setting of contraindication to ATD.
Disorders of Thyroid Function Friday Poster Case Report
Rarely, thyrotoxic patients may be refractory to antithyroid drugs. Achieving euthyroid state before definitive treatment with thyroidectomy or radioactive iodine is critical to prevent progression into thyroid storm (TS) which can be life-threatening.
Case 1: 29 y/o old female with h/o Grave's disease and 2 previous hospitalizations for TS presented again with impending TS with Burch-Wartofsky Point Scale (BWPS) of 35. Labs showed TSH <0.03 IU/ml (0.27-4.2), FT4 6.7 ng/dl (0.93-1.7), FT3 20 pg/dl (2-4.4). She was managed conservatively and discharged home with plan for thyroidectomy after achieving euthyroid state. Despite being treated with propylthiouracil (PTU) 100 mg q6hrly, propranolol, steroid, Lugol's iodine, cholestyramine, her FT4 and FT3 levels remained elevated. She was admitted for plasmapheresis. After 2 sessions, FT3 decreased to 8.8 pg/dl but FT4 remained unchanged. She underwent successful total thyroidectomy and was discharged home with resolution of her symptoms.
Case 2: 44 y/o old female with h/o Grave's disease presented with impending TS with BWPS of 40. Labs showed TSH <0.03 IU/ml, FT4 4.34 ng/dl, FT3 > 20 pg/ml. She was intubated for respiratory failure and admitted to ICU. She was treated with PTU 200 mg q4hrly, Lugol's iodine, steroid, propranolol, cholestyramine. Even after 17 days of maximized traditional therapy, her FT4 and FT3 remained high. Plasmapheresis was initiated and after 2 sessions, FT4 decreased to 2.74 ng/dl and FT3 decreased to 3.31 pg/ml. She underwent successful total thyroidectomy and was discharged home in a stable condition.
Most thyrotoxic patients respond to medical management, though if unsuccessful, plasmapheresis may be attempted as a last measure before definitive therapy. Plasmapheresis decrease the level of circulating free and bound thyroid hormones, enzymes, autoantibodies and cytokines, calming hyperthyroid state for further intervention. In patients with Grave's disease who are refractory to conventional therapy, plasmapheresis should be considered as a safe and effective treatment before thyroidectomy.
Disorders of Thyroid Function Friday Poster Case Report
Sporadic congenital non autoimmune hyperthyroidism (SNAH) is rare. Several reported cases show that symptoms were present for at least 2-6 months before diagnosis of hyperthyroidism was established. This late diagnosis of hyperthyroidism often leads to premature bone aging. We report a case of SNAH for which the diagnosis of hyperthyroidism was established by chance prior to the onset of symptoms due to thyroxine treatment of the mother during pregnancy. In spite of early diagnosis at 4 months chronological age, an advanced bone age of 1.5 years was already present.
At 4 months of age a female patient was diagnosed with hyperthyroidism based on suppressed TSH and increased free T3 and T4. The reason for thyroid hormone value assessment of the child at 4 months of age was thyroxine treatment of the mother during pregnancy. At the age of 4 months, the child was asymptomatic. There were no dysmorphic features present, her heart rate was in the upper normal range. She showed an enlarged thyroid as assessed by ultrasound, and advanced bone age of 1.5 years. Before the molecular diagnosis was established the patient was treated with thiamazole 5mg/day. The thiamazole dose had to be increased repeatedly. At 13 months of age the patient had a further increase in thyroid gland volume and a further increase in bone age of 2.5 years. Using high resolution melting PCR followed by Sanger sequencing of peripheral blood DNA, a heterozygous TSHR 1895C>T mutation, resulting in a T632I amino acid change was detected. This mutation has previously been functionally characterized as constitutively activating. Neither parent carries this mutation, thus it is a sporadic germline mutation. Early diagnosis of SNAH is essential and challenging in a neonate. This case demonstrates that premature bone aging can be present even before the onset of hyperthyroidism symptoms. Detection of germline TSHR mutation for patients suspicious for SNAH is important to direct therapy as non-autoimmune hyperthyroidism does not generally respond well to antithyroid drug treatment and surgical removal of the thyroid is necessary for these patients.
Thyroid Cancer Friday Poster Clinical
A high number of metastatic neck lymph nodes (>5) is significantly associated with the recurrence of PTC. The aims of this study are to analyze the demographic and sonographic features of cN0 papillary thyroid microcarcinoma (PTMC) associated with high volume lymph node metastasis (LNM). We retrospectively reviewed the medical records of 1952 cN0 PTMC patients who underwent surgery from October 2013 to December 2015. All the patients underwent central lymph node dissection; 56 patients underwent ipsilateral neck dissection. Number of metastatic lymph nodes was affirmed by histopathology. Preoperative demographic and sonographic features such as gender, age, tumor size, echogenicity, calcification, multifocality, vascularity and capsule invasion were recorded. Univariate and multivariate analysis were performed to identify preoperative features of cN0 papillary thyroid microcarcinoma (PTMC) associated with high volume LNM (>5). Among the 1952 cN0 PTMC patients, 73 cases (3.7%) have high volume LNM. The following features including age <45 years old (OR = 3.610, p < 0.001), male sex (OR = 2.185, p = 0.002), microcalcifications (OR = 2.586, p = 0.005), larger tumor size (>7mm) (OR = 2.604, p = 0.002) were independent risk factors of cN0 PTMC for high volume LNM.
Several risk factors of cN0 PTMC may associated with high volume LNM. As these features appear, the aggressive approach and careful follow-up are necessary to prevent PTMC recurrence.
Thyroid Nodules & Goiter Friday Poster Case Report
Sonography is routinely used in evaluating thyroid nodules and performing fine-needle aspiration cytology (FNAC). Occasionally, nonthyroidal lesions can mimic thyroid nodules on examination or imaging and get aspirated. A 55 year-old woman, with cough and neck discomfort, was reported to have an incidental right thyroid ‘‘nodule’’ during evaluation of the thyroid with a neck sonography. A heterogeneous 0.9 × 1.0 × 0.9cm extremely hypoechoic nodule containing intense calcification was visualized in the posterior aspect of the right thyroid lobe. A repeat sonography before the ultrasound-guided FNAC was performed the next day. The “nodule” turned into an isoechoic mass containing hyperechoic foci and the pattern of suspected calcifications had changed. We made a paratracheal air cyst model by trapping Foley Catheter between two slices of pork. The sonography of model showed the similar change when probe was sliding.
To rule out Zenker's diverticulum, barium swallow study and upper endoscopy were performed. Unexpectedly, both of the findings were negative. For further evaluation, neck CT scans and 3-Dimensional reconstruction were obtained, and an unusual air pocket was found on the right side of the trachea. It had an irregular wall, and multiplanar reformatted imaging showed that a slit-like structure linked it with the trachea. Chest radiographs revealed mild emphysematous change but did not depict the air pocket in the right lower neck region. After reviewing all the above findings, a paratracheal air cyst was diagnosed. At follow-up 3 years later, the patient remained asymptomatic with no increase of the “nodule” in sonography.
A paratracheal air cyst may be mistaken for a ‘‘thyroid nodule’’ on ultrasound if the subtle differentiating signs were missed. An awareness of this condition is important to avoid unnecessary needle biopsies.
Thyroid Hormone Metabolism & Regulation Friday Poster Case Report
Synthetic thyroxine is the treatment of choice for hypothyroidism. There are few reported cases of levothyroxine drug hypersensitivity reactions (DHR). We present two cases of DHR to thyroid replacement therapy (TRT) with subsequent management by desensitization (high pre-test probability for a DHR) and challenge (low pre-test probability for a DHR). Case #1 is a 45-year-old woman diagnosed with Papillary Thyroid Cancer. After thyroidectomy, she was started on Synthroid® 175 mcg daily which was not tolerated and she developed multiple adverse reactions (i.e. nausea, vomiting) to other types of oral TRTs (Armour®, Cytomel®). The patient developed flushing, dysphagia, urticaria, and angioedema within 30 minutes of IV thyroxine; she also failed pre-medications (diphenhydramine) and slow infusion rates. She developed similar symptoms with liquid forms of TRT. Skin testing to Levothyroxine was negative and the patient deferred challenge. She completed a novel 13-step oral desensitization to 125 mcg with only mild lip/nose pruritus during step #10. The patient has tolerated the TRT until date without further adverse reactions.
Case #2 is a 70-year-old woman with Hashimoto's Thyroiditis. She was initiated on 25 mcg of Levothyroxine daily. Due to poor response, her medication was changed to Synthroid® 50 mcg daily, with which she reported dysphagia, throat closing sensation, and lip swelling. The patient discontinued Synthroid® after the episodes and was off TRT for 1 year due to fear of another adverse reaction. The contents of each TRT preparation were analyzed for excipient/filler content. The patient tolerated an open oral challenge with Tirosint™, which contains only the active ingredient and gelatin, without further reactions. The patient has tolerated the TRT until date. Hypersensitivity reactions to TRT are secondary to the active ingredient, fillers or excipients in the medication. The reference standard for DHR is a challenge as there is no validated skin test. When a DHR is confirmed either through a challenge or skin testing, desensitization protocols may be a high value asset. We proposed a simple approach to adverse reactions to TRT.
Thyroid Nodules & Goiter Friday Poster Case Report
The vast majority of benign thyroid nodules do not require intervention. However, nodules leading to compressive symptoms or altered cosmesis often warrant either surgical or non-operative management, which may include radioactive iodine (RAI) treatment or radiofrequency ablation (RFA). A 94-year-old man with atrial fibrillation and multiple transient ischemic attacks presented with thyroid enlargement and progressive dysphagia, choking sensation, dyspnea, and hoarseness. Two fine needle aspiration biopsies were negative for malignancy, and thyroid function was normal. He had undergone two collagen injections for left vocal cord paralysis (likely due to stretching of the left recurrent laryngeal nerve) with only transient improvement. Imaging revealed a very large, right-sided thyroid nodule (6.4 × 5.6 × 8.4 cm), with significant leftward tracheal deviation, tracheal luminal compression, upper mediastinal extension, and displacement of the right subclavian and common carotid arteries. He was deemed a poor surgical candidate due to high risk for cerebral hypoxia. RFA was not pursued given the nodule's substernal extension. I-123 uptake revealed a 24-hour uptake of 45%, with heterogenous uptake in the nodule. He subsequently received therapy with 29 mCi of I-131. At 6 months, the nodule had decreased in size by approximately 1 cm in length; 12-month follow-up revealed a 20% decrease in nodule volume, improved symptoms, and continued euthyroidism. This case highlights the complexity of managing a large, symptomatic thyroid nodule in an elderly, comorbid patient. RFA has been shown to reduce nodule volume by an average of 78% at one year; however, nodule size and extension can affect this treatment's efficacy. RAI may reduce goiter volume by 40% at 1 year, with reduced effects in large goiters; higher doses may lead to more significant volume reduction. Using recombinant human TSH prestimulation may also lead to improved outcomes, especially in larger goiters with reduced RAI uptake or tracheal compression. In similar selected cases of benign goiters presenting with compressive symptoms, RAI therapy should be considered for significant shrinkage of the goiter and amelioration of pressure symptoms.
Thyroid Nodules & Goiter Friday Poster Case Report
Acute suppurative thyroiditis accounts for <0.7% of all thyroid pathology, and only 8% of cases occur in adults. A 67-year-old woman presented to the Emergency Department with 1 week of tender left neck swelling, fatigue and frequent loose bowel movements. She denied tremors, change in appetite or weight, palpitations, hair loss, recent dental infection or oropharyngeal instrumentation. She was diagnosed with multinodular goiter 15 years prior and denied recent FNA. Admission vitals noted temperature 102.9°F and heart rate 109 beats per minute. Blood cultures grew Streptococcus pneumoniae. Her thyroid was enlarged with a prominent warm, tender, firm mass on the left without appreciable adenopathy. Labs revealed TSH 0.044 uIU/mL (0.4-4.2 uIU/mL), free thyroxine 2.04 ng/dL (0.8-1.5 ng/dL), free T3 2.96 pg/mL (2.5-3.9 pg/mL), C-reactive protein 359.46 mg/L (<5.1 mg/L), ESR 120 mm/hr (<20), TSI <0.1 IU/L (<0.55 IU/L) and TSH receptor antibodies 0.8 IU/mL (<1.75 IU/L). HIV was negative 3 years prior. Initial non-contrast neck CT showed an asymmetric multinodular goiter without adenopathy. Ceftriaxone was started. 5 days later, neck CT with contrast revealed a 7 cm low-density mass within the left thyroid lobe surrounded by soft tissue streaking displacing the trachea and left carotid artery. Surgical drainage removed 200 mL of pus from both thyroid lobes; cultures returned sterile. After 2 days of dexamethasone for airway swelling, she was extubated and completed antibiotics. Evaluation of sinus anatomy and total thyroidectomy are planned. There is no standard of care for this rare endocrine emergency, which can be difficult to distinguish from subacute thyroiditis and malignancy, but most reports agree on the need for antibiotics and urgent surgical management. In light of widespread inflammation, we favor a guarded approach of drainage, postoperative intubation for airway edema and delayed thyroidectomy. Predisposing factors include immunosuppression, local trauma, infection or instrumentation, bronchial arch abnormalities, and possibly parenchymal disease. Our case highlights the importance of a broad differential diagnosis in a patient with multinodular goiter presenting with sepsis and thyrotoxicosis.
Thyroid Nodules & Goiter Friday Poster Case Report
Neck masses are a common presenting complaint. The differential diagnosis of anterior, midline neck masses includes thyroglossal duct cysts, thyroid nodules and pyramidal lobes. When neck imaging reveals a hypervascular nodule associated with the thyroid, paraganglioma is a rare, possible diagnosis.70 year old female, history of hypertension, asthma, and resected gallbladder cancer, presented with an incidental anterior, midline neck mass. It was stable and asymptomatic for many years. Family history was notable for a grandson with a thyroglossal duct cyst. Physical exam revealed a 4 cm midline thyroid mass that elevated with swallowing but not tongue protrusion. TSH and free T4 were normal. Thyroid ultrasound showed a well-circumscribed, complex, hypoechoic 1.4 × 4.9 × 1.4 cm midline structure with grade 3 vascularity consistent with isthmus nodule vs. thyroglossal duct cyst. CT neck showed a midline, well-defined, homogenously hypodense mass anterior to the thyroid cartilage and inferior to hyoid bone, most consistent with thyroglossal duct cyst. FNA revealed scant follicular cells and rare lymphocytes, classified as Bethesda III, Atypia of Unknown Significance. The mass was resected. Pathology showed a 3.7cm paraganglioma, without evidence of malignancy. Plasma fractionated free metanephrines were normal ruling out functioning paraganglioma. Whole body imaging and genetic counseling were recommended. Paragangliomas are rare neuroendocrine tumors that derive from extra-adrenal autonomic paraganglia. Those in the head and neck arise from parasympathetic paraganglia, usually from the carotid body or jugular bulb, and only up to 5% are functional. Only 28 cases of thyroid-associated paragangliomas have been reported, and are believed to arise from the inferior laryngeal paraganglia. Like other head and neck paragangliomas, perithyroidal paragangliomas rarely elaborate catecholamines. Up to 1/3 of paragangliomas are due to inherited syndromes. This case defines a rare, but important, cause of an anterior neck mass. Patients diagnosed with paraganglioma should have a hormonal evaluation for functional disease, imaging to evaluate for synchronous/metastatic disease, and genetic counseling.
Thyroid Nodules & Goiter Friday Poster Case Report
Radioactive iodine has been used as a treatment for Graves' disease since the 1940s. Symptomatic calcifications of a thyroid lobe after radioactive iodine treatment have only been reported once in English language literature. A 60-year-old woman presented with progressive stridor associated with odynophagia. Her medical history was positive for Graves' disease that was treated with radioactive iodine therapy approximately two decades ago. Flexible laryngoscopy revealed bilaterally immobile vocal folds. A computed tomogram of the neck was performed that showed large bilateral intrathyroidal calcifications. On direct laryngoscopy, the calcifications had partially eroded the anterolateral trachea wall. Tracheostomy was performed for airway protection. The calcifications were removed through the tracheostomy incision. One month post-operatively the patient was found to have bilaterally mobile vocal folds. We report a case of bilateral vocal fold paralysis secondary to bilateral intrathyroidal calcifications following prior administration of radioactive iodine that resolved upon removal of the calcifications. Presumably, the intrathyroidal calcifications were causing compression and neuropraxia of the bilateral recurrent laryngeal nerves. This is only the second time in the literature that large, symptomatic intrathyroidal calcifications have been described following radioactive iodine therapy. It is the first time that we are aware that bilateral intrathyroidal calcifications causing bilateral vocal fold paralysis have been described.
Autoimmunity Friday Poster Basic
Vanadium is a metal that has different states of oxidation (-1, 0, +2, +3, +4, and +5), and vanadium pentoxide (V2O5) is the most common form in commercial products. All the Vanadium compounds are considered toxic and their carcinogenic role on the thyroid has been recently suggested. Despite this, until now no in vivo or in vitro studies have evaluated the effect of the exposure to Vanadium on thyroid in humans and/or animals. We have evaluated the effects of V2O5 on normal thyrocytes viability and proliferation as well as its effect on T-helper (Th)1 chemokines [(C-X-C motif) ligand (CXCL)9 CXCL9, CXCL10, CXCL11] and Th2 chemokines (CXCL8) secretion. No effect of V2O5 on thyrocytes viability or proliferation has been observed. Furthermore it has been shown that it is able to induce the secretion of Th1 and Th2 chemokines into the thyroid, increasing the effect of important cytokines, as interferon (IFN)-γ and tumor necrosis factor (TNF)-α, and abolishing the inhibitory effect of IFN-γ on CXCL8 secretion. Our data show that V2O5 induces the secretion of Th1 chemokines into the thyroid, synergistically increasing the effect of Th1 important cytokines such as IFN-γ and TNF-α, leading to the induction and perpetuation of an inflammatory reaction into the gland. Future evaluations will be necessary to investigate thyroid function, and nodules, in occupationally exposed subjects, or living in polluted areas.
Autoimmunity Friday Poster Clinical
Several studies have reported an association between autoimmune thyroid disorders and other autoimmune disorders. We have focused on the prevalence of autoimmune diseases in subjects affected by Graves' Disease (GD) with/without Graves' Ophthalmopathy (GO).
Three thousand and two hundred-nine patients with GD were prospectively evaluated regarding the appearance of other autoimmune disorders, with respect to three age (+/− 5 years) and gender, matched (3:1), control groups. We have randomly enrolled control groups from the same general population of which: 1069 subjects without thyroid disorders; 1069 patients with non-toxic multinodular goiter; and 1069 patients having autoimmune thyroiditis. Diagnoses were made by specialist according to the criteria established by the scientific societies.
We have shown a significant increase of the prevalence of autoimmune disorders in GD patients, with respect to the controls for: chronic autoimmune gastritis (CAG), vitiligo (Vit), rheumatoid arthritis, polymyalgia rheumatica (Polym), celiac disease, diabetes type 1, sjogren disease, multiple sclerosis, systemic lupus erythematosus, sarcoidosis, systemic sclerosis, HCV-related cryoglobulinemia. The most frequent associations were GD+CAG+Vit and GD+CAG+Polym. The prevalence of non thyroid autoimmune diseases observed in GD patients with GO is significantly higher than that observed in GD patients without GO, with a spectrum of non thyroid autoimmune disorders non significantly different.
In order to avoid the delay in the diagnosis for other autoimmune disorders, we suggest that patients with GD (with/without GO) being still unwell, or who develop new not specific symptoms, despite adequate treatments, should be screened for the presence of other autoimmune disorders. Further population studies are needed to investigate and confirm or not the associations with other autoimmune disorders with a low prevalence, such as primary biliary cirrhosis, or dermatomyositis.
Autoimmunity Friday Poster Translational
Macro-thyroid-stimulating hormone (macro-TSH) is a high-molecular-weight form of TSH causing hyperthyrotropinemia. This study was undertaken to compare the methodologies for the diagnosis of macro-TSH and to examine the prevalence and nature of macro-TSH in females of reproductive age. Blood samples were taken from 1,794 female patients who visited the Hamada Obstetric and Gynecology Hospital in Tokyo, Japan complaining of infertility. The serum of 305 patients with TSH concentrations >2.5 mU/L was screened for macro-TSH by the polyethylene glycol (PEG) method. Samples with TSH precipitation ratios by PEG >70% were further analyzed using gel filtration chromatography (GFC), protein G columns and 125I-TSH binding experiments. The TSH precipitation ratio by PEG was 63.4 ± 12.3% in 305 patients and 63 of them showed >70% (mean +0.5 SD). TSH reference preparation in phosphate buffer containing γ-globulin plus albumin exhibited comparable precipitation ratios by PEG to those of serum TSH, suggesting that the high background might be due to the nature of TSH molecule being prone to be precipitated by PEG. GFC revealed that immunoreactive TSH, with a molecular weight of approximately 150 kDa, eluted at higher ratios (79.6 ± 24.4%) in 27 of the 63 patients, compared to 0.4 ± 2.0% in the control group. Serum TSH concentrations in 24 of the 27 patients were spuriously elevated due to human anti-mouse antibodies. We detected macro-TSH in the other three patients and one of them had anti-TSH autoantibodies. Eight of the remaining 36 patients, who did not have high-molecular-weight TSH assessed by GFC, had immunoglobulin G-associated TSH. Binding components forming macro-TSH may be dissociated from TSH during GFC causing discrepant results in these patients. Three commercially available TSH immunoassays (Elecsys®, Centaur®, and Architect®) all recognized macro-TSH leading to the elevated serum TSH concentrations. None of the methods for the diagnosis of macro-TSH were perfect. Prevalence of macro-TSH in infertile women would be between 0.17% (3/1794) and 0.61% (11/1794). Commercial TSH immunoassays recognized macro-TSH, resulting in the diagnosis of hyperthyrotropinemia.
Autoimmunity Friday Poster Clinical
Graves' disease is an autoimmune condition affecting the thyroid gland and is a common cause of hyperthyroidisim. The main treatment goals are the reduction in thyroid hormone overproduction either with antithyroid drugs (ATD), surgery or radioactive iodine (RAI) therapy. The aim of RAI (I-131) therapy is to treat hyperthyroidism by destroying sufficient thyroid tissue to render the patient either euthyroid or hypothyroid. The objective of this work was to examine the outcomes of RAI treatment for Graves' disease in a large patient cohort over a two year period in a West of Ireland tertiary referral academic medical centre. In particular we focused on the characteristics of those patients requiring a second RAI administration. Institutional Review Board approval was obtained for this study and thereafter the clinical records of all the patients who underwent RAI treatment were examined. The data demonstrated that 150 patients underwent RAI treatment from Jan 2014 to Dec 2015. Of this patient cohort 107 were female (mean age: 59 years, std dev ±15 years) and 43 were male (mean age: 62 years, std dev ±14 years). Sub analysis of the data showed that 14/150 patients required a second dose of RAI (10 females, 4 males) and one of those patients (female) required a third dose of RAI treatment and ultimately a thyroidectomy. The mean RAI dose administered was 360MBq, std dev: 36 MBq.
Analysis of the data for those patients requiring a repeat dose of RAI therapy demonstrated a male:female ratio (1:2.5) which was the same as the overall dataset ratio. However the consistent finding documented in the clinical notes in the majority of patients that required a second dose, was the failure to stop taking ATD's in the week before RAI administration.
A review of the literature shows that the influence of ATDs on the therapeutic efficacy of RAI in hyperthyroidism is controversial. Several authors have suggested discontinuation of therapy at least a week before administration of radioactive iodine therapy to improve outcomes and our data would support this premise. We have now updated our hospitals clinical pathway protocol to discontinue ATD a week before administration of RAI therapy for the treatment of Graves' disease.
Autoimmunity Friday Poster Case Report
A Grave's Disease patient was evaluated for sepsis syndrome and was eventually diagnosed with thyroid storm and severe pancytopenia induced by methimazole. A 30 y/o Chinese female with Grave's Disease, taking methimazole 10 mg three times per day, presented with fever, sore throat, nausea and vomiting. Vitals signs: temperature 102.9°F, blood pressure 110/82 and heart rate 153/min. Physical examination showed: thin woman, nonenlarged thyroid gland without thyroid nodules, bilateral hand tremors and hyperactive reflexes.
Initial labs: WBC 1.3, absolute neutrophil count 0, hemoglobin 8.1 and platelets 23. Methimazole was stopped and she was started on intravenous hydration with normal saline and empiric antibiotics. TSH was measured and was found undetectable and free T4 was 2.88 (0.76-1.46 ng/dL). Treatment initiated of every 6 hours: dexamethaxone 2 mg, propanolol 40 mg and Lugol's 5% 5 drops. Hematology/Oncology recommended filgastrim daily and WBC count rose from 1.3 to 15.4. Antibiotics were discontinued when all imaging and culture studies were negative for infection. Endocrine surgery was consulted and patient underwent total thyroidectomy.
Two weeks late, patient's free T4 was normal at 1.07 on 75 micrograms of daily oral levothyroxine. Methimazole or propylthiouracil, are the most common initial treatment for thyrotoxicosis in many countries. Agranulocytosis, although rare, is a life-threatening complication of such therapy. Thyroid storm is a rare and potentially fatal endocrine emergency which frequently occurs following a precipitant, such as an acute illness, and presents with symptoms of severe thyrotoxicosis including tachycardia, arrhythmia, cardiovascular collapse, hypotension, fever, psychiatric disturbances and gastrointestinal upset. A high index of suspicion is necessary since the symptoms may resemble disorders of other high cardiac output state, e.g., severe sepsis.Antithyroid drugs can cause hematopoietic changes and usually occurs within the first two to three months of treatment. These side effects can be severe and potentially fatal, reason is so important to follow this patients closely.
Disorders of Thyroid Function Friday Poster Clinical
Due to drug malabsorption, patients affected by autoimmune atrophic gastritis could have some issues in the L-thyroxine (L-T4) absorption, as it is influenced by different factors, such as dietary habits, interference with other drugs, absorption kinetics, age of the patient, adherence to therapy, etc. We have enrolled 32 patients affected by autoimmune atrophic gastritis with high serum thyrotropin (TSH) levels following a therapy with L-T4 in tablet formulation. L-T4 tablet formulation was changed to a liquid one, maintaining the same dosage.
The switch from L-T4 in tablet formulation to an oral liquid one with the same L-T4 dosage lead to a circulating TSH levels normalisation/reduction.
Eleven patients who were switched back again to receive L-T4 in tablets (using the same dosage) had a worsening of TSH levels, falling in the hypothyroid range.
Our collected data lead to hypothesize that the pH alteration issue caused by autoimmune atrophic gastritis could be overcome by the oral L-T4 liquid formulation administration.
Disorders of Thyroid Function Friday Poster Clinical
The effectiveness of levothyroxine (L-T4) in liquid formulation in patients recently subjected to total thyroidectomy is not yet well known. Our aim is to study the efficacy of L-T4 liquid formulation in comparison to L-T4 tablets, in patients recently submitted to total thyroidectomy, with no malabsorption or drug interference issues.
One hundred and forty two patients were included in the study of which 71 received liquid L-T4 formulation, while 71 took L-T4 tablets using the same dosage (1.5 mcg/kg/day). Treatments started the day after surgery, with L-T4 administered 30 min before breakfast. At week 6 (1st control), and then at week 12 (2nd control) for both the groups of patients thyrotropic hormone (TSH), free thyroxine (FT4), and free triiodothyronine (FT3) were evaluated. TSH values were significantly lower in the liquid L-T4 group, with respect to the tablet L-T4 group, in both the first (P < 0.05) and the second control (P < 0.01), while no significant differences were observed for FT4 and FT3 levels. The prevalence of patients in the hypothyroid range (TSH >3.6 mcU/ml) was higher in the L-T4 tablet group in comparison to the liquid L-T4 group.
A better efficacy of liquid L-T4 (versus L-T4 tablets) was observed in controlling TSH levels in patients previously undergone to total thyroidectomy for thyroid cancer without issues of malabsorption, gastric disorders, or drug interference.
Disorders of Thyroid Function Friday Poster Clinical
Several factors could influence L-thyroxine (L-T4) absorption, such as the age of the patient, dietary habits, interference with other drugs, absorption kinetics, adherence to therapy. Patients affected by celiac disease could have issues in the L-T4 absorption, due to drug malabsorption.
Twenty-one patients affected by celiac disease with high serum thyrotropin (TSH) levels following a therapy with L-T4 in tablet formulation were included in the study. All subjects switched to a L-T4 liquid formulation, without any change in the dosage.
All patients obtained a circulating TSH levels normalisation/reduction after the switch from L-T4 in tablet formulation to an oral liquid one with the same L-T4 dosage. Only nine patients switched back again to receive L-T4 in tablets, maintaining the same dosage, showing a worsening of TSH levels, with values falling into the hypothyroid range.
Our findings suggest that oral L-T4 liquid formulation administration could aid in the management of patients affected by celiac disease, then overcoming malabsorption issues.
Disorders of Thyroid Function Friday Poster Clinical
Treatment of Graves' disease (GD) and toxic nodular goiter (TNG) has the objectives to cure hyperthyroidism, prevent recurrent disease and preserve thyroid function. Treatment efficacies and long-term outcomes of antithyroid drugs (ATD), radioactive iodine (RAI) or surgery varies in the literature. We report outcome of treatment, cure rate and risk factors for relapse for GD and TNG in an unselected cohort. A prospective incidence-cohort of de novo diagnosed GD and TNG patients (n = 2916) from 2003-05, were invited to a follow-up 6 - 10 years after diagnosis. Questionnaires were sent to 2430 patients regarding treatments, cure rate, recurrence, quality of life, demographic data, comorbidities and life-style factors. Patients were treated according to clinical routine with ATD, RAI or surgery.
Of those included, 1186 (83.3%) had GD and 237 (16.7%) had TNG.
In GD patients, 351 (45.3%), 264 (81.5%), and 52 (96.3%) were cured by ATD, RAI or surgery respectively as first line treatment. Of those, 77.0%, 15.4% and 3.8% respectively were without levothyroxine supplementation at follow-up at 8 ± 0.9 years. Including all treatment modalities, 851 (71.8%) of GD patients were cured within one treatment period. At follow-up, 278 (23%) of GD patients had been operated.
In TNG patients, RAI cured 88.6% and surgery 92.9%, whereof 52/154 (33.8%) and 3/15 (20%) had no levothyroxine supplementation post RAI and surgery, respectively.
The proportion that did not feel fully recovered at follow-up was 25.3% of GD and 18.1% of the TNG patients.
Overall, treatment of hyperthyroidism results in preserved thyroid function only in 35.3% and 44.7% of GD and TNG cases, respectively.
As many as 23.4% of the GD patients end up with surgery although only 4.6% choose it from the beginning. Our treatment tradition cures 71.8% of GD patients and 78.1% of TNG patients within one treatment period. The high number of patients who do not feel recovered 6 -10 years after hyperthyroidism in GD and TNG is a reminder of the chronic nature of hyperthyroidism.
Disorders of Thyroid Function Friday Poster Clinical
In Graves' disease (GD), brain derived symptoms like fatigue, loss of concentration, emotional lability and anxiety are common and are attributed to the hyperthyroidism per se. It has also been observed that the volume of structures important for cognition, as the medial temporal brain lobes (MTL) that include the hippocampi, are reduced in hyperthyroidism and that the reduction in the left hippocampus correlates negatively to the levels of free thyroxine (fT4). We hypothesise that thyroid autoimmunity is also a key role player in the mental symptomatology in GD and we aim to determine the role of thyroid hormones and thyroid autoantibodies for structural brain changes in the MTL.
The CogThy project is a longitudinal case-control study where 65 premenopausal women with fT4 > 50 pmol/L (ref 12–22) were included after diagnosis of GD when still hyperthyroid but after start of anti-thyroid drugs. Free thyroid hormones (fT3 and fT4), thyroid-stimulating hormone receptor antibodies (TRAb) (Roche Cobas), thyroid-stimulating immunoglobulins (TSI) (Siemens IMMULITE) and the volumes of MTL structures were evaluated at baseline and after 15 months of thyroid treatment in euthyroidism. MTL structures were measured by a 3 T magnetic resonance (MR) scanner and analyzed with automatic segmentation using MAPER. The MR data were normalized to intracranial volume. We here present baseline results in patients. Thyroid hormone levels are before start of treatment. There were weak trends towards negative correlations between free thyroid hormones (fT3 and fT4) and the volumes of hippocampus and amygdala. Negative correlations were detected between the volume of right amygdala and TRAb Cobas (r = −0.30 p = 0.020) and TSI (r = −0.35, p = 0.006). There was also a negative correlation between the left amygdala volume and TRAb Cobas (r = −0.29, p = 0.027). There were non-significant trends towards negative correlations between the hippocampal volumes and the thyroid immunological markers. These markers correlated positively to fT3 and fT4. These data support our hypothesis that thyroid autoimmunity, measured as TRAb and TSI, also affect MTL structures, beside the effect from thyroid hormones.
Disorders of Thyroid Function Friday Poster Clinical
Amiodarone is the most commonly used anti-arrhythmic drug worldwide. Despite its impressive profile as an antiarrhythmic agent, its use is hampered potential adverse effects, including thyroid dysfunction. Amiodarone impacts thyroid hormone metabolism via inhibition of type I and II 5’-monodeiodinase, inhibition of T4 transport into the cell, decreased binding of T3 to the thyroid nuclear receptor, and decreased renal clearance of reverse T3. Amiodarone also has primary thyroid gland toxicity which is thought to be related to the high iodine content of the medication. This includes amiodarone-induced hypothyroidism and thyrotoxicosis.
The NASPE has published guidelines based on adults for monitoring thyroid function. There has not been any study published on thyroid function in pediatric patients.
The primary objective is to determine the incidence of amiodarone induced alterations in thyroid hormone metabolism in children and adolescents. The secondary objectives are to compare incidence of amiodarone induced alterations in thyroid hormone metabolism in a pediatric population compared to published data in adults and to identify the variance in thyroid hormone surveillance and management of pediatric patients with amiodarone-induced altered thyroid hormone production and metabolism. This is a single site, retrospective chart review of individuals treated with amiodarone at Children's Hospital of Philadelphia between 1/1/2007 and 12/31/2017.
Exclusion Criteria
Individuals with primary thyroid disease on thyroid hormone replacement prior to starting amiodarone.
Sample size based on sample of all diagnosed cases within the date range. Baseline descriptive statistics, demographics and clinical characteristics will be presented as mean ± SD or median for continuous variables and counts with percentages for categorical variables. Differences will be evaluated for continuous data by student's T-test or Mann-Whitney U-test. We have 473 patients treated with amiodarone at CHOP since 2007. We are dividing these in to acute and chronic exposures to amiodarone. We will then see the incidence of thyroid dysfunction and how many days in to treatment this occured. We plan to expand to multi-center.
Disorders of Thyroid Function Friday Poster Clinical
Reduced glomerular filtration rate (GFR) is a major cardiovascular disease risk (CVD) factor in elderly subjects. Our aim was to study the relationship of elevated TSH with cardiometabolic risk factors and GFR in an elderly population at high CVD risk. Elderly patients (age >65ys) who attended our Endocrinology Unit were prospectively included in this cross-sectional study. High CVD risk was defined by two or more CVD risk factors (high blood pressure(HBP), smoking(S), diabetes(DM), high total cholesterol, low HDL cholesterol, previous cardiovascular event, metabolic syndrome (defined according to the harmonized IDF criteria). Patients with known thyroid disease and/or L-T4 use were excluded. TSH >6mU/l with normal free T4 levels (0.6-1.8ng/dL) was defined as subclinical hypothyroidism (ScH). GFR was estimated by the Berlin-Initiative Study (BIS)-1 formula which was developed for an elderly population. Urinary albumin to creatine ratio was calculated (uACR). IL-6 and TNA were determined by chemiluminescence. Carotid intima media thickness (CIMT) was determined by Doppler ultrasound. Differences were evaluated by U Mann-Whitney test and correlations by Spearman test. Multiple linear regression was used to identify independent predictors of GFR. The studied group comprised 246 patients (68% females) from which 20 (8%) had ScH. Diabetes was less frequent in the group of patients with ScH vs euthyroidism (35 vs 58%, p = 0.039) in spite of being older (median, Q1-Q3: 77,72-78; 72,68-77 years, p = 0.01). In addition, they showed lower fasting glucose (−20%, p = 0.01), GFR (−14%, p = 0.01) and freeT4 (-10%, p < 0.001) than euthyroid patients. GFR was correlated with age (r-0.482, p < 0.001), TSH (r-0.172, p = 0.004), IL-6 (r-0.150, p = 0.047), TNA (r-0.274, p < 0.001), uACR (r-0.170, p = 0.009) and cIMT(r-0.189, p = 0.004). Multiple linear regression identified TSH (Bst -0.131, p = 0.023, R2 = 0.25) as an independent predictor of GFR in a model adjusted by age, sex, BMI, uACR, S, DM and HBP. The present findings suggest that higher TSH in the elderly could contribute to low GFR and consequently to excess CVD risk. If low thyroid function is a mere bystander or contributes to renal disease in the elderly should be addressed in longitudinal studies.
Disorders of Thyroid Function Friday Poster Clinical
POTS is a condition of Dysautonomia characterized by abnormal increments in heart rate upon assumption of the upright posture accompanied by symptoms of cerebral hypoperfusion and sympatho-excitation. An increase in heart rate equal to or greater than 30 BPM or to levels higher than 120 BPM during a head-up tilt test is the main diagnostic criterion. The symptoms of pots are widespread because the autonomic nervous system plays an extensive role in regulating functions throughout the body. However, hypothyroidism is a common condition of thyroid hormone deficiency. Clinical manifestations of hypothyroidism range from serious life threatening symptoms to no signs or symptoms. The most common symptoms in adults are fatigue, lethargy, cold intolerance, weight gain, constipation, change in voice, and dry skin, but clinical presentation can differ with age and sex, among other factors. The standard treatment is thyroid hormone replacement therapy with Levothyroxine. A retrospective study done on 798 POTS patients was conducted from June 2014 till September 2017. We reviewed the medical records for 798 POTS patients for Hypothyroidism.
The aim of this study is to determine co-dominance and association between POTS and Hypothyroidism as those patients have shared symptoms including fatigue, temperature intolerance, bradycardia, and muscle aches. Out of 798 POTS patients we found 125 out of 678 (18.43%) females with the mean age of 37.981 +/− 12.368 were diagnosed with Hypothyroidism. We also found 12 out of 114 males (10.52%) with the mean age 40.666 +/− 16.408 who were also diagnosed with hypothyroidism. The patients have been consistently taking their hypothyroidism drugs, however have not seen improvements in their POTS symptoms. Our study has shown that some patients with Hypothyroidism may not show improvement in their symptoms which are obscured because of the presence of POTS. These patients need additional attention and specific management for their POTS condition.
Disorders of Thyroid Function Friday Poster Clinical
While patients with hyperthyroidism may develop myopathy, significant elevations in creatine kinase (CK) are rare. Myositis is commonly seen in hypothyroidism and occasionally caused by anti-thyroid drugs (ATD); however, rhabdomyolysis resulting from rapid reduction in thyroid hormone may also occur, thereby posing a dilemma in management. We report a patient with Graves' disease on carbimazole (CMZ) who developed myositis secondary to relative hypothyroidism. A 23-year-old lady presented to the Emergency Department with myalgia and muscle cramps without weakness. She had been diagnosed by primary care to have Graves' disease 2 months earlier, having presented with clinical and biochemical hyperthyroidism (FT4 [Free Thyroxine] >100 pmol/L [Reference Interval (RI): 12 – 22], TSH [Thyroid Stimulating Hormone] <0.005 mIU/L [RI: 0.27 – 4.2]) and high titres of TSH receptor antibody (6.2 IU/L [RI: <1.8]). She had been treated with CMZ 20 mg twice a day, which improved her thyrotoxicosis, but resulted in rapid lowering of FT4 within a month. Her symptoms had developed a month after starting CMZ, which had already been adjusted to 15 mg daily with FT4 8.1 pmol/L and TSH 0.020 mIU/L at point of review. CK was elevated at 2300 U/L (RI: 24 – 200). Systems review was unremarkable and renal function was normal, with no other cause of myositis identified. CK and myalgia improved with hydration and reduction of CMZ dose to 5 mg daily. Thyroid hormone has multiple effects on skeletal muscle, and there have been increasing reports of myositis after treatment of Graves' disease. While the mechanism remains unknown, associations with ATD and relative hypothyroidism have been suggested. Given that patients on treatment are generally on ATD and have reductions in levels of thyroid hormone, aetiology is difficult to determine. As musculoskeletal complaints are common in patients with hyperthyroidism, relative hypothyroidism-induced myositis may be more common than reported. Anticipating this condition will allow clinicians to intervene with early dose reduction to alleviate myositis. Reduction of ATD doses with close monitoring instead of discontinuing treatment or extensive investigation may be a prudent course of action.
Disorders of Thyroid Function Friday Poster Clinical
Amiodarone-induced thyrotoxicosis (AIT) is a diagnostic and management challenge, especially during severe thyrotoxicosis accompanied by cardiovascular compromise. In this study, we aimed to identify outcomes of AIT and potential influencing factors. Retrospective cohort study of adults with heart disease (other than congenital) who were evaluated at Mayo Clinic for AIT between 1-1-2013 and 12-31-2016. Thyroid size, vascularity, iodine uptake and TSH receptor antibodies (TRAb) were used to differentiate type of AIT. We assembled 67 consecutive AIT cases over the study duration. They had been on amiodarone (average dose 2.4 mg/kg/day) for a median of 30 mo. Median TSH was 0.005 mIU/L, free T4 2.5 ng/dL and total T3 122 ng/dL. TRAb were elevated in 4/34 (12%). AIT was classified as type 1 in 34%, type 2 in 21%, mixed in 15%, undefined due to absence of ultrasound in 30%. 79% were symptomatic. Initial management included observation in n = 21 and medical therapy in n = 46 (ATD in 12, glucocorticoid in 7, combination in 27). Amiodarone was discontinued in n = 36, n = 1 received perchlorate and n = 3 received cholestyramine. Final management (after excluding 5 lost to follow up) included observation in n = 18, medical therapy in n = 41 and thyroidectomy in n = 3. Median follow-up duration after AIT was 22 mo. AIT resolved in 81% after median of 5 mo (57% became euthyroid and 31% hypothyroid). Time to resolution was longer and proportion of resolution lower in mixed AIT (compared to AIT types 1 and 2) and medical therapy (compared to observation and thyroidectomy) groups. Complications included hospitalization for arrhythmia or heart failure (39%), ejection fraction decline from any cause (27%), worsening arrhythmias (24%), and mortality (10%). The observation group had lower rates of worsening arrhythmia (p 0.03) and hospitalization for heart failure (p 0.02) as compared to medical therapy. 32 patients continued or re-initiated amiodarone at last follow-up with 1 having recurrence (3%). Mixed AIT cases have a protracted course with less likelihood of resolution. Observation when utilized for mild cases does not lead to worse outcomes. Amiodarone continuation or re-initiation does not seem to affect AIT outcomes or recurrence.
Disorders of Thyroid Function Friday Poster Clinical
Thyroid storm (TS) is a rare but potentially life-threatening manifestation of hyperthyroidism, often accompanied by multi-organ dysfunction. It requires early recognition and aggressive restoration of euhormonal state for optimal outcomes. Thyroidectomy has been described for refractory disease acutely but evidence is predominantly limited to case reports. Experience at our institution suggests that surgery may be employed safely in the setting of TS to definitively treat the underlying disease. Using both the Burch-Wartofsky (BW) scoring system (≥45) and Akamizu (JTA) Criteria, patients were identified that were treated with total thyroidectomy during hospitalization for TS between 2011–2017 at a tertiary care center. Retrospective review was conducted on presenting features, treatment regimens, surgical timing, perioperative course, and long-term outcomes. Eight patients (3 female, 5 male) met inclusion criteria. Mean age was 29 years, and all had Graves' disease. By JTA criteria, 5 patients were classified as more severe (TS-1), and 3 patients had less severe disease (TS-2). BW scores ranged from 45-125 (median 77.5), and precipitating factors included infection (n = 3), medication noncompliance (n = 4), and recent iodine load (n = 1). All patients were treated with maximal medical therapy for TS; acute comorbidities including cardiorespiratory failure (n = 5), liver dysfunction (n = 4), and renal insufficiency (n = 4) were managed with supportive care. Patients underwent surgery 8-23 days after admission (mean 15.5 ± 5.7) and demonstrated improving clinical status and normal, or near-normal, thyroid hormone preoperatively. Major complications included 1 cervical hematoma, and 1 patient requiring 48 hours of extracorporeal life support perioperatively. No permanent hypoparathyroidism, laryngeal nerve injury, or persistent hyperthyroidism was observed. Median postoperative length of stay was 4 days (range 1-31). Thirty-day mortality was 0, though there was a late mortality secondary to abdominal sepsis after feeding tube dislodgement. Patients with TS are generally considered poor surgical candidates; however, this series reinforces that thyroidectomy can be a safe, effective component in the management of this disease.
Disorders of Thyroid Function Friday Poster Clinical
Graves' orbitopathy (GO) is the most common extra thyroidal manifestation of Graves' disease (GD). According to Rundle's curve, GO is characterized by an initial phase of increasing activity (inflammatory phase), a severity peak, and a stable plateau phase (fibrotic phase). This overview has an implication in GO therapeutics. Different patterns that are still distinct from Rundle's curve have not yet been described. There were 567 patients with GD from a single clinical center, who were analyzed according to the Clinical Activity Score (CAS) for GO activity. GO evolution was evaluated every 6 months using the CAS. The patients were divided into 2 groups according to the GO evolution: Group 1 (G1): patients who follow Rundle curve; Group 2 (G2): patients whose characteristics followed GO improvement and worsening over time. Follow-up in both groups was seen at 60 months. From 567 initial patients, 204 patients were included. G1 (n = 132), mean (± SD), age at diagnosis was 39 ± 11 years, 80% were female, with smoking present in 36% of patients. TSH and free T4 were 0.014 ± 0.026 IU/mL and 4.40 ± 2.09 ng/dL, respectively. Thyrotropin receptor antibodies (TRAb) were positive in 84% patients. In G2 (n = 72), age at diagnosis was 41 ± 11 years, 73% were female, and smoking was present in 51% of patients. TSH and free T4 were 0.017 ± 0.031 IU/mL and 3.92 ± 1.82 ng/dL, respectively. TRAb were positive in 85% patients. Both groups had similar characteristics except for smoking (p < 0.05).
The changes of CAS in G1 were: initially, 1.20 ± 1.20, 6 months: 0.89 ± 1.02, 12 months: 0.64 ± 0.87, 24 months: 0.55 ± 0.72, 36 months: 0.55 ± 0.72, 48 months: 0.33 ± 0.58, and 60 months: 0.38 ± 0.56. However, in G2, CAS changes were: initially, 2.34 ± 1.50, 6 months: 1.79 ± 1.69, 12 months: 1.39 ± 1.36, 24 months: 1.36 ± 1.31, 36 months: 1.40 ± 1.40, 48 months: 1.36 ± 1.47, and 60 months: 1.00 ± 1.16. GO evolution had better outcomes with G1 in all periods (two-way ANOVA, p < 0.001). We did find differences between GD treatments and smoking (Log-rank test). We described a group of patients with GO, characterized by periods of worsening and improvement of inflammatory signs. These data indicate that GO is a recurrent chronic disease.
Disorders of Thyroid Function Friday Poster Case Report
Agranulocytosis is a life-threatening complication seen in 0.2-0.5% of patients on methimazole (MMI) for treatment of Graves' Disease. Neutropenia that does not resolve after cessation of MMI should prompt investigation for alternative etiologies. We present a case of severe neutropenia due to occult infection.66 year old woman with osteoarthritis on hydroxychloroquine & recent diagnosis of Graves' disease on MMI 20 mg daily presented to ED with syncopal episode. 1 week prior she had fever, sore throat, vomiting & diarrhea. She was diagnosed with strep throat & treated with amoxicillin. Vitals:101.1, HR 140-150 (new Afib), BP 111/45. Labs notable for severe neutropenia WBC of 0.4, ANC 0. TSH was <0.005, thyroxine 2.49. MMI & hydroxychloroquine were discontinued. Empiric broad spectrum antibiotics were started. 72 hours later, daily high grade intermittent fevers & agranulocytosis persisted. Blood & urine cultures were negative. CT of neck & chest were negative. Re-examination revealed oral ulcerative mucosal lesions. Swab for viral DNA PCR of these lesions confirmed diagnosis of HSV-1. Prompt start of acyclovir resulted in resolution of fevers & agranulocytosis. Methimazole was a known risk factor for agranulocytosis, but did not explain degree of severe leukopenia here. Although hydroxychloroquine carries risk of agranulocytosis, no cases are reported in the literature of concomitant use increasing this risk. Cases from MMI occur in 1st 3 months after initiation. Doses <30 mg/d are less likely to cause this side effect. Average recovery time is 10 days to 2 weeks after discontinuation. Lastly, HSV related neutropenia is rarely seen in adults. In this patient low dose of MMI was used. MMI & hydroxychloroquine was discontinued 1 week prior to presentation. Despite this, neutropenia with daily high-grade fevers persisted. Identification & treatment of oral HSV infection led to resolution of fever & improvement of agranulocytosis. Drug induced agranulocytosis can mimic sepsis, unless the precipitant is truly an infection. This case exemplifies the need for close clinical monitoring, broad differentials & good investigative skills when treating life threatening rare complications of anti-thyroidal medications.
Thyroid Cancer Friday Poster Case Report
Coexistance of medullary and papillary thyroid carcinoma is a variant of thyroid carcinoma. They account for less than 1% of the thyroid malignancies and very few cases have been reported so far. We are describing a case of thyroid tumor with both papillary and medullary features.65 year old man presented for evaluation of incidental bilateral thyroid nodules. Subsequent ultrasound of thyroid revealed multiple high risk nodules with irregular borders and microcalcifications. FNA was performed on bilateral single dominant nodules, and cytology indicated malignant cells. Total thyroidectomy was performed. Pathology revealed a sclerosing variant of PTC in the left lobe with ETE, evidence of vascular and perineural invasion with AJCC pathologic stage of pT3NXMX. Right lobe lesion was 1.2 cm medullary carcinoma stage pT1Nx. Follow up CT scan was negative for malignant adenopathy. Post operative labs included CEA 3.0 ng/mL (≤3.0 ng/mL), calcitonin 9.0 (≤10 pg/mL). Target TSH is 0.1 – 0.5 uIU/mL. Radioactive iodine ablation of microscopic remnant disease with close surveillance for recurrence with ultrasound and thyroglobulin level is planned. Mixed papillary and medullary thyroid cancers have different clinical and biological behavior from tumors that have only papillary or medullary carcinoma features. PTC originates from follicular cells whereas MTC arises from parafollicular cells. They both follow different molecular pathways of cancer. Three hypotheses for their origin exist: stem cell theory, collision theory, and hostage theory. The diagnosis is confirmed by histology and immunohistochemistry. Differentiated papillary thyroid cancer expresses thyroglobulin, on the other hand, medullary thyroid cancer expresses calcitonin. Surgery is the treatment of choice; however, the role of radioiodine therapy in medullary thyroid cancer is controversial. Clinicians should be aware of this rare clinical entity of mixed variety of thyroid cancer. Precise diagnosis is essential for management. These mixed variety of thyroid cancers are treated differently and followed with different tumor markers.
Thyroid Hormone Metabolism & Regulation Friday Poster Case Report
Since 2015, megadoses of Biotin are being used in Progressive Multiple Sclerosis (MS). This has increased the incidence of laboratory errors related to thyroid function tests. Abnormalities may go undetected, or, if acted on can lead to misdiagnosis & devastating outcomes. We describe a case that emphasizes the importance of clinical correlation with laboratory results for accurate diagnosis.71 y.o.F with active Graves' Disease & MS presented to the hospital with hypothermia, hypotension & bradycardia. Core temp was 30.4 C, systolic blood pressure 80-90s, with sinus bradycardia of 30-40s. Exam revealed a critically ill, lethargic elderly woman with bradycognition, delayed reflexes, periorbital puffiness, slow respiratory rate & nonpitting edema of legs suggestive of myxedema coma. X-Ray revealed multifocal pneumonia. TSH was expectedly elevated at 15.20 uIU/mL. Congruently elevated fT4 3.03 ng/dL (0.58-1.64 ng/dL) & TT3 of 407 ng/dL did not correlate with the clinical picture. Quick review of medication history revealed use of Biotin 100 mg daily for treatment of MS, 100x daily allowed dose. Query to pathology department revealed our assays yielding fT4 & fT3 employed biotin-streptavidin competitive immunoassay resulting in falsely elevated fT4 & fT3. Repeat labs were sent to outside facility that did not employ biotinylated immunoassays & revealed elevated TSH (10.29 uIU/mL) with normal fT4 & TT3. Biotin-streptavidin affinity immunoassays are of two kind: 1) Competitive immunoassay that can cause falsely elevated TT3 & fT4 2) Sandwich immunoassay that leads to falsely low TSH result in setting of biotin excess. In our patient, biotinlyated competitive immunoassay gave falsely elevated results. 48 hours after Biotin discontinuation, repeat labs matched those from outside lab. The profound clinical presentation in this case drove the rapid investigation of incongruent test results. Biotin interference with immunoassays can lead to inaccurate laboratory results, misdiagnosis and delay in patient care. Endocrinologists should be aware of this interference, know which immunoassays are currently employed in their hospital & which labs can reliably and rapidly be used for diagnosis & monitoring of treatment.
Disorders of Thyroid Function Friday Poster Case Report
Cardiovascular effects of hypothyroidism include bradycardia, hypertension, decreased myocardial contractility, dilated cardiomyopathy and pericardial effusions. Pericardial effusions are fairly common in hypothyroid patients, with a reported incidence of 30-80% in severe hypothyroidism. However, these effusions seldom come to clinical attention and only rarely present as frank cardiac tamponade. Most of the existing knowledge on the topic is based on published case reports and clinical experience. We present an 86-year-old female with a history of hypothyroidism who was sent to the ED after being found in a state of confusion at home. Further history revealed non-adherence to levothyroxine therapy. On admission, she had a temperature of 100.3 F, heart rate 66 beats/min and blood pressure 123/64 mmHg. Physical exam revealed an obese female (BMI 33.6 kg/m2) with generalized dry skin and expiratory wheezing in bilateral lung fields. Electrocardiogram showed first-degree AV block with low voltage QRS complexes. Serum chemistry studies showed thyrotropin levels 72 mIU/L (0.4-4.2), T3 was 46 ng/dL (87-178) and T4 4.2 ng/dL (5.0-12.2). An enlarged cardiac silhouette and a small right pleural effusion were seen on chest radiograph. Transthoracic Echocardiography (TTE) showed a medium to large circumferential pericardial effusion with mild RV free wall collapse, suggesting tamponade. She was started on thyroxine replacement and underwent pericardiocentesis with removal of 870 ml of clear, serous fluid. Fluid analysis showed an exudate (protein 4.2 g/dL, LDH 158 U/L); bacterial, viral, and fungal cultures were negative, and no acid fast bacilli or malignant cells were seen on microscopic examination of the fluid. Repeat TTE showed resolution of the pericardial effusion, and the patient was discharged on levothyroxine. Hypothyroidism is a rare cause for cardiac tamponade, but should be considered after exclusion of other potential etiologies. In addition to thyroxine replacement, patients often require pericardial fluid drainage for complete resolution. However, lack of strict management guidelines leaves the decision-making largely to the clinician's best judgment.
Disorders of Thyroid Function Friday Poster Case Report
Hyperthyroidism can often result in sinus tachycardia and cardiac arrhythmias, most commonly atrial fibrillation, with an incidence of around 5-15%. We present a 22 year-old male with no significant past medical history who presented to the ED with palpitations, excessive sweating and a history of weight loss. On physical exam, the patient was tachycardic and had an irregularly irregular pulse. Electrocardiogram showed atrial fibrillation with a rapid ventricular rate (RVR) at 140 beats/min. Serum chemistry studies revealed thyrotropin level <0.003 mIU/L (0.4-4.2), total T4 22.2 ng/dL (5.0-12.2), free T4 4.03 ng/dL (0.8-1.5) and T3 > 800 ng/dL (87-178). Thyroglobulin antibodies and thyrotropin receptor antibodies were elevated at 83.8 IU/mL (0.00-4.1) and 31.49 IU/L (0.00-1.75) respectively. He was initially treated with propylthiouracil (PTU), iodine, hydrocortisone and propranolol. He was later switched from PTU to methimazole, which eventually had to be discontinued owing to development of neutropenia. He was started on digoxin for additional rate control, but continued to remain in atrial fibrillation with RVR despite maximal doses of propranolol and digoxin. Given his young age and the arrhythmia refractory to pharmacotherapy, he was taken for a semi-urgent thyroidectomy. The patient tolerated the procedure well, with reversion to normal sinus rhythm and a heart rate in the 90s on post-operative day 1. He was discharged upon successful recovery, and eventually started on levothyroxine replacement in the outpatient setting. Management of atrial fibrillation secondary to thyrotoxicosis focuses on treating the cause using antithyroid medications, coupled with beta-blockers for rate control. Most patients revert to normal sinus rhythm with normalization of thyroid function. However, in patients refractory to initial treatment or those with serious adverse reactions to therapy, alternate treatment options such as radioactive iodine ablation or thyroidectomy have to be considered. Thyroidectomy as a treatment for atrial fibrillation arising from hyperthyroidism has not been studied in detail, but can be considered an option for patients who are refractive to, or do not tolerate pharmacotherapeutic measures.
Disorders of Thyroid Function Friday Poster Case Report
Agranulocytosis is a rare but serious complication of antithyroidal drug therapy, estimated to be 0.2-0.5%. Generally, this presents early in the course of thionamide treatment, though cases of delayed agranulocytosis have been described. Since there is no definitive test or clinical finding for this condition, extensive evaluation must be performed to rule out alternate causes of neutropenia including underlying hematologic disease. There is mixed evidence regarding a relationship with dose. This case describes a misdiagnosis of methimazole-induced agranulocytosis that may have delayed lymphoma diagnosis and treatment.
The patient is a 69 year old female with a history of hyperthyroidism secondary to toxic multinodular goiter. She was diagnosed with hyperthyroidism and started methimazole at age 59. For the last year, she was on a stable dose of 10 mg per day. During routine bloodwork by her PCP, she was found to have leukopenia and neutropenia, with WBC 1.8 and ANC 100. She also had normocytic anemia. Her WBC was normal one year prior to this set of labs. Methimazole was promptly discontinued. Bone marrow biopsy showed no increase in blast cells or dysplasia, and autoimmune and infectious workup was unremarkable. Therefore, agranulocytosis was attributed to thionamide therapy. Six weeks after discontinuation of methimazole, her TSH was 0.063 and free T4 was 1.12. The patient was highly symptomatic for hyperthyroidism, including diarrhea, so radioactive iodine ablation with 14.8 mCi of I-131 was performed.
Her WBC gradually rebounded two months after discontinuation of the drug, without the use of G-CSF. However, her persistent diarrhea led to a CT scan which revealed extensive lymphadenopathy. Biopsy was consistent with stage IV Hodgkin lymphoma. This case demonstrates the difficulty in establishing a causal relationship between neutropenia and antithyroidal drug therapy, especially because of the risks involved in re-exposure to the drug. With no pathognomonic features aside from temporal relationships with the potential offending agent, thionamide-induced agranolocytosis is largely a diagnosis of exclusion. Radioactive iodine ablation is a safe and effective alternative therapy for patients with neutropenia, regardless of the etiology. Methimazole can be a red herring in the evaluation of neutropenia. Caution must be exercised in attributing hematologic abnormalities to thionamide use, and repeated re-evaluation is needed after ascribing this diagnosis.
Disorders of Thyroid Function Friday Poster Case Report
Hypothyroid myopathy is seen in patients with long standing and untreated hypothyroidism. It presents with nonspecific symptoms of myalgias, muscle cramps and muscle weakness. We report a case of a middle aged male with hypothyroid myopathy due to intolerance to levothyroxine.41-year-old male seen in our office for uncontrolled hypothyroidism, diagnosed two years ago with symptoms of weight gain and muscle aches. He was prescribed levothyroxine but he developed intolerance to it causing mental fogginess and he stopped taking it. Labs showed a thyroid stimulating hormone (TSH) of 157.6 IU/ml, unmeasurable free thyroxine (FT4), creatinine 1.39 mg/dl and a creatine kinase (CK) of 3,948 U/L (Normal 20-200 U/L). Electromyography, nerve conduction velocity and imaging were unremarkable and a diagnosis of hypothyroid myopathy with rhabdomyolysis from uncontrolled hypothyroidism was made. He was treated with thyroid extract (desiccated thyroid) and his TSH started to trend down. At a follow-up visit 2 months later his TSH was 15.4 IU/ml, FT4 0.69 ng/dl and CK 475 U/L with complete resolution of his symptoms indicating good response to treatment. His thyroid extract dose was increased to get tighter control of his thyroid function. There are four subtypes of hypothyroid myopathy: Hoffmann's, myasthenic, atrophic and Kocher-Debre-Semelaigne syndromes. Patients with severe or untreated hypothyroidism can develop significant muscle disease leading to functional limitations. Deficiency of thyroid hormones causes reduced mitochondrial oxidative capacity, which leads to an insulin resistant state of the cell resulting in abnormal glycogenolysis and myopathy.
CK levels are commonly elevated in these patients and rhabdomyolysis is a fatal complication that can occur in severe disease. Management of hypothyroidism is the mainstay of treating hypothyroid myopathy. With adequate thyroid replacement and restoration of normal thyroid function, gradual resolution of neuromuscular symptoms is seen. Untreated hypothyroidism can lead to hypothyroid myopathy. This case highlights the importance of prompt management of hypothyroid myopathy with adequate thyroxine replacement in order to prevent fatal complications like rhabdomyolysis.
Disorders of Thyroid Function Friday Poster Case Report
Hypothyroidism is prevalent among patients after irradiation for primary cancer. Many studies have also shown that hypothyroidism is common among women with breast cancer. Interestingly, we presented a case of a patient with breast cancer and radiation treatment with hyperthyroxinemia and non-suppressed TSH. A 75-year-old female with long-standing hypothyroidism, diagnosed in the 1990's, with recent diagnosis of breast cancer undergoing radiation treatment was consulted to us in November 2017 with symptoms of weight gain and fatigue along with elevated TSH (7.73) and FT4 (1.47). Physical exam was unremarkable. Initial TSH elevation was noted at 13.449 u/UmL in July 2017. Thyroid function testing in August 2017 revealed TSH 3.470 with Free T4 (FT4) 1.19 ng/dL. At that time, Levothyroxine dosing was decreased to 112 mcg from 125 mcg daily by her Primary Care Physician due to report of tremors and difficulty sleeping. Repeat labs found persistently elevated TSH and FT4, along with Cortisol 10.3 ug/dL, IGF-1 103 ng/mL, Prolactin 10.2 ng.mL, ACTH 31 pg/mL and MRI without pituitary abnormality. Further workup revealed T4 total 12.21 ug/dL, T3 total 93.71 ng/dL, TSH antibody negative, T4 antibody negative, TSH HAMA treated 7.11 mIU/L, TSH untreated 7.10 mIU/L, T3 reverse 30 ng/dL, FT4 direct dialysis 2.7 ng/dL. There was no analytical interference in thyroid function testing; genetic testing was not performed due to cost. We decided to increase her dose slightly from 112 mcg daily to 112 mcg daily and 25 mcg for one day and her thyroid function test has improved from TSH 7.396 in March 2018 to 4.148 in May 2018 and FT4 1.35 to slightly higher 1.46 with improvement of her symptoms. Thyroid dysfunction may slowly develop after radiation in about 15 percent to 66 percent of patients within 6 years. However, there is no case report reporting post radiation caused hyperthyroxinemia with non-suppressed TSH. We are suspicious that radiation might cause her to have thyroid resistance syndrome. Studies suggest that thyroid dysfunction in breast cancer patients occur at an increased frequency after undergoing radiotherapy. It is recommended in all patients after radiotherapy to have routine thyroid function monitored.
Disorders of Thyroid Function Friday Poster Case Report
Ferritin level can represent a good index of iron stores in the body. Liver disease, malignancies, hematopoietic disease, and inflammation can increase ferritin levels independently of iron stores. We present a case of Graves' disease associated with hyperferritinemia. A 57-year-old man presented with palpitations and dyspnea for one week. Review of systems was positive for heat intolerance, anxiety, and weight loss. Past medical history was significant for hypertension and type 2 diabetes mellitus. He denied smoking or alcohol use. He did not receive blood transfusions in the past and he was not taking iron supplements. He denied family history of hemochromatosis. Physical exam showed tachycardia with an irregularly irregular rate, lid lag, lid retraction, and non-tender thyromegaly. Laboratory data showed TSH 0.006 mIU/L, free T4 6.69 ng/dL, thyroid stimulating immunoglobulin >500%, TSH binding inhibitory Ig >40 IU/L, ferritin 23767 ng/mL, iron 73 mcg/dL, TIBC 199 ug/dL, transferrin % Sat 37. A complete blood count was normal and there was no evidence of an acute or chronic infection. The patient was diagnosed with Graves' disease and was started on methimazole; after two months of therapy his ferritin level normalized. Ferritin levels have clinical significance in the early diagnosis and management of iron deficient and iron overload states. Yet, hyperferritinemia can be caused by a wide variety of conditions. Whereas some studies found a positive correlation between levels of thyroid hormones and ferritin, others did not. The mechanism of hyperthyroidism-associated hyperferritinemia remains poorly understood. Still, ferritin levels usually normalized after achievement of a euthyroid state. Elevated ferritin in hyperthyroidism may reflect an expansion of iron storages induced by ineffective erythropoiesis, escape of ferritin from damaged reticuloendotelial cells, impaired clearance of ferritin, or merely stimulatory effect of thyroid hormones at the genetic level on ferritin and hepcidin synthesis. Hyperthyroidism is a reversible cause of hyperferritinemia. Ferritin levels cannot be used as an index of iron stores in the setting of hyperthyroidism, as it can increase ferritin levels disproportionally compared with iron stores.
Iodine Uptake & Metabolism Friday Poster Clinical
Before iodination of Swedish table salt in 1936, severe iodine deficiency was common, resulting in goiter and hypothyroidism. We hypothesized that water iodine concentration (WIC) contributed to the previous high frequency of goiter in Sweden and that it still contributed to the urinary iodine concentration (UIC) and thyroid volume, despite the high iodination program. The aim of this study was to collect drinking water from water treatment plants nationally and test if WIC correlated to UIC and to former and recent thyroid outcome. Water was collected from 247 water treatment plants, located in 57% (165 of 290) of all Swedish municipalities. Analysis of WIC was done in both these and in 30 samples of earlier collected tap water from randomly selected schools in a national follow-up study of the Swedish iodine fortification programme in 2007. Pre-iodination data, derived from the map of goiter frequency drawn in 1929, allowed us to test the correlation of WIC to thyroid volume before iodination. Data from the national follow-up study in 2007, allowed us to test the correlation of WIC to the children's UIC and thyroid volume after iodination. WIC and UIC were analysed with the Sandell-Kolthoff reaction. The median WIC from water treatment plants was 4.0 μg/l (range 0-27 μg/l). WIC from drinking water from coastal areas (4.1 μg/l) and from inland areas (3.5 μg/l) did not differ. WIC was lower in former goiter areas (goiter frequency >15% in 1929, before iodination) than in non-goitre areas (goiter frequency <4%) (p < 0.001). WIC from water treatment plants, correlated to UIC of children from schools of the same area (p < 0.01), but not with their thyroid volume. WIC from tap water from the schools did not correlate to UIC or to thyroid volume of the children. These results suggest that WIC is a determinant for iodine deficiency in the absence of iodination program. WIC in Sweden still contributes to iodine nutrition, despite the iodination program. The iodination overrides the goiter effect in the areas with low WIC and rather high WIC in other areas increases the total iodine intake.
Iodine Uptake & Metabolism Friday Poster Case Report
Radioactive iodine uptake is commonly used during thyroid cancer treatment to assess for metastatic disease. However, other causes of abnormal iodine uptake should be considered.
A 48 year old female was diagnosed with papillary thyroid cancer (PTC) following fine needle aspiration of a high suspicion thyroid nodule. She underwent total thyroidectomy; pathology demonstrated multifocal PTC, 2 cm in the greatest dimension, with both classic and follicular variants. Perineural invasion was present. One of two central neck lymph nodes were positive for presence of metastatic disease. Post-operative thyroglobulin (Tg) was undetectable but in the setting of elevated thyroglobulin antibodies (8.2 IU/mL, normal <1.0). She underwent adjuvant treatment with 141.6 mCi of I-131 following stimulation with recombinant TSH. Post treatment SPECT-CT revealed a surprising intense focus of iodine avid liver uptake, without anatomic correlate. Physiologic thyroid bed uptake was also present. There were no additional abnormal foci of iodine uptake. MRI of the liver was normal, without evidence of metastatic disease.
Abnormal hepatic uptake of iodine has been reported in the setting of biliary duct dilation, hemangiomas, and liver cysts, none of which were present in our patient. Rarely, gallbladder uptake has been found, usually in the setting of chronic cholecystitis. In our patient, the lesion was ultimately felt to represent misregistration artifact from adjacent physiologic gallbladder uptake. Clinical history is essential in interpretation of iodine uptake scans during treatment of thyroid cancer. Artifactual causes of abnormal uptake should be considered.
Thyroid & Development Friday Poster Basic
It has been suggested that thyroid hormone concentration at birth may have some role in regulating foetal growth. The aim of this study was to investigate any association between thyrotropin (TSH) concentration within the normal range and growth parameters at birth in full-term newborns. In this cross-sectional study conducted in Tehran, Iran, 314 mother–newborn pairs were randomly selected from health care centres responsible for congenital hypothyroidism screening. Neonatal TSH concentration was measured using a heel-prick blood sample taken from all neonates 3–5 days after birth, as part of routine neonate screening. Anthropometrics, including birth weight, length, and head circumference were obtained from birth record of each neonate. The Z-score values for weight-for-age, weight-for-length, length-for-age, and head-for-age were calculated using the World Health Organization growth standards. Median (interquartile range [IQR]) neonatal TSH value was 0.9 mIU/L (0.4–1.7 mIU/L). Neonates in the top tertile of TSH values had higher birth weights and weight-for-age Z-scores than those in the bottom tertile (P < 0.05). In addition, neonatal TSH was associated with weight-for-age Z-scores in unadjusted (β = 0.113, p = 0.020) and adjusted (β = 0.122, p = 0.013) analysis. However, in both unadjusted and adjusted analysis, no association was observed between TSH concentrations of neonates and weight-for-length, length-for-age, and head-for-age Z-scores. Findings indicate a positive association between the normal range of neonatal screening TSH concentration and birth weight; however, this association was not observed for other anthropometric parameters at birth.
Thyroid & Development Friday Poster Clinical
Vitamin D insufficiency or deficiency may be associated with Graves' disease (GD). However, many researches were still contradictory, a clinical trail with large number of subjects is required. The aim of our study was to investigate the association of vitamin D levels with the clinical factors in newly onset GD patients. From May 2016 to October 2016, 665 patients newly diagnosed as GD were enrolled. Course of disease, age, gender, thyroid function, autoantibodies (include TRAb, TPOAb and TGAb), Parathyroid hormone (PTH), Calcitonin (CT), 25(OH)D levels and thyroid volume were tested and record. According to Vitamin D levels, patients were divided into three groups, VitD deficiency (47.52%) and insufficient (30.98%) were more prevalent than VitD adequate (21.50%). There were significant differences with the volume of thyroid, the level of TRAb, CT, PTH and 25(OH)D between this three groups (p < 0.05), and no statistically significant difference between the course of disease, age, FT3, FT4, TSH and TGAb, TPOAb(p > 0.05). Correlation analysis showed that 25(OH)D levels were negatively correlated with TRAb (rs = −0.414), PTH (r = −0.175) and thyroid volume (r = −0.094), (P < 0.05), as well as positively correlated with CT (r = 0.115, P = 0.003). Multivariate logistic regression analysis confirmed that higher TRAb level is an independent risk factor for VitD deficiency and insufficient (OR = 1.124, OR 95% C.I 1.086∼1.153, P < 0.001). ROC curve analysis revealed that the cut off value of TRAb was 12.99IU/L.The prevalence of VitD deficiency and insufficient were even higher in patients newly diagnosed as GD. In addition, the serum 25(OH)D levels were negatively correlated with TRAb and thyroid volume, and TRAb is an independent risk factor for VitD deficiency and insufficient.
Thyroid & Development Friday Poster Clinical
Various approaches for thyroid surgery became possible with the use of robotic systems. Transoral robotic thyroidectomy (TORT) is one of the newest approaches and draws attention because of its cosmetic excellence. In this study, we compared the surgical outcomes of TORT and conventional open thyroidectomy (OT). We retrospectively reviewed and compared the medical records of consecutive patients who underwent TORT or OT for thyroid carcinoma from April 2009 to March 2017. Propensity score matching using 10 clinico-pathologic factors was used to generate 2 matched cohorts, each composed of 186 patients. The study included 372 patients who underwent TORT (n = 186) or OT (n = 186). Mean age, tumor size, gender was not different between both groups. The two groups showed similar surgical outcomes, except for a longer operative time for TORT. Lower pain score was showed in TORT group than open group but it had no significant difference. The extrathyroidal extension(ETE) was not observed frequently in one group than the other group, but just one gross ETE was observed in OT group. There was one patient with immediate postoperative bleeding in the TORT group. The patient underwent re-operation for hemostasis with endoscopic approach. In the OT group, one patient had wound seroma, which was treated by several rounds of needle aspiration without infection. Vocal cord palsy was present in one patient in the TORT group, which was recovered in 3 months. TORT could be performed safely and had comparable surgical outcomes with OT in the selected patients. TORT may be a suitable operative alternative for patients who do not want to leave scars on the neck.
Thyroid Cancer Friday Poster Basic
Thyroid cancer incidence has been increasing globally, mostly due to the incidental diagnosis of papillary microcarcinomas. There's a lack of epidemiological data to characterize the trends of thyroid cancer diagnosis in Guatemala. The main objective of the study was to determine Thyroid Cancer prevalence in the Guatemalan Metropolitan Region in order to evaluate diagnostic trends and mortality. A retrospective, observational study was performed in three reference centers of the Guatemalan Metropolitan Region, evaluating pathology reports that confirmed a thyroid cancer diagnosis and mortality obtained from a local, government-run registry, from 2008 to 2013.331 cases were encountered in the five years of collected data. Age, gender and histological variant distributions correspond to globally reported trends, but both prevalence and mortality remained stable. All of the cases reported were clinically palpable tumors, which explains the lack of increase in prevalence. Additionally, imaging is not routinely used as a diagnostic tool, as a consequence, no microcarcinomas were reported. More research is needed to evaluate specific mortality due to thyroid cancer in our region.
Thyroid Cancer Friday Poster Basic
Thyroid cancer is the most common endocrine malignancy. Anaplastic thyroid cancer is one of the most aggressive thyroid tumors. It has been widely described that activation of oncogenes and/or inactivation of tumor suppressor genes in tumor cells promotes tumorigenesis. The microenvironment of the tumor also plays a key role on cancer development and progression in a variety of tumors. However, the mechanisms by which tumor-stroma crosstalk in thyroid cancer remains poorly characterized. In this study we aimed to understand how interactions between fibroblasts and anaplastic thyroid cancer cells contribute to thyroid carcinogenesis process. We first characterized the phenotypic changes of human fibroblasts in vitro through co-cultures by using transwells as well as by using anaplastic thyroid cancer cells-derived conditioned media. We found that fibroblasts acquired an activated phenotype or also known as cancer-associated fibroblast phenotype after being in contact with soluble factors secreted from anaplastic thyroid cancer cells, compared to the fibroblasts in mono-cultures. All the changes were partly mediated through Src/Akt activation. Remarkably, conditioned media obtained from these activated fibroblasts promoted cell proliferation and invasion of follicular thyroid cancer cell line, FTC-133 cells. Thus, a reciprocal and dynamic interaction exists between tumor and stromal cells, which results in the promotion of thyroid tumorigenesis process. The present studies have advanced the understanding of the molecular basis of tumor-stroma communications, enabling identification and targeting of tumor-supportive mechanisms for novel treatment modalities.
Thyroid Cancer Friday Poster Basic
Tyrosine Kinase Inhibitors for aggressive de-differentiated thyroid cancers have modest effects on progression-free survival and are associated with dose-limiting toxicity. Novel targets are needed for treating patients with these aggressive thyroid cancers. Somatic re-activation of telomerase, mediated via mutations in the telomerase reverse transcriptase promoter (TERTp), is associated with poorer prognosis in thyroid cancer. Aurora Kinases (AURK; A/B/C) are crucial cell cycle regulators with different roles in the process. In cancer, aberrant expression may lead to unchecked cell cycle regulations leading to disordered and continuous proliferation. We have identified that AURK inhibitors affect TERT expression and we sought to investigate the mechanism underlying the downregulation of TERTp in thyroid cancer. Anaplastic Thyroid Cancer derived cell lines (SW1736 & C643) were treated with the AURKB inhibitor Hesperadin and molecular assays were conducted at various post treatment times. Gene expression of TERT was detected using RT-qPCR, telomerase activity by quantitative Telomeric Repeat Amplification Protocol (qTRAP) and Phospho-protein western blots (P-WB) were performed with targets for the MAPK, PI3K/AKT/mTOR pathways to elucidate the signalling pathway(s) involved in the downstream reduction of TERT. Gene expression of TERT is significantly reduced 72-hours post treatment (hpt) of Hesperadin in both cell lines (8-fold, p > 0.001). In SW1736 cells, the relative telomerase activity was significantly reduced at 72 hpt (6-fold, p < 0.01) and 96 hpt (4-fold, p < 0.05) when compared to vehicle controls. Furthermore, P-WB revealed a significant inhibition of pERK (>95%, p < 0.001) from 1 to 12 hpt. There was an inhibitory effect on pAKT from 1 to 6 hpt (>95%, p < 0.001) but no significant effect on pS6 levels. We have discovered that inhibition of AURKB by Hesperadin significantly reduces both TERT expression and telomerase activity. The mechanism by which Aurora kinases regulate TERT is yet to be established, although may involve downstream inhibition of one or several kinase pathways. AURKB inhibitors should be studied in clinical trials of poorly differentiated thyroid cancers associated with TERT overexpression.
Thyroid Cancer Friday Poster Basic
This study analyzed symptoms reported by patients with papillary thyroid cancer (PTC) in the first year after undergoing total thyroidectomy (TT) and their impact on quality of life (QOL). PTC patients were evaluated at five different timepoints: before TT and again at 2 weeks, 6 weeks, 6 months, and 1 year after TT. At each time, patients completed a quality of life survey and reviewed a collection of index cards showing a range of symptoms experienced by PTC patients. Patients sorted the cards based on which symptoms they had, how much symptoms bothered them and how much symptoms interfered with their daily activities. Patients reported an average of 8.9 ± 6.5 symptoms before TT. This increased to 11.5 ± 6.5 symptoms at 2 weeks post-op, decreased to 9.1 ± 5.8 at 6 weeks, and plateaued at 6.8 ± 5.3 at 6 months and 1 year. The majority of symptoms related to either voice and swallow (VS) symptoms or low energy. VS symptoms were reported by 93.6% (n = 44) and were the most bothersome and interfering symptoms at 2 weeks, even though only 21.2% of patients at this time had vocal cord dysfunction present. The number of patients ranking these issues as very bothersome decreased from 26 (55.3%) at two weeks to 4 (11.1%) at 6 months. Low energy was a major problem for patients at all timepoints. Low energy was reported by 57.5% (n = 47) of patients at two weeks and was still ranked as very bothersome by 33.3% (n = 11) at one year. Weight gain was not an issue at 2 weeks but was one of the most common symptoms by 1 year, experienced by 51.5% (n = 17) and ranked as most bothersome by 30.3% (n = 10).
Before TT, patients had a global QOL score on the EORTC QLQ-C30 of 73.6 ± 19.6, which then decreased to 65.9 ± 23.4 at two weeks (p = 0.01). Thankfully QOL scores increased above baseline over time to 79.6 ± 15.5 at 1 year (p = 0.04). However, patients who reported low energy at one year did not have the same increase in QOL as a cohort. Their mean score at one year was similar to baseline (p = 0.19).VS symptoms are common in the immediate post-operative period but resolve for most patients by six months. While low energy and weight gain are major issues for PTC patients, as a whole patients have improvement in their QOL after treatment.
Thyroid Cancer Friday Poster Basic
Cell-cell fusion refers to the process by which two cells combine their plasma membranes to become a single hybrid cell. Cancer cell fusion enhances tumor heterogeneity, affects micro-environment and favors development of metastases. Cell fusion has not been examined in thyroid cancer.
Thyroid Cancer Friday Poster Translational
Radioactive iodine (RAI) is an effective targeted therapy for thyroid cancer. However, patients with RAI refractory disease are associated with worse prognosis as they cannot benefit from RAI therapy due to insufficient RAI delivery and/or intrinsic radioresistance. To date, differential 131I radiosensitivity among thyroid tumors and their underlying mechanisms have not been investigated. We (a) enable sodium iodide symporter (NIS)-mediated RAI uptake in six human thyroid cancer cell lines via stable expression of exogenous NIS; (b) evaluate radiosensitivity to 0.8 mCi of 131I and to 2-8 Gy of external beam radiation treatment (EBRT) via clonogenic assay; and (c) investigate the effect of trametinib on 131I radiosensitivity among human thyroid cancer cells with various capabilities of RAI uptake, i.e. various dose-rate and various total absorbed dose of 131I radioactivity.FTC133-NIS cells had the highest NIS-mediated RAI uptake, followed by FTC238-NIS cells, and then the other four NIS-expressing cell lines. FTC133, 8505C, and BCPAP cells with or without exogenous NIS expression were relatively radioresistant to EBRT and 131I, compared to FTC238, TPC1, and Hth74 cells. Among three radioresistant cell lines, both 8505C and BCPAP cells carry BRAF(V600E) mutation. FTC133 and FTC238 cells were derived from a lymph node metastasis and a lung metastasis, respectively, from the same patient who had follicular thyroid cancer. Whereas FTC133 cells were radioresistant to EBRT and 131I, FTC238 cells were relatively radioresistant to EBRT and 131I at low dose but became relatively radiosensitive at high dose. Trametinib did not increase RAI uptake in cells expressing exogenous NIS. However, trametinib radiosensitized FTC133-NIS, 8505C-NIS, BCPAP-NIS, and TPC1-NIS cells to 131I, as shown by a decreased survival fraction in trametinib-treated cells (p value <0.04). We showed that (a) differential radiosensitivity to 131I is not solely determined by the extent of RAI uptake, tumor histology, tumor driver mutation, or growth rate; and (b) MEK inhibitor can improve RAI therapeutic efficacy in patients with RAI refractory disease by increasing 131I delivery and increasing intrinsic 131I radiosensitivity in target lesions.
Thyroid Cancer Friday Poster Translational
About 60% of sporadic Medullary Thyroid Carcinomas (sMTC) harbour mutually exclusive somatic mutations in RET or RAS genes. Previous studies performed in limited series and using next generation sequencing (NGS) methods found very few novel mutations, including gene fusions in RET and ALK genes. Taking into account the results of these studies, up to 30-40% of sMTC remain orphan of a genetic driver mutation. The aim of this project is to characterize the mutational profile of a large series of sMTC by targeted NGS sequencing. DNA obtained from a total of 169 sMTC tissues was sequenced in a Ion Torrent S5 using a NGS target sequencing custom panel able to sequence the whole RET, H-, K- and N-RAS genes gene and hotspot exons in the TP53, GNAS, PPM1D, PTEN, MET, BRAF, EIFA1X, AKT1, CHEK2, CTNNB1, STK11, PIK3CA, TSHR genes. C228 and C225 hotspots mutations in the promoter of the Telomerase Reverse Transcriptase (TERT) gene were evaluated by Sanger sequencing. Sequencing with our custom panel we found 137/169 (81.1%) cases that were positive for somatic mutations and 32/169 (18.9%) negative for all mutations studied. Among positive cases, 82/137 (59.8%) presented a single RET mutation: 49 M918T, 15 in codon C634, 8 indels, 2 C620R, 2 A883F, 1 C630R, 1L790F, 2 S891A, 1 C618R, 1 S1024F. Another 41/137 (29.9%) presented mutations in the RAS genes: 28 in HRAS (24 in Q61 and 4 in G13); 12 in KRAS (9 in G12, 2 in Q61, 1 in A146) and 1 in NRAS (Q61K). Additional 3/137 (2.2%) presented mutations in other genes: CHK2 W114*, EIF1AX G135A, TSHR I630L. Simultaneous presence of 2 or more mutations was present in additional 11/137 (8.1%) cases: 3 RET+RET, 3 RET+RAS, 3 RET+MET, 1 RET+TP53, 1 RAS+MET. Mutations in classical hotspots of the TERT gene promoter were absent in all cases studied. Applying NGS targeted sequencing we confirmed RET and RAS somatic mutations as principal drivers in sMTC and the rate of negative cases is lowered at about 20% of cases. The prevalence of RAS mutations appears to be higher with respect to previously reported. Rare mutations found in other genes will be further investigated in order to assess their role in sMTC pathogenesis. Finally, TERT gene promoter mutations do not have a role in sMTC.
Thyroid Cancer Friday Poster Translational
There are significant variations in the management, treatment and outcomes of thyroid cancer. A proven strategy to reduce variations in outcome and to improve survival is to measure and compare it using high quality clinical registry data. To benchmark clinical care, clinical quality registries require systematic measurement at predefined intervals and the capacity to report back information to participating clinical units. The aim of this study was to develop a core set of clinical quality indicators (CQIs) that enable measurement and reporting of quality of care for patients with thyroid cancer. Preparatory work and scoping was conducted to identify existing high quality, clinical guidelines and best practice for thyroid cancer both nationally and internationally, as well as relevant literature. A bi-national panel was invited to participate in a modified Delphi process. Panelists were asked to rate each proposed indicator on a Likert scale of 1–9 in a three-round iterative process. A total of 236 potential CQIs were identified. One hundred and ninety-two indicators were removed to reflect the data capture by the Australian and New Zealand Thyroid Cancer Registry (ANZTCR) (from diagnosis to 90-days post-surgery). The remaining 44 indicators were presented to the panelists for voting. A further 21 indicators were later added by the panelists bringing the total potential CQIs to 65. Of these, 21 were considered the most important and feasible indicators to measure quality of care in thyroid cancer, of which 12 were recommended for inclusion in the final set. The consensus indicator set spans the spectrum of care, including: preoperative; surgery; surgical complications; staging and post-surgical treatment planning; and post-surgical treatment. This study provides an evidence-based, consensus set of CQIs to measure quality of care in thyroid cancer. Inclusion of these CQIs into monitoring databases, such as clinical quality registries, will enable opportunities for benchmarking and feedback on best practice care leading to reduced variation and improved patient outcomes, thereby lessening costs and healthcare burden to the Australian and New Zealand community.
Thyroid Cancer Friday Poster Translational
The thyroid gland is one of the most susceptible organs to the carcinogenic effects of ionizing radiation and about 90% of these cancers are papillary, presenting a RET/PTC chromosomal rearrangement in 70% of cases. Radiations are a known factor implied in up-regulation of NADPH oxidase DUOX1 that can promote long-term persistence of oxidative stress which causes DNA damage likely related to the development of RET/PTC rearrangement. The objective of this study was to evaluate the Duox1 protein expression in RET/PTC positive and negative papillary thyroid cancer (PTC) tissues and in normal thyroid tissues (NTT) and to correlate the rate of Duox1 protein expression with the clinico-pathological features of PTC cases.
We analyzed Duox1 protein expression in 28 PTC tissues (RET/PTC positive and negative, irradiated and not irradiated) and in 28 NTT. We correlated these data with the clinical pathological features of PTC tissues.
Immunohistochemistry performed on formalin-fixed, paraffin-embedded thyroid tissues showed that 54% of PTC tissues had a Duox1 moderate-strong staining pattern and only 11% of NTT showed a Duox1 moderate-strong staining pattern with a statistically significant difference between the two groups (p = 0.0007). Moreover Duox1 moderate-strong expression were present in 57% of PTC cells and in only 36% of normal thyroid cells (p = 0.11). Finally, no statistically significant correlation between the Duox1 protein expression and the clinical-pathological features of the PTC tissues was foundThese data suggest that the expression of Duox1 protein is greater in PTC tissues than in normal thyroid tissues, irrespectively of the presence of RET/PTC rearrangement. Duox1 protein expression does not seem to be a poor prognostic factor in PTC. The impact of DUOX1on the endogenous oxidative and replicative stress underlying the formation of RET/PTC1 translocation in PTC is under investigation.
Thyroid Cancer Friday Poster Translational
The DICER1 syndrome is a rare, autosomal dominant inherited disorder that predisposes to a variety of cancerous and noncancerous tumors of mostly pediatric- and adolescent-onset, including differentiated thyroid carcinoma (DTC). DICER1-related DTC has been hypothesized to arise secondary to the increased prevalence of pre-malignant lesions, i.e. thyroid hyperplastic nodules. Limited data are available on the acquired genetic variants that induce malignant transformation. We performed somatic DICER1 mutation analysis and extensive somatic DNA variant and gene fusion of ten patients with DICER1 syndrome and young onset DTC. Median age at DTC diagnosis was 13.5 years and no patients developed recurrent or metastatic disease (median follow-up 8 years). All thyroid specimens showed on re-inspection diffuse nodular hyperplasia with at least one focus suspect for DTC, but without infiltrative growth, extra-thyroidal extension, vascular invasion, or lymph node metastasis. Distinct somatic DICER1 RNase IIIb domain variants were identified in most presumed-malignant (and benign) nodules tested from each patient's tumor, suggestive of multiple distinct poly-clonal tumors. Furthermore, 9 of 10 DICER1-related DTC lacked well known oncogenic driver DNA variants and gene rearrangements. On the basis of our clinical, histological and molecular data, we consider that DICER1-related DTCs form a low-risk subgroup. As these tumors may arise from one of many benign polyclonal nodules, right, left or total thyroidectomy may be often required, but radioiodine treatment may be unnecessary, given the patients age and their low propensity for metastases.
Thyroid Cancer Friday Poster Clinical
Thyroid Imaging Friday Poster Clinical
Bipolar radiofrequency ablation (BRFA) currently has been established as a highly efficient and reasonably method to control/ completely eliminate thyroid nodules. The novel coaxial bipolar device, Thyrablator was developed by our group and was tested to evaluate the morphological changes (gross and microscopic characteristics) in the human thyroid tissue. During the period from January 2017 to January 2018, 22 patients (male to female ratio 1:10, age range 29–67 years) with 28 benign thyroid nodules underwent thyroid surgery. The study was approved by the hospital ethics committee, and written informed consent was obtained from each patient. The Thyrablator was used in the thyroid nodules with the power of 5 Watts for 20-40 seconds (EMED-Spectrum electrosurgical unit (EMED, Poland) at the stage of surgical separation of the organ from the surrounding tissues (with preserved normal bloodstream). Then the nodule was surgically removed and its morphological study was carried out. On gross examination the coagulated lesion was sharply demarcated against the visually unchanged thyroid tissue. Microscopically total destruction of the thyroid tissue with complete homogenization of the stroma and parenchymal structures were seen in the center of the lesion zone (median 3.4 mm) in close proximity to the Thyrablator. In the borderline zone (median 5.3 mm) nuclear changes of the chief cells showed chromatin basophilia, nuclear shrinkage and/or its elongation. There was connective tissue injury with edema accompanied by a compression of the microvasculature. Some areas showed homogeneous metachromatic fibers. The color gradient of the chief cells stained with TTF-1 antibody shifted from weak to strong diffuse intensity. The Thyrablator induces reproducible lesions of sufficient clinical size and could be suitable for the treatment of thyroid nodules.
Thyroid Cancer Friday Poster Clinical
The Bethesda Classification System (BCS) allows the communication of Fine-Needle Aspiration Biopsy (FNA) in a standardized form. The estimated risk of malignancy for categories 3 and 4 was originally estimated to be 5-15% and 15-30%.
In 2015 our group analyzed the correlation between FNA with the respective pathology results. We have observed that in patients with Follicular Lesion of Undetermined Significance (FLUS) or Follicular Neoplasm (FN), the rate of malignancy was significantly higher to the ones described in the literature.
Our aim is to update these results, considering the 2017 revision of the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC), and the recent reclassification of some thyroid neoplasms as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). This is a restrospective sudy (2013 - June, 2017) of patients with cytopathology results of FLUS and FN. For the statistical analysis we used SPSS Statistics (version 23). We have found 150 lesions of FLUS, of which 59 were surgically excised and obtained 15 results of Papillary thyroid carcinoma (PTC), 8 of NIFTP and 1 incidentally discovered neoplasm. There was a significant association (p = 0,009) between male gender and the presence of malignancy.
All patients with result of FN (102 lesions) were submitted to surgery. In this group we have found 28 PTCs, 2 NIFTPs, 1 Follicular Carcinoma and 2 incidentally discovered malignancies.
We have verified a 39% rate of malignancy in the patients with FLUS (superior to the one described in the BCS). In the 2017 revision of TBSRTC the reestimated risk of malignancy for this category is of 10-30%. These values probably represent an overestimated risk of malignancy due to a selection bias.
Concerning the patients with FN, there was a 30% rate of malignancy.
Considering the reclassification of NIFTP, the malignancy rates for patients with FLUS and FN is of 25% and 28%, which represents a 36% reduction in the expected risk of malignancy for a FLUS result and a 7% reduction for FN. The evaluation of the expected risk of malignancy associated with a result of FLUS or FN is extremely important, so that the surgeon can choose the most adequate approach for his patient.
Thyroid Nodules & Goiter Friday Poster Clinical
During recent years, the number of outpatient thyroidectomies has been increasing. However, there is still controversy about which patients are eligible for this type of procedure.
Our goals are to evaluate the results of thyroid surgery, performed both as an outpatient and inpatient procedure and to identify which factors are associated with more post-operative complications. This is a retrospective study including the patients submitted to total thyroidectomy or hemithyroidectomy from January to December 2017, in our hospital (a high-volume center for thyroidectomy). We excluded patients who have undergone other procedures in the same operative time and reinterventions.
All reported p values are two-tailed, with a p value of 0.05 indicating statistical significance. Analyses were performed using SPSS Statistics (version 23). We have studied 132 patients. 84 were submitted to outpatient thyroidectomy (70 total thyroidectomies and 14 hemithyroidectomies). In the inpatient group, a total thyroidectomy was performed in 47 patients and a hemithyroidectomy in 1 patient.
The most frequent complications in both the outpatient and inpatient groups were transient dysphonia and hypocalcemia. There was need for prolonged hospital stay in three patients from the outpatient group. None of the patients developed a cervical hematoma. There were no readmissions nor reinterventions.
The mean age, mean gland weight and mean operative time were superior in the inpatient group. This group also had a greater number of patients with higher ASA score.
We have verified a complication rate similar to the ones most frequently reported in the literature, favoring the outpatient group.
There was a significant association (p = 0.021) between ASA score III and development of symptomatic post-operative hypocalcemia. We have also observed a significant difference in the mean gland weight (p = 0.024) and mean operative time (p = 0.011) in the groups that have and have not developed post-operative hypocalcemia. The success of outpatient thyroidectomy relies on a careful patient selection, based on the knowledge of the factors that might influence surgical outcome.
Thyroid Cancer Friday Poster Clinical
Adequate post-operative risk assessment constitutes the treatment principle of differentiated thyroid cancer (DTC). Based on this concept, the American Thyroid Association published the new guideline, improving the assessment of the recurrence and persistence risk of DTC. According to this consensus, an elevated initial post-operative stimulated thyroglobulin (ips-Tg) value, out of proportion, is as an isolated criterion to characterize patients with high risk of recurrence or persistence disease. Nevertheless, this ips-Tg value is still uncertain. Thus, our first end point is to achieve a cutoff off of ips-Tg that may indicate the presence of distant metastasis and so, a high risk patient. This research was carried out using clinical records of a public institution. 664 DTC patients were included. All were submitted to total thyroidectomy and radioactive iodine therapy (RIT) and had an ips -Tg above 10 ng/mL (following levothyroxine withdrawal, measured at least 3 months after surgery and just before the first RIT). Patients with positive Tg antibodies were excluded. The presence of distant metastasis was considered when post-dose 131I whole body scan were positive for metastatic secondary lesion. Mann-Whitney test was used to compare the groups. The cutoff values of ips-Tg were obtained using ROC analysis. All statistical analyses were performed using SPSS 13.0 software. Of the 664 patients, 70 (10.5%) had pulmonary and 18 (2.7%) had bone metastasis. When comparing the ips -Tg level among patients with and without metastases, a significant difference could be found (P < 0.001). The cutoff value of ips -Tg related to the presence of pulmonary metastasis was 69.15 ng/mL (sensitivity: 69.5%; specificity: 71.1%). The cutoff point related to bone metastasis was 79.2 ng/mL (sensitivity: 76.5%; specificity: 70%). When patients with pulmonary or bone metastases were analyzed together, the cutoff point was 66.5 ng/ mL (sensitivity: 70.7%; specificity: 70.1%). Our findings confirm the clinical value of ips-Tg in the identification of DTC metastases and high risk patients and suggest an ips- Tg cutoff of 66.5 ng/mL as an isolated risk factor in the identification of these patients.
Thyroid Cancer Friday Poster Clinical
Radioiodine ablation of thyroid tissue remains the cornerstone of treatment for patients with differentiated thyroid carcinoma after thyroidectomy. Selecting an optimal dose of radioiodine for successful ablation is a continuous challenge in these patients. Many authors have advocated for the use of lower than the conventional dose of 2775-3700 MBq of Iodine-131 for remnant ablation to reduce the radiation exposure. However there were concerns of suboptimal response with lower dose. Aim of the study was to evaluate the comparative efficacy of low dose and high dose iodine-131 therapy for ablation of residual only thyroid tissue in patients of differentiated thyroid carcinoma.
We retrospectively compared the treatment response of 68 patients with thyroidectomy having a single focus of remnant tissue in neck on diagnostic Iodine-131 whole body scan. Patients having more than one foci of tracer uptake or involvement of any extra-thyroidal structures were excluded from the study. There were 35 patients in the high-dose group who received 2775-3700 MBq Iodine-131 as a single oral dose, where as there were 33 patients in the low-dose group who received 1110-1480 MBq of Iodine-131 as a single oral dose. The response to treatment was defined as successful or unsuccessful according to a second diagnostic Iodine-131 whole body scan done 180 days post-therapy.
The 35 patient of the high dose group received an average dose of 3324 MBq, where as 33 patients of low dose group received an average dose of 1332 MBq. Remnant tissue was successfully ablated in, 75.7% patients in the low-dose group, and 74.2% patients in the high-dose group. In the high-dose group, patients were exposed to higher dose of ionizing radiation and consequently had to spend more time in isolation.
When only a single focus of remnant tissue is demonstrated on diagnostic Iodine-131 whole body scan without any extra-thyroidal involvement, low dose therapy with 1110-1480 MBq has similar efficacy as compared to higher dose therapy with 2775-3700 MBq of I-131.
Thyroid Cancer Friday Poster Clinical
Poorly differentiated thyroid carcinomas (PDTC) account for 3-5% of all thyroid carcinomas. The prognosis is generally poor. Despite the development of defined pathological criteria in 2006 (Turin Criteria), the cytological diagnosis is often problematic. By applying the Turin Criteria, we identified 39 patients with PDTC at the University Hospital of Bern between January 2007 and October 2017. A pathological review was done for all cases (blinded to clinical data and outcome).
Mean age at diagnosis was 66.7 years (range 38-90), 56% were men. 20 out of 39 patients (51%) had a fine needle aspiration (FNA) prior to surgery: only 4 nodules (20%) were classified as Bethesda V, 10 nodules (50%) were classified as Bethesda IV, 4 nodules (20%) as Bethesda III and 2 as Bethesda II (10%). Surgery was performed on all patients: 21 patients (53%) underwent total thyroidectomy, while 18 patients (46%) initially had a hemithyroidectomy and needed completion surgery. Intraoperative frozen section was performed in 24 cases (60%): of these, only 10 (42%) were reported as suspicious for malignancy, 7 (29%) as uncertain, 7 (29%) as probably benign.
Our data suggest that, due to the lack of defined cytological criteria, the diagnosis of PDTC is rarely suspected based on the result of FNA. Moreover, we found that only a minority of intraoperative frozen sections were reported as suspicious for malignancy. This often resulted in a less extensive initial procedure and in the need for additional surgery. Therefore, the cytological diagnosis of PDTC remains a challenge. Future studies should focus on molecular markers which could help to improve cytological accuracy.
Thyroid Cancer Friday Poster Clinical
Sorafenib and lenvatinib are oral MKIs approved for pts with RAI-R DTC, but there is no consensus on when pts with asymptomatic RAI-R DTC should start MKI treatment. We have previously reported global data of baseline patient characteristics from an interim analysis of RIFTOS MKI (Brose MS et al. JCO 2017; abstract 6084).RIFTOS MKI is an ongoing, global, non-interventional study enrolling pts with asymptomatic RAI-R progressive DTC. The study assessed time to symptomatic progression from study entry in the real-life setting; two cohorts were defined by the treating physician's decision to initiate an MKI at study entry (yes or no). A total of 551 pts in the global population were enrolled and valid for the planned second interim analysis. Here we report baseline characteristics for a subgroup of US pts and safety from the global sorafenib treated population. Of 144 US pts enrolled, 54% were male and the median duration of observation from study initiation was 8.5 months. At study entry, the median age was 68 years and most pts had an ECOG performance status of 0 or 1 (97%) and distant metastases (83%). The most common histology was papillary (74%) and the median time from initial diagnosis of DTC to study entry was 7.6 years. The median administered cumulative activity of prior RAI treatment was 7.57 GBq (204.59 mCi). RAI refractoriness was mainly due to a lack of RAI uptake (65%). From the global population (n = 551), a total of 113 pts were included in the sorafenib safety analysis, 3 of whom were from the US. Of these 113 pts, 106 (94%) had ≥1 adverse event (AE) and 28 (25%) had ≥1 serious AE; hand–foot skin reaction (HFSR) was reported in 54 pts (48%) and grade ≥3 HFSR in 11 pts (10%). The RIFTOS MKI study is the largest non-interventional study in RAI-R DTC. US data on pt characteristics from the second interim analysis is similar to those reported for the global population. Global safety data from pts treated with sorafenib are consistent with the known safety profile of sorafenib. Of note, HFSR seems to be reported less frequently in real-life practice than in phase 3 clinical studies.
Thyroid Cancer Friday Poster Clinical
Approximately 10% of patients with thyroid cancer experience a recurrence of their disease, usually in cervical lymph nodes. This study analyzes the safety and efficacy of revision surgery at Mayo Clinic in Florida for patients who have experienced recurrence or cervical metastases of their thyroid cancer.
A total of 102 consecutive patients who underwent surgery for recurrent or metastatic thyroid cancer in the neck between June 2004 and April 2017 were included in this retrospective study. Information was collected regarding baseline information, recurrent surgery (RS) information, and outcomes. Median age of diagnosis was 45 year (14–88), 64% female, 90% white. 88% of the primary surgeries were performed outside. Primary surgery included thyroidectomy; 35% had also central compartment nodal dissection and 15% had also lateral neck dissection. 86% patients had papillary carcinoma. 75% had one RS, 13% had two, 10% had three, 1% had four, and 1% had five RSs. Median follow-up length after first RS was 3.2 years (0.1–13.4).
Two of the 102 patients had recurrent laryngeal nerve (RLN) paralysis after first RS; no RLN paralysis after second RS (N = 26); 1 RLN paralysis after third RS (N = 12).
60% of non-medullary cancer patients were cancer free in the neck at last visit, 32% were stable, 8% had progression, and 7% died. 24% of these patients had recurrence after first RS, 46% after second RS, and 18% after third RS. 10% of all patients had distant metastasis. We had 7 patients with recurrent medullary carcinoma in the neck; 2 were cancer free in the neck at last visit.
RS for recurrent thyroid carcinoma in the neck is safe and effective when performed by an experienced surgeon. 75% of the patients did not require any other surgeries after first recurrent surgery. Relatively short follow-up period and retrospective design are the limitations of this study.
Thyroid Cancer Friday Poster Clinical
The incidence of differentiated thyroid cancer (DTC) in the pediatric population is lower than adults and, although it frequently presents at a more advanced stage, it is generally associated with an excellent prognosis. Nevertheless, the incidence of pulmonary metastasis at diagnosis is estimated at roughly 25%, 3-4 times higher than in adults. Our understanding of the factors predicting pulmonary metastasis in children lack pediatric-specific data. Beyond the association between lateral cervical lymph node disease and pulmonary metastases, little is known about factors that predict or predispose to pulmonary metastases in children.
Thyroid Cancer Friday Poster Clinical
Hurthle cell carcinoma is a rare type of thyroid cancer, classified by the WHO as an oncocytic variant of follicular carcinoma. Generally, patients with Hurthle cell carcinoma have a more aggressive clinical course than other forms of differentiated thyroid cancers. We report the results of tumor profiling from patients seen at Yale Cancer Center / Smilow Cancer Hospital including one with microsatellite instability (MSI) and a mutation in MSH2.5 patients with metastatic Hurthle Cell Carcinomas were identified between 2014-2017. Tumor profiling was performed at Yale using the Oncomime assay as well as at Foundation Medicine and at Memorial Sloan Kettering Cancer Center. Tumor profiling results are shown in Table 1. Some of the patients were offered mutation – directed treatments as noted in the table. One patient with an MSH2 mutation and MSI, had an ongoing partial response when treated with pembrolizumab.
Table 1 Patient Characteristics
Tumor Profiling Mutation-directed Status
mutations Treatment
Case 1 No mutations N/A Alive
Case 2 TP53, ARID2. ATRX None Transformed to anaplastic
LATS1 NF1 RB1 TERT thyroid cancer (ATC) died of disease
Case 3 BARD1, CDKN2C, DAXX Phase 1 candidate Alive
Case 4 MSH2, NOTCH1, NF1, ATM, Pembrolizumab Ongoing response
PTEN, DNMT3A
Case 5 None NA Transformed to ATCHurthle cell carcinoma is an aggressive form of thyroid cancer but may have mutations that are amenable to directed therapy. The finding of MSI has been reported in thyroid cancer but in one series was not seen in Hurthle cell carcinomas[i]. The response of Case 4 to pembrolizumab confirms the activity seen in other MSI high tumors treated with immune checkpoint inhibitors. Other targetable mutations identified include BARD1, CDKN2C, NOTCH1 and PTEN. The activity of other targeted agents in this setting will need to be evaluated in ongoing and future trials.
Thyroid Cancer Friday Poster Clinical
There is little information on the impact of persistent or early recurrent differentiated thyroid cancer (DTC) on patient quality of life. Using the Georgia and Los Angeles Surveillance, Epidemiology, and End Results (SEER) cancer registries, we identified eligible patients diagnosed with DTC between 2014-2015. Patients were surveyed by mail and queried on current disease status and quality of life approximately 2.5 years after their diagnosis. Physical and mental health were evaluated using the Patient-Reported Outcomes Measurement Information System (PROMIS)- Global Health v1.2 questionnaire. Meaningful change in global health was defined as a minimal difference of a half standard deviation compared with the mean (T score = 50) of a sample population matching the US 2000 General Census. Patient reported data were linked to registry data. Of the 2,097 patients completing the survey to date, 1,616 (77%) were female, 1,234 (59%) were white, and the median age was 51 years (range 20-83). Persistent disease was reported by 114 (5.4%) individuals and early recurrence by 74 (3.5%). Factors associated with increased likelihood of persistent disease included AJCC T3 or T4 tumor (p = 0.003), central compartment lymph node involvement (p < 0.001), lateral compartment lymph node involvement (p < 0.001), and distant metastatic disease (p < 0.001). Factors associated with increased likelihood of early recurrence included younger age (p = 0.011), central compartment lymph node involvement (p = 0.009), and lateral compartment lymph node involvement (p = 0.017). When compared to the general population norms, the lower median scores in patients with persistent disease met criteria for meaningful change in global physical health (T-score = 44.9) and global mental health (T-score = 43.5). Median scores in patients with cured or recurrent disease did not meet criteria for meaningful change. Compared to the general population, persistent disease, but not early recurrence, was associated with meaningful reductions in PROMIS global physical and mental health scores. These findings suggest a need to better understand reasons for impaired quality of life in patients with persistent DTC.
Thyroid Cancer Friday Poster Clinical
Retropharyngeal (RP) nodal metastases secondary to thyroid carcinoma are rare. RP nodal disease creates a surgical challenge due to its proximity to vital structures and potential for significant post-operative morbidity. Surgical planning is therefore paramount. Patients with thyroid carcinoma and RP nodal disease were identified from an institutional database. Clinical data of these patients was retrospectively reviewed. Those that underwent excision of the RP nodal disease at our institution, either as part of initial treatment or recurrent disease, were included in the analysis. Twenty-five patients were identified as having RP nodal disease secondary to thyroid carcinoma and subsequent surgery at our institution between 1999 - 2017. Thirteen patients had their initial thyroid surgery at an outside institiution. The median age was 51 years (range 21-85). Eight patients had RP metastases at presentation and 17 patients developed RP metastases following initial treatment. Twenty-two patients had either N1a or N1b disease and 13 patients were deemed ATA high risk after initial treatment. Eight patients had the histological subtype tall cell variant or tall cell features on initial pathology.
Seventeen patients had RP surgery in conjunction with a formal neck dissection and 8 patients underwent resection of the RP nodal metastases in isolation. Three different surgical techniques were used to access RP nodal disease - transcervical (19 patients), transoral open (2 patients) or a transoral robotic (4 patients) approach. The mean maximum dimension of the RP node was 2.3cm (range 0.7–4.2cm).
Five patients reported dysphagia post-operatively and 4 patients developed weakness of cranial nerves VII, IX, X, XI or XII, all of which were temporary. All complications were seen following surgery with the transcervical approach. RP nodal disease secondary to thyroid malignancy remains a surgical challenge; it requires thorough radiological work-up and pre-operative planning. Counselling of potential complications is essential.
Thyroid Cancer Friday Poster Clinical
Malignant thyroid nodules are typically cold on routine thyroid nuclear scans and hot with metabolic tracers, a metabolic mismatch. Ultrasound (US) cystic nodules usually are matching cold on both scan types and benign. Complex cystic and solid nodules often occur and may have mixed nuclear scan results and moreover, more chance of sampling error on thyroid fine needle aspiration (FNA). Genetic tests increase accuracy of FNA, but also its cost. Routine thyroid scans and uptakes used 300 microCi I-123 oral after 4 hr. Metabolic scans were >1 hr after 10 mCi FDG IV with 5.5 mm resolution PET of the neck or 5 min after 4.5 mCi Tl-201 IV. Collimators were routinely 4 mm pinhole for thyroid scans and parallel hole for gamma camera uptakes. Average nodule diameters were measured on nuclear scans after background correction and with 50% thresholds of peak counts, with US, using a 7500 MHz probe, and from surgical pathology. A 51 year-old man with thyroid radiation from fluoroscopy and head CT for his cerebral aneurysm had a right thyroid nodule, complex and 3.0 cm on US and cold, 2.9 cm on I-123, with 2.2 cm FDG metabolic mismatch. Thyroid FNA had “benign” follicular cells; genetic testing was not insurance covered. Surgical pathology showed a 2.2 cm follicular thyroid cancer, with capsular and angio invasion. A 42 year-old woman who had 20 dental x-rays and a 3.3 cm right thyroid nodule, complex on US, with a 1.9 cm cystic center and cold, 2.1 cm on I-123, with benign FNA one and also 180 months earlier, also refused genetic tests. Her Tl-201 scan had a 1.9 cm metabolic mismatch; at surgical pathology she had a (2.0 × 1.1 × 1.0) cm papillary thyroid cancer, follicular variant. In both cases, frozen sections were nondiagnostic at initial hemithyroidectomy and after 6 weeks thyroidectomy was completed. With backgrounds 5% to 35% of peak counts, two technologists had average nodule diameters + - 0.2 cm. Except for conditions usually treated medically, such as FDG avid metastases or thyroiditis, metabolic mismatch >1.2 cm diameter on background-corrected thyroid nuclear scans is likely a surgical indication, even with negative FNA, and more so with thyroid radiation exposure.
Thyroid Cancer Friday Poster Clinical
During follow up, after total thyroidectomy serum stimulated Tg measurement is the best means for detecting the presence of normal or malignant thyroid tissue. Stimulated Tg can be measured either by withdrawal of thyroxine or by thyrogen which is recombinant human TSH (rhTSH) injections. This paper focuses on whether undetectable suppressed Tg level during follow-up post total thyroidectomy and I-131 ablation, assure absence of persistence and/or recurrence, and would spare the use of stimulated Tg. A prospective cross-sectional study. We reviewed 196 patients all of them have Differentiated Thyroid carcinoma (DTC) treated from April 2014 to February 2016. All of them were treated with at least total thyroidectomy, followed by remnant ablation with Iodine 131 (RAI)
We grouped the patients according to Tg level. We evaluated the sensitivity and specificity of suppressed Tg according to the level using stimulated Tg as the gold stander considering the negative test when the level is <2 ng/mL and positive if >2 ng/ml. Both Tg levels must be done not more than 3 months apart. One-twenty two patients (98%) with undetectable T4 suppressed Tg had no increase after stimulation. Only two of 122 (2%) patients with baseline Tg below 0.1ng/ml had sTg above 2 ng/ml. Spearman's correlation test showed that the obtained values nsTg were positively correlated with sTg, r = 0.65, p < 0.001. Kruskal-Wallis test showed significant difference of sTg test between the nsTg groups to detect recurrence (Tg >2) of thyroid cancer disease, p < 0.001 (Figure 2).
Discussion: The main focus of this study is on the utility of suppressed TG (thyroglobulin) in ruling out disease recurrence, without the need to do the TG with TSH stimulation. In our study, the undetectable, nsTg (<0.1 ng/ml) in 122 patients, Tg remained undetectable in 120 patients (98%) after stimulation. In comparison to the articles published in JCEM 2012, and in 2009 we have comparable dataIn agreement with all previously published studies, suppressed thyroglobulin using highly sensitive new generation assays would help to detect any recurrence specially if thyroglobulin level <0.1 ng/ml. this would eliminate the routine use of stimulated Tg in the follow up of such patients
Thyroid Cancer Friday Poster Clinical
The differentiated thyroid carcinoma is a rare disease, which incidence is estimated in 3-5% annually. Generally, patients had a good prognosis, with survival close to 97.8% at 5 years. The principal objectives of treatment are the complete surgical removal of the tumor and minimize the recurrence risk and metastasis. The use of external beam radiotherapy has been used to diminish the local recurrence, but the role of this treatment remains controversial. We performed an observational, retrospective, cross-sectional study. We included patients who had Total Thyroidectomy for Differentiated Thyroid Cancer, between 1989-2009 and received External Radiotherapy following the next year after surgery (dose 45 Gy in 25 sessions). We aim to describe the outcome according to American Thyroid Association (2015). We performed an observational, retrospective, cross-sectional study. We included patients who had Total Thyroidectomy for Differentiated Thyroid Cancer, between 1989-2009 and received External Radiotherapy following the next year after surgery (dose 45 Gy in 25 sessions). We aim to describe the outcome according to American Thyroid Association (2015). We included 66 patients for the descriptive analysis, with a follow-up media of 8.8 years (2-17 years); characteristics: initial stage I in <45 years 37 (56.2%), initial stage IVa in >45 years 22 (33.3%). General survivor 95.5%, 2 deaths (66.6%) caused by respiratory insufficiency in patients with lung metastasis. Outcome according ATA 2015: Excellent response 25 (37.9%), incomplete biochemical 12 (18.2%), Incomplete Structural Failure: Locoregional failure 4 (6.1%), Distant metastasis 14 (21.2%); 78% with lung metastasis and 14% with lung and bone metastasis. The evidence of non-iodine-avid tumour and extrathyroidal extension in the initial thyroidectomy are the principal risk factors for locoregional recurrence or distant metastasis. The follicular variant of papillary thyroid carcinoma was associated in 20% to the presence of distant metastasis. The use of multimodal therapy, with external radiotherapy as adyuvant in patients with extrathyroidal extension, improves locoregional recurrence.
Thyroid Cancer Friday Poster Clinical
Although thyroid cancers are known to have a relative low risk of recurrence, there are factors associated with a higher risk of recurrence such as extrathyroidal extension, nodal metastasis, BRAF or TERT mutation. However, predicting disease recurrence and prognosis in patients undergoing thyroidectomy is clinically difficult. To detect new algorithms to predict recurrence, inductive logic programming was used. From January 2009 to June 2010, 797 cases of thyroid cancer patients who underwent bilateral total thyroidectomy with following radio-iodine treatment from our database were studied. 638 (80%) cases were used to create algorithms to detect recurrence. 159 (20%) cases were analyzed for validation of created rules. Least Generalized Generalization LGG was chosen as a method of inductive logic programming to extract rules which represents algorithms to predict recurrence. Delmia PRD was used for analysis. Of the 638 cases, there were 46 (7.2%) cases with recurrence. There were 4 rules detected which could predict all of the cases with recurrence. Algorithms included factors such as age, anti-thyroglobulin antibody level, thyroglobulin levels, BMI, height, positive lymph nodes, size, multiplicity, numbers and postoperative thyroglobulin levels. Postoperative thyroglobulin was the most powerful variable which correlated with recurrence. When the 4 recognized rules were applied to 159 cases for validation, it was possible to predict 72.7% (8 cases among 11 of the recurrences). When factors known for high and intermediate risk were selected for creating rules, the most optimal combination could only predict 66.7% of the recurrence cases. From our database, rules to predict recurrence were identified which were able to predict recurrence more precise than already known high and intermediate risk factors.
Thyroid Cancer Friday Poster Clinical
Transoral robotic thyroidectomy (TORT) is a new remote access approach to avoid a cervical incision. The purpose of this study is to compare two approaches used to avoid a cervical incision: transoral and bilateral axillo-breast approach (BABA) in robotic thyroidectomy.
A total of 90 patients were enrolled prospectively between September 2016 and April 2017. The BABA group was 43 and the TORT group was 47 patients respectively. The parameters including clinicopathologic data, operative time, complications, laboratory data, hospital stay, postoperative pain, and cosmetic satisfaction were analyzed.
Complications were not different among the two groups. The operative time of TORT was longer than BABA until 15 cases of TORT were completed, but there was no difference after that. The VAS score in TORT was lower than BABA in all the periods. TORT showed a higher cosmetic satisfaction after surgery. There was no infection, or permanent mental nerve hypoesthesia in TORT.
Our study showed TORT had less postoperative pain and a greater cosmetic satisfaction than the BABA. There were no significant differences in the post-operative surgical results between the two groups. TORT is a comparable to the BABA in outcome with higher cosmetic satisfaction and less pain.
Thyroid Cancer Friday Poster Clinical
Molecular analysis is an important tool to detect cancer in thyroid nodules (TN) with an indeterminate cytology and multiple genetic alterations may predict aggressive behavior. We report a case series of eleven patients with TN with more than 1 genetic alteration detected by the ThyroSeq molecular/genetic assay. The pathology, initial staging, risk stratification and response to therapy are evaluated. Between 2/2015 – 12/2017, 1,400 sequential biopsies were performed on TN >1 cm. 546 TN (18.3% Bethesda I, 6.8% Bethesda II, 3.8% Bethesda VI, and 73.4% Bethesda III, IV, V) from 513 patients were evaluated by ThyroSeq, and 504 samples had adequate DNA/RNA for analysis. 11/504 (2.2%) patients had multiple positive markers. 7 of 11 had thyroid surgery with pathology showing 5 cancers and 2 benign TN. The malignant group contained 1 poorly differentiated cancer (PDTC; NRAS, TERT and EIF1AX) with a biochemical incomplete response, 1 papillary cancer (PTC; RET/PTC and TERT) with a structural incomplete response, and 3 follicular variant PTC (TERT plus KRAS; NRAS plus PTEN; NRAS and TERT) with an acceptable response. The two benign nodules contained mutations, EIF1AX, GNAS plus SLC5A5 and low levels of both NRAS and EIF1AX. Although there was no pathology in 4 patients, one was a PDTC (BRAFV600E, TERT and TP53) who died from thyroid cancer while the other 3 patients included one with a Bethesda V cytology and multiple suspicious nodes on CT scan (NRAS and TERT) but medically unstable for thyroid surgery, 1 with Graves' disease (EZH1 and TSHR), and 1 solitary nodule (NRAS and TP53). After 3-5 years of follow-up with imaging, these 3 nodules have remained clinically stable. The present case series derived from 1,400 biopsies suggest multiple molecular alterations detected by ThyroSeq is uncommon but associated with a high risk of thyroid cancer but not always with persistence disease. Specific molecular markers associated with aggressive behavior include BRAFV600E, NRAS or RET/PTC in combination with TERT while other combinations such as TSHR, EIF1AX, and GNAS are found in tumors with low malignant potential with a good response to therapy.
Thyroid Cancer Friday Poster Clinical
Papillary thyroid cancer (PTC) diagnoses are rapidly increasing over time, mostly due to an increase of tumors ≤10 mm of maximum diameter. Controversy exist on the optimal management of these tumors. Aim: to investigate the risk of recurrence estimated at the time of primary treatment in a cohort of PTCs stratified by size.
Thyroid Cancer Friday Poster Clinical
The current status of initial management of differentiated thyroid cancer (DTC) in China after the implementation of the Chinese guidelines on DTC management in 2012 is unknown and was investigated here. This was set to be a multi-center, prospective and registry study (Clinicaltrial ID: NCT02638077). Patients who were identified as intermediate or high risk DTC after the first-time thyroidectomy were enrolled and followed up at least one year. During follow-up, comprehensive medical records were collected and summarized using descriptive statistics. From 2014 to 2016, a total of 2013 DTC patients (568 males and 1445 females, mean age 41.77 years) from 9 institutions were eligibly enrolled in the study. 1. The situation of initial management: 83.1%, 10.0% and 6.9% of the patients underwent total/near-total, lobectomy plus Isthmusectomy and other types of thyroidectomy. 99.0% of patients had a central or a lateral neck lymph nodes dissection or both. Moreover, 48.0% of patients were given radioiodine therapy after thyroidectomy and 91.5% of patients were given TSH suppression therapy. 2. The clinicopathologic characteristics: The rate of extrathyroid invasion, lymph node metastasis, distant metastasis and multi-foci were 44.0%, 82.3%, 0.4% and 38.5% respectively. 3. Clinical outcomes at one year: 61.4% of patients achieved serum TSH target values. Moreover, recurrence or metastasis occurred in 27 patients (1.3%) and 2 patients died due to lung metastasis. The results of this study showed that the initial management for Chinese DTC patients remains to be improved. Follow-up of the patient cohort in this study is currently ongoing to more accurately assess the efficacy of the current treatment strategy and the feasibility of the Chinese guidelines on DTC.
Thyroid Cancer Friday Poster Clinical
The rise of the aging population coupled with the increasing incidence of thyroid cancer warrants a better understanding of thyroid cancer epidemiology in older adults. Our primary objective was to investigate the clinico-pathological characteristics and disease-specific mortality in older adults with thyroid cancer. We performed a retrospective cohort study using the Surveillance, Epidemiology, and End Results (SEER 9) program to examine patients with thyroid cancer between 2000-2014. Patients were stratified by age into: adults (18-64 years), older adults (65-79 years), and super-elderly (>80 years). Chi-squared test was used to compare clinico-pathological features across age groups. Hazard ratios were calculated for disease-specific survival analysis. We identified 145,009 patients with thyroid cancer of which, 80.4% were adults, 16.1% were older adults, and 3.5% were super-elderly. Over the study period, the overall incidence of thyroid cancer increased, attributable to the increase in well-differentiated thyroid cancer. Older adults and super-elderly were more likely to develop anaplastic cancer, medullary cancer, and Hürthle cell carcinoma compared to adults. Super-elderly were more likely to develop larger tumor size, and distant metastasis compared to adults. In patients with well-differentiated thyroid cancer, however, fewer older adults and super-elderly underwent surgery (96.2% vs. 93.1% vs. 79.2% P:<0.001) or received RAI (86.2% vs. 61.5% vs. 38.1% P:<0.001). Older adults and super-elderly had higher risks of dying from thyroid cancers (HR:4.4, CI:4.0-4.7, P:<0.001, and HR:7.2, CI:7.2-8.7, P < 0.001 respectively). Thyroid cancers in older adults are more likely to present with larger tumor size, distant metastasis, aggressive histology, and higher grade compared to adults, decreasing their survival. However, fewer older adults underwent surgery perhaps leading to worse survival than their younger counterparts. Future studies are needed to assess this disparity.
Thyroid Cancer Friday Poster Clinical
Transoral robotic thyroid surgery(TORT) has gained growing attention as an ideal method for minimally invasive thyroidectomy. Compared to pre-existing “minimally invasive” methods, this procedure requires less flap dissection and produces no visible scars. Nonetheless, application of TORT still brings concerns, especially in Western countries, regarding its safety and effectivity due to its confined approach access and restricted view in obese patients. Here, we present 14 cases of TORT among patients with Body mass index(BMI) over 30 for its safety and outcomes. This study retrospectively reviewed all TORT operations performed from March, 2016 through April, 2018 at Korea University Anam Hospital, Seoul, Korea. Among all patients who underwent TORT operation, patients with BMI ≥30 kg/m2 were selected for evaluation. Their surgical outcomes were retrospectively reviewed. Of the 265 patients who underwent TORT operation, 14 patients had BMI higher than 30 (mean BMI 33.3 ± 2.9kg/m2; range 30.2-41.3kg/m2). Among 14 patients (mean age 37.9 ± 11.9 years; range 20-58 years), 11 patients were female (78.6%) and 3 were male (21.4%). 13 patients were diagnosed with papillary thyroid carcinoma (PTC) and only one patient was diagnosed with follicular neoplasm. Three patients underwent total thyroidectomy with bilateral central neck dissection, and 11 patients underwent unilateral thyroid lobectomies with or without ipsilateral central neck dissection. The average surgical time was 280 ± 43.6 minutes (range 250-330 minutes) for total thyroidectomy and 207.3 ± 43 minutes (range 150-280 minutes) for unilateral thyroid lobectomies. The mean tumor size was 1.0 ± 0.9cm (range 0.4-3.8cm) and the number of retrieved central lymph nodes in the PTC patients was 4.7 ± 3.9. The mean hospital stay was 2.8 ± 0.6 days (range 2-4 days), and one patient experienced oral commissure taring which required conservative management. There were no reports of transient or permanent vocal cord palsy, recurrence, or mortality during the median follow-up period of 8.3 months. TORT was performed safely among patients with BMI ≥30kg/m2 while avoiding incisional scars. Thus, TORT approach can be a safe alternative for scarless thyroid surgery in obese patients.
Thyroid Cancer Friday Poster Clinical
Revised American Thyroid Association (ATA) guidelines have recommended expanded approaches to the management of thyroid cancer. Although patient engagement has taken an increasingly important role in decision-making, patients' views on key recommendations including observation and less surgery for low risk disease as well as more selective use of RAI have not been studied.
To seek patient opinions regarding changes in the thyroid cancer guidelines, 7 expert surgeons and endocrinologists designed a survey, approved by the ATA board. The 30-item survey was distributed electronically to thyroid cancer patient advocacy organizations and members of the ATA to distribute to their patients. Multiple choice and open-ended items included demographic, treatment history and disease status, reflections on treatment course, and “what-if” scenarios.
1937 patients voluntarily completed the survey and 66 participants were excluded for not having a diagnosis of thyroid cancer. 56% of respondents were diagnosed in the past five years (range 1960-2018). Mean age was 49 years old, 76% were female, and 66% identified themselves as white. Participants represented all stages of disease, extent of surgery, and adjuvant therapy [65% received radioactive iodine (RAI)]. 35% stated they would have considered active surveillance, 45% would have opted for lobectomy over total thyroidectomy, and 68% would have foregone RAI if outcomes were the same. Concerns for considering observation included distance from provider, quality of care/expertise, and financial instability. Common themes included improved communication and lengthened time with physician to discuss treatment options, evidence based decisions, and poor quality of life on thyroid hormone replacement. Patients requested more quality of life research and to stop being tagged with the “good cancer”.
Thyroid cancer survivors and patients support a more personalized approach to thyroid cancer treatment and encourage the opportunity to engage in the decision-making process for their own care. Development and utilization of a patient reported outcome measure could aid in addressing quality of life issues in this population.
Thyroid Cancer Friday Poster Clinical
There are a rapidly growing number of thyroid cancer (TC) survivors. Some TC survivors report chronic symptoms of neurocognitive impairment after thyroidectomy, Our objective was to perform a systematic review of the literature and meta-analysis, to determine whether the body of published literature suggests that neurocognitive function is worse in TC survivors compared to controls. We searched 7 electronic databases for relevant citations and this was supplemented by a review of the co-authors`personal records. Citations and full-text papers were independently screened by two reviewers. Primary authors were contacted for additional information, as needed. The reviewers achieved consensus on the papers included in the review. Data were independently abstracted and individual study quality appraised by two reviewers. Random effects meta-analyses were conducted for tests in common among studies. We retrieved a total of 1,430 citations from our electronic search, which yielded 1,174 citations after removal of duplicates. We reviewed 10 full-text papers and ultimately 7 studies, including a total of 241 TC survivors and 273 controls. The mean or median TSH concentration was subnormal in the TC group in 4/7 studies and control groups were euthyroid. Neurocognitive tests were grouped according to the following domains: Attention/Concentration, Speed of Processing, Motor/Psychomotor, Language, Visuoperceptual/Visuospatial, Immediate Recall, Delayed Recall, Recognition Memory, or Executive Function. In general, we observed variability amongst differences between TC survivors and controls, within and between neurocognitive domains. Among 3 studies examining subjective neurocognitive complains, TC survivors reported worse symptoms than controls in one study. Most of the included studies (6/7) had one or more limitations predisposing to the risk of bias. There is conflicting evidence as to whether TC survivors have worse neurocognitive function compared to euthyroid controls. Larger prospective studies are needed to better elucidate neurocognitive function in this TC survivors.
Thyroid Cancer Friday Poster Clinical
Previous studies have suggested that lower socioeconomic status (SES) might be associated with advanced presentation of well differentiated thyroid cancer (WDTC) at diagnosis. However, the impact of SES on WDTC outcomes is less clear. We examined the effect of SES on presentation, and outcomes of WDTC. We conducted a retrospective cohort analysis of patients with WDTC diagnosed between 2000 and 2010 in six Canadian centers. SES was determined using the Census-derived neighborhood income quintiles (Q1 = lowest, Q5 = highest), and assigned based on patients' residential postal codes. Regression analyses were performed to test for associations between SES quintiles and thyroid cancer hazard of recurrence and the probability of disease free status. We included 2652 patients, 78.9% women, mean age at diagnosis was 47.8 years. SES was not significantly associated with AJCC stage at presentation (p = 0.277). Lower SES quintiles were more likely to have larger and more invasive tumors at presentation. T4 tumours were found in 3.7% and 3.0% of patients in Q1 and Q2, and in 2.6%, 2.9% and 1.9% of Q3, Q4 and Q5 patients, respectively (p = 0.004). Recurrences were seen in 88 (3.3%) of patients during the average 7.7 years of follow up, but did not differ according to SES quintile. Compared to the lowest quintile, adjusted HR for those in the Q2-Q5 were 0.55, 1.24, 0.87 and 0.80 respectively (P = NS for all). The odds of disease free survival were also not different between SES quintiles regardless of radioactive iodine administration. In a universal health care system, SES may not adversely impact presentation of WDTC or patients' outcomes.
Thyroid Cancer Friday Poster Clinical
Remote-access surgery (endoscopic approach without scar in the neck) should not be applied to the operations for advanced thyroid carcinoma in terms of curability, safety, as was suggested by ATA statement (Thyroid, 2016). We developed hybrid-type endoscopic thyroidectomy (HET: Tori's method; Surg Endosc 2014) for advanced thyroid carcinoma. To standardize HET, efficacy and feasibility of total thyroidectomy (HET-total) should be clarified. We present operative results of HET-total compared with traditional total thyroidectomy (trad-total). (Approach) For total thyroidectomy with central component node dissection (CCND) or unilateral modified radical neck dissection (MRND), one small skin incision (2-2.5cm) 1.5cm above the clavicula of either side and two ports (5mm) 3.0cm below the clavicula (both sides) are made. For total thyroidectomy with bilateral MRND or if tracheal resection (shaving) necessary, two small skin incisions in both sides with two ports are made. For 5 years between May 2011 and May 2016, the number of HET-total was 92 (Age: 50.9 ± 14.4, Male 13, female 79). These cases were clinically examined retrospectively, compared with the trad-total performed during the same period (n = 181). Evaluation of cosmesis and pain scale was added to the results. Among 92 HET-total cases, CCND was performed in 72 cases, while MRND (uni, bil) in 20 cases. Shaving of the trachea was added in 15 cases, esophageal partial resection in 3 cases, shaving of the recurrent nerve in 9cases. All were papillary carcinoma (stage I: 39, II: 2, III: 40, IVA: 11). The operative time was 145.3 ± 46.1 min. Blood loss was 5ml (5-280). VAS scale on POD 3 was 0 (0-2). Hospital stay was 6 days (4-10). As to the prognosis, all of the operative cases are alive, and all but one case (lymph node metastasis of the opposite side) are now free from recurrence. As to the perioperative complications, none were encountered in HET-total. Pts were satisfied with cosmesis in HET-total. VAS scale and hospital stay were significantly better in HET-total, compared with those in trad-total. These results strongly support the idea that HET-total could be standardized with feasibility and safety including excellent cosmetic benefits and curability.
Thyroid Cancer Friday Poster Clinical
Differentiated thyroid carcinoma (DTC) is the most common endocrine malignancy with a low mortality but a high rate of lymph node recurrence (LNR). The aim of the study was to evaluate: the risk factors, the predictors of disease free status and the efficacy of the different treatments (surgery vs 131-I). To this end, 187 patients treated between 1984 and 2011 for DTC-related LNR at the Department of Clinical and Experimental Medicine of the University of Pisa were retrospectively studied. The risk factors for LNR were male gender, the larger size of the primary tumor, extra-thyroid extension, multifocality and the presence of lymph node metastases at diagnosis. At the end of the follow-up (9.9 + 4.7 years) the patients were divided into two groups: disease free or persistent. Predictors of persistent disease included: a younger age at diagnosis (p = 0.03), a larger primary tumor size (p = 0.0005), the presence of extra-thyroid extension (p < 0.0001), an advanced stage according to AJCC-TNM (III+IV) (p = 0.006) and the risk class according to the ATA classification (p = 0.0004). Patients were also studied on the basis of the treatment performed for LNR. Group-A was underwent surgery (± 131-I) and Group-B only 131-I treatment. Group-A had a significantly higher disease free rate (26.8%) than Group-B (15.8%). However, a non negligible number of patients from the first group underwent a third surgical procedure for a second LNR (27.4%). The re-operation had a rather low complication rate (5%). At the end of follow-up, 32.4% of patients of Group-A were disease free compared to 15.8% of Group-B who became disease free more frequently at the first treatment with 131-I and never after the third treatment. In conclusion, patients with LNR are generally younger and with a more advanced disease at diagnosis and achieve “complete remission” in only 25-30% of cases. The most effective treatment modality to obtain a disease free status is surgery which had an unexpected low complication rate even when repeated.
Thyroid Cancer Friday Poster Clinical
To investigate the different expression levels of death-associated protein kinase (DAPK) related miR-191 and phosphatase and tensin homolog deleted on chromosome ten (PTEN) related miR-494 in fine-needle aspiration biopsy (FNAB) samples and blood of benign and malignant thyroid nodules, and to find new clinical molecular diagnostic marker. FNAB specimens and peripheral venous blood were collected from 113 patients with thyroid nodules(48 cases of malignant and suspected malignant thyroid nodules, 38 cases of nodular goiter and 27 cases of thyroid adenomas). The expression levels of miR-191 and miR-494 were detected by realtime fluorescence quantitative reverse transcription PCR (qRT-PCR). Apply qRT-PCR to detect miR-191, miR-494 expression level in 98 patients with thyroid nodules and peripheral circulation. Using receiver operating characteristic curve (ROC curve) to measured sensitivity and specificity of miR-191, miR-494 to diagnose malignant thyroid nodules.(1) The sensitivity of FNAB in diagnosing thyroid cancer was 93.6% (44/47) and the specificity was 88.2% (30/34), the diagnostic accuracy was 91.35%. (2) In FNAB samples and peripheral circulation, the relative expression of miR-191 in thyroid cancer group is significantly lower than the benign group, while the relative expression of miR-494 in thyroid cancer group is significantly higher than the benign group, and the difference between groups was statistically significant (P < 0.05). (3) The sensitivity and specificity of miR-191, miR-494 is acceptable (area under the ROC curve >0.7). Sensitivity and specificity of miR-191 in FNAB and peripheral circulation were 76.9%, 73.5% and 61.5%, 64.1%; miR-494 were 63.6%,76.5% and 72.7%, 84.6%. (4) In thyroid cancer FNAB samples and peripheral circulation, the difference between the relative expression level of miR-191, miR-494 and the clinical characteristics of age, gender, nodule size, calcification, with or without cervical lymph node enlargement, thyroid function and thyroid antibodies with or without abnormalities were not statistically significant (P < 0.05). MiR-191 and miR-494 can be used as molecular diagnostic markers for early diagnosis of thyroid carcinoma with adjunctive FNAB.
Thyroid Cancer Friday Poster Clinical
Minimally invasive follicular thyroid cancer (miFTC) is a unique entity with unclear long-term outcomes. As the initial surgery for miFTC is often a lobectomy for an indeterminate nodule, we aimed to determine whether there are factors associated with recurrence that could inform treatment.MiFTC was defined by 3rd WHO classification. We retrospectively reviewed a prospective tumor registry at a large tertiary cancer from 2005-15. Surgeries performed at an outside institution (OSI) had pathology re-reviewed at the study institution. X2, fisher's exact, and student's t-test were used to compare groups. We identified 66 cases of miFTC. Forty-five (68%) had initial surgery at an OSI, 45 (68%) were female, mean age was 44y (±16), mean size was 30mm (±18), 7 (11%) underwent lobectomy only, 41 (62%) underwent staged total thyroidectomy, 18 (28%) underwent initial total thyroidectomy, and 44 (68%) received RAI. On pathology, 28 (43%) had lymphovascular invasion (LVI), 5 (9%) had positive margins, and 16 (24%) were greater than 4cm in size. After a median follow up of 4.7 years, 4 developed distant bone metastases and 2 had local-regional recurrence; 1 patient (2%) died of disease. Rates of lobectomy, RAI, LVI, tumor size, patient age and sex were similar between those who recurred and those who did not. Two of the recurrences were from tumors that did not have LVI; one was to bone and the other was local. All 6 recurrences were initially treated at an OSI. In patients who underwent completion or initial total thyroidectomy, recurrences were more likely to have a detectable thyroglobulin level at 6 months post treatment (80% vs 8%, p-value 0.001). MiFTCs greater than and less than 4cm had similar clinical-pathologic features and had similar recurrence rates (10% vs 7%, p-value 0.568). Although likely confounded by referral bias, these data suggest that patients diagnosed with miFTC can develop recurrent disease and disease-specific mortality independent of tumor size. There were no clear clinical-pathologic differences between patients who recurred and those who did not. Further research is needed to identify predictors of long-term outcomes in order to optimize upfront management of miFTC.
Thyroid Cancer Friday Poster Clinical
A dynamic risk stratification is crucial for full-course management in differentiated thyroid cancer (DTC) patients. This paper aimed to compare the predictive value of ATA and CTA risk-stratification system (ATA-RRSS and CTA-RRSS). ATA-RRSS was based on recurrence risk stratification system of 2009 ATA guideline for DTC patients and CTA-RRSS was based on 2014 CTA guideline. Unselected DTC cases diagnosed from 2013-2016 and actively monitored at our institution were reviewed. All the patients were stratified into low-risk, intermediate-risk and high-risk groups by the two RRSSs. The associations between stratifications and latest response-to-therapy were analyzed and compared.
Totally 1043 patients were enrolled. The median follow-up period was 2 years. Both guidelines performed well in predicting the latest therapeutic response. By ATA guideline, the recurrence rate was 2.8% (1/36) in low-risk group, 4.7% (34/725) in intermediate group and 42.9% (121/282) in high-risk group. By CTA guideline, the counterparts were 0% (0/29), 3.7% (26/698) and 41.1% (130/316) respectively. The recurrence rate of low-risk group defined by ATA is higher than that of low-risk group defined by CTA (2.8% vs 0%). More patients with exact clinical recurrence were precisely classified into high-risk by CTA guideline (n = 130) compared with ATA guideline (n = 121), A cutoff value of ps-Tg at 26.75 ng/ml was obtained by receiver operating characteristic curve for differentiating SIR from either excellent, indeterminate, or biomedical incomplete responses. Both ATA guideline and CTA guideline are credible in predicting therapeutic response. CTA guidelines tend to prevent true low-risk patients from over-aggressive treatment or follow-up, and prevents patients with recurrence/resistance risk from under-administration. It is due to thyroglobulin being one of key weight factors in CTA guideline.
Thyroid Cancer Friday Poster Clinical
Active surveillance (AS) is a newer strategy for patients with papillary thyroid microcarcinoma. Our goal was to evaluate the use of AS and barriers to implementation. We used Qualtrics© to survey members of the American Thyroid Association (ATA), American Association of Endocrine Surgeons, and American Head & Neck Society. We assessed AS use with an established model of barriers to guideline adherence and analyzed data with Chi-square and t-tests as appropriate. A total of 345 physicians completed the survey (99 endocrinologists and 246 surgeons). 94% of respondents were quite or very familiar with the 2015 ATA guidelines, but 6% were not at all familiar with AS. Overall, 63% of respondents utilized AS, and 81% felt AS is underused. Endocrinologists used AS more frequntly than surgeons (7 ± 11 vs. 4 ± 5 patients/yr, p = 0.02). Barriers to AS included the belief that patients were not aware of (81%) or interested in AS (52%), which was more common among surgeons (p = 0.05). Respondents also agreed the psychological burden of AS is too high (31%) or will not improve patients' quality of life (26%). When asked, 29% of respondents agreed the 2015 ATA guidelines are too vague, 18% the evidence for AS too weak, and 6% felt AS may lead to poor outcomes. Overall, 19% of respondents had reservations about AS, and 16% were not comfortable offering AS. Other barriers included not knowing how to select appropriate patients or perform AS (9%). Concerns about malpractice (18%) and costs (15%) existed, and surgeons had more concerns about resources (14% vs. 9%, p = 0.04), negative impact on referrals (16% vs. 6%, p < 0.001) or reimbursement (11% vs. 5%, p < 0.001). When asked about how to increase AS use, respondents supported having a standardized consent form (37%) and more information for patients (27%). Most endocrinologists and surgeons believe AS is underused. Significant barriers to increasing the use of AS appear to be concerns about data supporting AS and clarity of guidelines as well as the belief that patients are not interested in AS, which may affect whether providers discuss or offer AS. Interventions to increase the use of AS should focus on improving patient and provider knowledge and developing a formal consent process.
Thyroid Cancer Friday Poster Clinical
Treatment with tyrosine kinase inhibitors (TKI) often cause thyroid dysfunction in non-thyroidal cancer, while researches about the effect on thyroid hormone in patients after thyroidectomy were so limited. The aim of this study was to evaluate the effect of apatinib, a novel TKI targeting VEGFR-2, on thyroid hormones for progressive RAIR-DTC patients. We studied serum thyrotropin (TSH), free thyroxine (FT4) and free 3,5,3-triiodothyronine (FT3) and thyroxine dose in 20 patients from the phase 2 clinical trial (NCT 02731352). Data were collected at baseline, every 2 weeks during the initial 8 weeks and 8 weeks thereafter.4 patients were excluded due to TSH >0.100 mU/L at baseline. 16 patients were analyzed (female 9, male 7, age 55.9 ± 14.0 years). During the 40-week apatinib treatment, 13 patients (81.3%) exhibited significantly increased TSH >0.100 mU/L (median change 4140.7%, range 776.7%, 76827.3%) in a median of 8 weeks (range 4, 32). An increase thyroxine dose of 0.3 ± 0.2 μg/kg was required in order to make TSH resume to less than 0.100 mU/L within a median of 8 weeks (range 2, 28). The change of TSH was much apparent than the corresponding reduction of FT4 (23.0% ± 16.9%, P < 0.01) and FT3 (median 46.3%, range 0, 64.2%, P < 0.01). Most of the patients (9/13) reached the first TSH >0.100 mU/L in the first 8 weeks (median 4, range 4,8), while the others (4/13) reach the first peak TSH concentration with a median time of 28 weeks (range 16, 32, P < 0.01). 6 patients were observed a second time that TSH was above 0.100 mU/L.TSH might be a sensitive marker in reflecting thyroid hormones in RAIR-DTC patients under apatinib treatment, and should be monitored regularly, especially in the initial period.
Thyroid Cancer Friday Poster Case Report
Differentiated thyroid carcinoma (DTC) has a favorable prognosis following surgery, radioiodine (RAI) and thyroxine therapy. However, after becoming refractory to RAI (RAIR), the 10-year survival rate was as low as 10%. We previously found that RAIR DTC patients respond well to apatinib, an oral anti-angiogenic inhibitor targeting VEGFR-2. While, poorly differentiated papillary thyroid carcinoma (PTC) is a type of highly aggressive DTC. Herein, we report a case of RAIR poorly differentiated PTC who responded to apatinib. This was a 51-year-old male patient with pulmonary metastases. The postoperative pathology confirmed right poorly differentiated PTC (insular carcinoma), and the tumor showed positive VEGF expression. Due to the even increasing Tg level (316.7 to 643.2 ng/mL) and new metastases lesions after the first 131I therapy, the patient was identified as RAIR after two times of 131I therapy (150 mCi and 200 mCi, respectively) following surgery. Treatment with apatinib was initiated at a dose of 750 mg qd. Four weeks represented a cycle. The Tg level rapidly declined (from 3869.0 to 830.8 ng/ml) at week 2 and maintained a relatively low level until week 60. The sum of diameter of target lesions sharply decreased by 48.4% after two cycles (from 30.3 to 15.6 mm). Partial response was detected at cycle 2 and maintained to cycle 18. Progressive disease was confirmed by imagological examination after 18.5 months of apatinib therapy. Apatinib medication was interrupted for 7 times mainly due to grade 3 neutropenia and gastro spasm. Dose reduction was required due to grade 3 diarrhea and grade 2 abdominal pain. Most drug-related adverse events (DRAEs) were grade 1/2. Main DRAEs of grade 3 included neutropenia, hypertension, and diarrhea. The patient was diagnosed as poorly differentiated PTC with pulmonary metastases, and developed RAIR, which indicated poor prognosis. However, a progression free survival as long as 18.5 months was achieved following apatinib treatment. As apatinib selectively inhibits VEGFR-2, the activated VEGF signaling might contribute to the rapid and long-term response to apatinib. This report indicates that apatinib is a viable treatment option for RAIR poorly differentiated PTC.
Thyroid Cancer Friday Poster Case Report
Primary thyroid lymphoma (PTL) is a rare cause of both thyroid malignancy and extranodal lymphoma representing approximately 2% to 5% of all thyroid malignancies, most commonly the B-Cell type (68 %). The coexistence of PTL in the setting of Lymphocytic thyroiditis (LT) is rare.
Herein, we report the case of a 54-year-old woman who had left lobectomy which was diagnosed as nodular goiter in a background of lymphocytic thyroiditis. 2 years later, the patient presented with recurrent large, tender, diffuse, hard, enlargement of remaining thyroid fixed to the trachea and encroaching on the great vessels of the neck. This was associated with dysphagia and occasional orthopnea. Fine needle aspiration (FNA) was performed and cytology revealed features suggestive of lymphocytic thyroiditis.
Since the clinical impression based on the clinical presentation was suspicious for malignancy, Thyroid Multidisciplinary Tumor Committee recommended a completion thyroidectomy. Histopathology revealed a diffuse large B-cell lymphoma (DLBCL) in a background of florid LT. The patient was then treated with chemo-radiation therapy.
This report is a reminder that although the coexistence of PTL in the setting of LT is rare, PTL can masquerade as a LT. Furthermore, essential guidelines necessary to distinguish PTL from LT are presented including the importance of monitoring LT patients with nodular lesions, especially if they have long-standing disease, careful review of the clinical presentation and the utilization of ancillary study such flow cytometry analysis of the fine needle aspiration sample if there is clinical suspicions of lymphoma.
PTL should be considered for differential diagnosis in elder LT patients who present with sudden rapidly thyroid enlargement. Awareness of this rare entity is important in order to achieve an early diagnosis and implement correct treatment.
Thyroid Cancer Friday Poster Case Report
Thyroglossal duct cysts (TGDCs) are a common cause of central neck mass, resulting from failure of involution after thyroid migration during development1. Likewise, papillary thyroid carcinoma (PTC) is the most common thyroid cancer subtype, and one retrospective study found concomitant PTC in 2.6% of patients with primary hyperparathyroidism2,3. However, there have been no previously report cases of concomitant TGDC, PTC, and primary hyperparathyroidism. A healthy 64-year-old male presented to his primary care physician with an asymptomatic palpable midline anterior neck mass. Laboratory studies incidentally revealed asymptomatic primary hyperparathyroidism (calcium 12.0 mg/dl, parathyroid hormone 75 pg/ml). Preoperative ultrasound demonstrated a 2.6cm complex cyst in the anterior neck, consistent with a TGDC, a normal sized thyroid with a single 6mm benign-appearing nodule, and no visible parathyroid adenoma. Computed tomography (CT) confirmed these findings. He was referred to endocrine surgery clinic and scheduled for a parathyroid exploration with Sistrunk procedure. Intraoperatively, a firm paratracheal nodule was noted in right Level VI, and frozen pathologic section diagnosed a lymph node containing metastatic papillary thyroid carcinoma. Subsequently, a left inferior parathyroid adenoma was identified and removed, with confirmation of an appropriate decrease in intraoperative parathyroid hormone levels. A formal Sistrunk procedure was performed, and given the finding of PTC in a lymph node, a total thyroidectomy was also performed. No other abnormal lymph nodes were identified. Postoperative recovery was uncomplicated, and he was discharged postoperative day one. Final pathology revealed a benign parathyroid adenoma, a benign TGDC, and PTC in the thyroid gland and excised lymph node.TGDC, PTC, and primary hyperparathyroidism are not uncommon conditions. PTC has been found in 2.6% of patients with primary hyperparathyroidism, and there have been multiple case reports of concomitant TGDC and PTC3. However, there are no reports in the literature of all three pathologies occuringly simultaneously. We report the first case in the literature with concomitant TGDC, PTC, and primary hyperparathyroidism.
Thyroid Cancer Friday Poster Case Report
Primary tubeculosis of the thyroid gland is a very rare disease and rarely accompanied by papillary thyroid cancer (PTC). Thyroid tuberculosis is often diagnosed by histopathologic examination because of lack of symptoms and difficulty of bacteriological diagnosis. We report a case of primary thyroid tuberculosis with papillary thyroid cancer involving ipsilateral lymph node. A 37-year old woman with thyroid nodules in the left lobe was referred our hospital. She had no clinical symptoms and no history of tuberculosis. Thyroid hormone levels and other laboratory tests were normal. There was no specific finding on chest radiography. Ultrasonography showed 0.5cm hypoechoic nodule and 1.1cm cystic nodule on the left thyroid. She was diagnosed with PTC through fine needle aspiration cytology and operated left thyroidectomy with central node dissection. The pathologic report revealed papillary microcarcinoma with chronic granulomatous inflammation with central caseous necrosis, and in the central lymph node, the same result was noted. The tuberculosis PCR was negative in the thyroid and lymph node. We concluded primary thyroid tuberculosis with PTC involving ipsilateral lymph node. The patient was given antituberculous treatment for 6 months. On follow-up ultrasonography, there was no progression or recurrence. We report a case of concurrent primary thyroid tuberculosis and PTC involving ipsilateral lymph node. Although very rare, thyroid tuberculosis should be kept in mind in the differential diagnosis of thyroid mass and cervical lymph adenopathy even after being diagnosed with PTC.
Thyroid Cancer Friday Poster Case Report
Struma ovarii is a rare monodermal teratoma that is predominantly composed of thyroid tissue. Only 5% of struma ovarii have malignant transformation and usually this is a small focus of the tumor. Here we present a case of a woman with one of the largest reported malignant struma ovarii of 18.5 cm in size with a 12 cm papillary thyroid carcinoma. A 45-year old female presented with left lower abdominal pain and nausea. Physical exam revealed a large abdominopelvic mass. Subsequent CT imaging demonstrated an 18.5 cm predominantly cystic mass with enhancing solid components arising from the left ovary. CEA was elevated at 697 units/mL (normal 0-35), and TSH was normal. She had a remote history of a right oophorectomy due to a benign ovarian teratoma that was incidentally found during a cesarean section. Thus, she underwent a left salpingo-oophorectomy and right salpingectomy. Pathology demonstrated a 12 cm papillary thyroid carcinoma without invasion outside of the left ovary. She underwent a total thyroidectomy, and a coexistent 0.5 cm non-invasive follicular thyroid neoplasm with papillary-like nuclear features was noted in the right thyroid lobe. Nuclear whole body scan showed residual functioning tissue in the thyroid bed without evidence of distant metastases. Treatment with 30 millicuries of iodine-131 was given. Post therapy whole body scan showed expected uptake only in the thyroid bed. Stuma ovarii is an ovarian teratoma that has a lot of controversy in terms of diagnosis and treatment due to its rarity. There is no uniform criteria for diagnosis, and their appearance on imaging varies. The tumor marker CA-125 can be elevated but it's not specific and it can be high in benign lesions as well. It usually has an indolent course and metastasis is very rare. Surgery is the initial treatment, but there is still lack of consensus on the use of ablative therapy, chemotherapy, as well as the best monitoring methods after therapy. This is one of the largest thyroid carcinomas in a struma ovarii that has been reported in the literature. Due to its size, treatment with surgery and radioactive ablation was performed. Response to treatment will be monitored with CA-125 and thyroglobulin levels.
Thyroid Cancer Friday Poster Case Report
Heterophile antibodies rarely influence the measurement of thyroglobulin in the evaluation of differentiated thyroid carcinoma. However, in some cases, the presence of these antibodies could interfere with thyroglobulin measurement, leading to a false diagnosis of biochemically persistent thyroid carcinoma. In this cases, the recommendation is to test for the presence of heterophile antibodies using commercially available antibody blocking tubes, recovery testing or serial serum dilution. The present report describes two patients (A and B) with differentiated thyroid carcinoma, with persistent high thyroglobulin, with no other evidence of persistent focus of remaining disease. Thyroglobulin was initially measured by Beckman Access Tg (Beckman Coulter), serial serum dilution was performed using the same method. Due to lack of availability of antibody blocking tubes, the samples were also evaluated by other two methods, Roche Elecsys Tg II (Roche Diagnostics) and liquid chromatography, tandem mass spectrometry assay (Tg-MS) performed at the Mayo Clinic (Rochester, Minnesota). Thyroglobulin antibodies analysis were performed using two methods, Siemens-Immulite TgAb (Siemens) and Roche Elecsys TgAb (Roche Diagnostics). The initial thyroglobulin concentration was 30 ng/dL in patient A and 17 ng/dL in patient B; both patients presented negative neck ultrasound, iodine scan and patient A have no evidence of remaining disease at PET/CT scan. The thyroglobulin concentration linearity was preserved in the serial dilution, and both Roche and MS-MS methods resulted in undetectable thyroglobulin. Both patients presented negative thyroglobulin antibodies in the two assays analyzed. Despite expert recommendations to investigate heterophile antibodies using serial serum dilution, in both cases this strategy did not detect the interference, showing the importance to use other methods, specially Tg-MS that would be an alternative for possible interferences in immunoassays, avoiding unnecessary and expansive investigation.
Thyroid Cancer Friday Poster Case Report
Primary squamous cell carcinoma of the thyroid (PSCCT) is a rare malignancy, with few cases reported in the literature. An 80 year old man with remote tobacco use and rheumatoid arthritis presented with progressive anterior neck swelling for 2 months and severe right face and neck pain. Associated symptoms included hoarseness and right eye pressure. After failing empiric antibiotic treatment for presumed sinusitis, he was seen by otolaryngology. Physical exam revealed a non-tender, hard, fixed right thyroid mass. TSH was normal. Laryngoscopy revealed right vocal cord paralysis. Head and neck ultrasound revealed a dominant 1.4 × 2.3 × 2.1 cm, hypoechoic, ill-defined, taller-than-wide nodule in the right thyroid. Also found were 3 sub-centimeter left thyroid nodules and 3 right cervical lymph nodes. Fine needle aspiration of the dominant nodule showed squamous cell carcinoma. PET-CT showed a hypermetabolic thyroid lesion and 3 hypermetabolic right cervical lymph nodes. No distant metastatic lesions were identified. Pre-operative endoscopic ultrasound revealed involvement of the cervical esophagus, without intraluminal extension.
Total thyroidectomy with right modified radical neck dissection, bilateral central neck dissection and paratracheal lymphadenectomy were performed. Partial cervical esophagectomy and total laryngectomy were additionally performed due to extension into those structures. Pathology showed a 3.1 cm primary thyroid, poorly-differentiated carcinoma with squamous features, and tumor extension beyond the thyroid capsule. 5 of 41 lymph nodes were involved. Immunohistochemical staining was consistent with squamous differentiation. A 2 month follow-up PET-CT revealed new metastatic lesions in the vertebrae and left lung base. He is being treated with systemic chemotherapy and zolendronate for bone metastases. PSCCT often presents as a rapidly enlarging anterior neck mass, and is typically very aggressive with a poor prognosis. Factors associated with better outcomes include younger age at diagnosis, less extensive disease, and complete surgical resection with clear margins. Because the thyroid does not naturally contain squamous epithelium, the origin of PSCCT is unclear.
Thyroid Cancer Friday Poster Case Report
Elevated TSH is necessary for adequate uptake of radioiodine by a remnant or malignant thyroid tissue. Use of rhTSH is preferred over the withdrawal of thyroid hormone suppressive therapy due to concerns of impairment in quality of life, and promotion of thyroid tumor growth. Extensive clearance of rhTSH through the kidneys makes it challenging to determine the appropriate dose of rhTSH in patients on hemodialysis. Use of full dose rhTSH in this subgroup is associated with GI side effects and malaise. A 55-year-old female who is on HD due to Lithium nephrotoxicity was diagnosed with metastatic papillary thyroid cancer in the cervical lymph node (LN). She underwent total thyroidectomy and central neck LN dissection. Pathology confirmed two foci of papillary microcarcinoma without extrathyroidal extension nor lymphovascular invasion. There were 6 out of 11 positive perithyroidal/central lymph nodes. Remnant ablation was performed 9 months after surgery due to intermediate risk of recurrence and persistently positive thyroglobulin (Tg) levels. Basal serum TSH was 0.03 miu/ml before rhTSH was given. 2 doses of half the conventional dose of rhTSH was administered on 2 consecutive days. TSH, Tg and anti-Tg antibodies (Tgab) were measured 3 and 5 days after rhTSH administration. 75 mCi of I-131 was given after ascertaining the maximal tolerable dose by dosimetry. HD was done 20 and 44 h after I-131 treatment. 3 foci of uptake in the region of the anterior neck, likely thyroid remnants were found in WBI 6 days after I-131 therapy. TSH was 266 miu/ml, Tg was 132 ng/ml and Tgab was less than 1.8 IU/mL on the day of I-131 administration. The day after RAI ablation, TSH was168.3 miu/ml with Tg of 480 ng/ml. The patient continued to have down trending positive Tg level in the setting of suppressed TSH. In neck US, a LN on the right side, level 3/4 was found with microcalcifications, of unclear clinical significance. High serum TSH levels were achieved after the administration of half-dose of rhTSH. Since rhTSH is cleared mainly by the kidneys, patients requiring HD may not require full dose. Because the therapeutic response is multifactorial, it is difficult to associate with rhTSH dose and thyroid cancer cure.
Thyroid Cancer Friday Poster Case Report
Progressive differentiated thyroid cancer (DTC) refractory to standard treatment can be fatal. Since sorafenib and lenvatinib are the only 2 multikinase inhibitors (MKIs) approved for this indication, treatment resistance is a challenge. Activation of the mTOR pathway has been demonstrated in aggressive DTC. A study of sorafenib/everolimus in thyroid cancer including 10 patients with follicular thyroid cancer (FTC) or poorly differentiated thyroid cancer showed either stable disease (SD) or partial response in all patients. Moreover, the combination of everolimus and lenvatinib (E/L) is effective for renal cancer. Therefore, a rationale exists to consider this regimen in DTC. We present a patient with rapidly progressive FTC in whom E/L resulted in SD. A 73-yr old man presented with worsening back pain. Imaging showed liver and bone lesions which were proven to be thyroid cancer. He received radiation to the skeleton and thyroidectomy revealed a 5.5 cm widely invasive FTC with oncocytic features and a poorly differentiated component. He was deemed inappropriate for I-131 as he received iodinated contrast and rapidly progressed in the 2 months prior to presentation at our institution. He started lenvatinib and after 10 months of monotherapy without progression, the liver metastases grew rapidly. Next generation sequencing showed a NF1 mutation. Given data suggesting efficacy of everolimus in DTC and the presence of a NF1 mutation, E/L was recommended by our multidisciplinary team. To date, imaging has demonstrated SD over 6 months. Although there are data evaluating everolimus in thyroid cancer, our literature review did not identify use of E/L in DTC. Stabilization of rapidly progressive liver metastases using E/L represents an innovative strategy in the treatment of thyroid cancer. Furthermore, a correlation between NF1 mutations and response to everolimus has been proposed and warrants further investigation. Although the kinase inhibition profile of sorafenib differs from lenvatinib, this patient's experience strengthens the suggestion that combination MKI and mTOR inhibition can be a useful addition to our armamentarium. Nonetheless, prospective studies are needed to assess the efficacy of E/L in DTC.
Thyroid Cancer Friday Poster Case Report
Thyroglobulin (TG) is used as a tumor marker in the follow up of well differentiated thyroid carcinoma. Elevated or rising TG prompts further evaluation for recurrent or metastatic disease. TG assays are usually immunoassays which are subject to a number of interferences. The most common interference is when TG antibodies (ab) are present, which usually results in a false negative TG.
We report a 54-year-old female with rheumatoid arthritis (RA) and Follicular Variant of Papillary Thyroid Carcinoma, AJCC 7, stage T2N0M0, status post total thyroidectomy and RAI ablation, with ATA excellent response to therapy. Ten years after diagnosis, she presented with sudden elevation in TG of 111 ng/mL. On repeat testing, TG ranged from 111-300 ng/mL with undetectable TG ab. Imaging did not reveal evidence of recurrent disease. On further investigation, she reported starting adalimumab for her rheumatoid arthritis one-year prior. Tenfold dilution of the sample showed a decrease in TG from 300 to 47 ng/mL in a non-linear manner, suggestive of interference. The serum was treated with blocking agents and the TG decreased to 2.7 ng/mL suggesting the presence of HAMA. TG testing via mass spectrometry was undetectable.
Heterophilic abs like Rheumatoid Factor (RF) or HAMA are human abs that interact with assay abs. In 2-site immunometric “sandwich complex” assays, they often generate false-positive results. Those with RA are at risk of interference from RF or they can generate abs from exposure to immunotherapies that use chimeric abs. Our patient presented with false positive TG after starting therapy with adalimumab. She was found to have HAMA as the cause of her false positive results. Adalimumab is a fully human monoclonal ab, so not expected to result in production of HAMA. The association between HAMA development and adalimumab in this patient is unknown.
The assay interference in this case is likely due to either RF or HAMA from an unknown source. In the follow up of thyroid cancer patients, if TG is discordant with imaging and history, further evaluation for assay interference should be considered.
Thyroid Cancer Friday Poster Case Report
Alemtuzumab (AT) is an anti-CD52 immunomodulator used in the treatment of multiple sclerosis (MS), given as 2 courses of infusions 1 year apart. AT is known to suppress the immune system, causing autoimmune diseases, including thyroid disorders. Here we present a case of autoimmune thyroid disease leading to thyroid cancer after AT exposure. A 44-year-old female presented with hypothyroidism after 2 infusion courses of AT. The patient had no history of thyroid disorders prior to AT therapy. Thyroid stimulating hormone (TSH) level was consistently normal before and during therapy. Two months after the last infusion, her TSH was elevated to 31.4 uU/mL (Ref: 0.358 - 3.740 uU/mL). Her free T4 was 0.52 ng/dL (Ref: 0.76 - 1.46 ng/dL). She was treated with levothyroxine. Her TSH became persistently low at 0.01 uU/mL despite multiple adjustments of levothyroxine. TSH receptor antibody and thyroid stimulating immunoglobulin were both elevated, confirming Graves' disease. Levothyroxine was discontinued. Thyroid ultrasound revealed a 1.9-cm hypoechoic left inferior ill-defined thyroid nodule with no microcalcifications. Fine needle aspiration biopsy showed atypia of undetermined significance. The patient was provided with the options of a repeat biopsy with molecular testing versus thyroidectomy. She elected to undergo a total thyroidectomy, which took place a year after the last AT infusion. Pathology revealed 2 papillary thyroid microcarcinomas with lymphocytic thyroiditis. In the 5-year follow up of the Phase II trials of AT, the incidence of thyroid dysfunctions was as high as 39%. However, the incidence of thyroid cancer is low. In all clinical trials, 29 of 1,486 AT-treated patients developed malignancies, 6 (0.4%) of which were papillary thyroid carcinomas. To date, only one other case of papillary thyroid carcinoma has been reported since AT has been approved. A Belgium taskforce containing MS and thyroid experts recommends thyroid monitoring every 3 months over 4 years after AT therapy. As shown in this case, AT can cause thyroid cancer. Vigilant thyroid screening tests, autoimmune profiles and thyroid imaging may allow for early diagnosis and prevention of thyroid cancer in patients treated with alemtuzumab.
Thyroid Cancer Friday Poster Case Report
38 y/o man presented with a right neck mass first noted in 2013. Physical exam showed enlarged right neck lymph nodes and a palpable right thyroid nodule. Neck U/S demonstrated 1.5 cm right thyroid nodule and enlarged right lateral neck lymph nodes (LNs). FNA of thyroid nodule revealed medullary thyroid carcinoma (MTC). Labs showed calcitonin 3129 pg/mL, CEA 108 ng/mL and normal calcium, PTH & plasma metanephrines. RET mutation testing was negative. CT & PET scans confirmed right neck lymphadenopathy but no distant metastases. Bone scan was negative. Patient went to surgery for planned total thyroidectomy, central neck dissection, and right modified radical neck dissection (MRND) with intraoperative nerve monitoring. After completion of right hemithyroidectomy and right central neck dissection, during which multiple abnormal LNs were dissected off the right recurrent laryngeal nerve (RLN), the intact nerve lost signal. Right MRND was completed; due to right RLN palsy and lack of documented disease on the left, left thyroidectomy was not performed. Pathology confirmed MTC stage IVA (pT1b, N1b): 1.6 cm tumor in right upper lobe with +8/15 central and +8/24 lateral neck LNs. At 6 weeks, calcitonin decreased to 21 pg/mL & CEA to 3.3 ng/mL. Right vocal cord paresis recovered fully at 3 mos. The option of not completing left thyroidectomy was discussed at Tumor Board given high risk for distant metastases and no documented disease in the left. Patient chose close observation. Neck U/S, CT & PET scan at 4 mos. showed no disease and stable calcitonin. Approximately 25% of MTC cases are from MEN-2 syndromes; the majority are sporadic. Total thyroidectomy is indicated in hereditary MTC, but completion thyroidectomy after an unplanned hemithyroidectomy maybe more debatable in sporadic MTC when the remaining thyroid has no abnormalities on imaging and patient has high risk of distant metastases. Most patients with extensive LNs metastases and calcitonin >1000 pg/mL have systemic disease and will not be cured with thyroidectomy and locoregional dissection. Control of known locoregional disease, however, is important for prevention of local invasion into adjacent vital structures such as the RLN and aerodigestive tract.
Thyroid Cancer Friday Poster Case Report
Ethanol ablation is emerging as an effective alternative treatment for local recurrence of differentiated thyroid cancers such as papillary thyroid carcinoma (PTC). This minimally invasive technique may be considered when more traditional approaches such as repeat surgery or I-131 treatment are not successful or practical. A 55 year-old woman with history of PTC diagnosed 6 years prior underwent total thyroidectomy (T3N1bMx) followed by I-131 treatment (unknown dose) and external beam radiation. Recurrent disease in an anterior cervical lymph node (LN) was confirmed by fine needle aspiration (FNA) 3 years later. Repeat neck dissection showed severe fibrosis and the procedure was aborted. She received a second I-131 (185 mCi) therapy with post treatment whole body scan which showed no signal uptake in the neck or elsewhere.
Nine months later, neck ultrasound (US) again showed a suspicious 2.4 cm LN with prominent vascularity in the right thyroid bed. Serum thyroglobulin (Tg) was <0.2 ng/ml, but FNA confirmed PTC. Further imaging showed no distant metastases. Due to previous failed surgery, ethanol ablation of the LN was performed. Subsequent neck US at 5 and 8 months showed the treated lesion to be 2.9 cm and 1.1 cm, respectively, with significant decrease in vascular flow. Repeat FNA of the LN was negative for malignant cells and thyroglobulin on washout. No adverse events from the ablation were noted. Ethanol ablation for local PTC recurrence shows promising results in small case series. Treatment in our case can be deemed successful with evidence of elimination of significant tumor blood flow and reduction in tumor size which are two of the criteria for successful ethanol ablation published by Hay et al. In published series, participants had local recurrence following initial surgical intervention and I-131 therapy and were no longer surgical candidates. We present a successful case of ethanol ablation for locally recurrent PTC in which second surgery and I-131 treatment were unsuccessful. Ethanol ablation for local recurrence of PTC appears to be an effective and less-invasive treatment compared to surgery and may be utilized in specific cases when other treatment modalities are unsuccessful.
Thyroid Cancer Friday Poster Case Report
Iodine resistant metastatic Papillary Thyroid Cancer (PTC) with BRAF V600E mutation remains a therapeutic challenge due to ineffectiveness of Radioactive Iodine ablation (RAIA). We present a case in which adjuvant Dabrafenib was used for 6 years which led to sustained disease remission and eventual resensitization to Iodine. Our study highlights the success of prolonged systemic therapy with single agent Dabrafenib to inhibit metastatic BRAF+ PTC and reaffirms its ability to restore RAI uptake allowing RAIA to play a role in treatment. A 60-year-old female presents with T4aN1bM1 PTC with lateral neck and lung metastasis. She underwent thyroidectomy and diagnostic RAI whole body scan (WBS) which only showed uptake in the thyroid bed despite known metastatic FDG avid disease. Sequencing revealed BRAF V600E mutation. Patient was treated with single agent Dabrafenib without RAIA for over 6 years with disease remission. Repeat RAI-WBS revealed new iodine avid lung and neck disease seen on FDG PET initially. She underwent I-131 ablation and Dabrafenib was discontinued after 75 months of treatment and she continues to have remission of disease. Activating mutations within the MAP kinase pathway (often BRAF V600E) result in aggressive differentiated thyroid cancers (PTC) which are insensitive to RAI uptake and are metastatic at diagnosis. RAIA, which is first-line for metastatic PTC, is rendered ineffective when BRAF V600E mutation is present. Dabrafenib selectively targets BRAF kinase within the MAPK pathway, thus reducing tumor burden and inducing RAI uptake in tumor cells by reactivating Sodium-Iodine symporters (NIS). This enables RAIA to have a role in treatment. Initial studies used Dabrafenib for a median of 8.4 months with longest treatment of over 2.5 years. Our patient received Dabrafenib for 75 months with minimal adverse events and stable disease. This demonstrates Dabrafenib's success as prolonged systemic therapy to maintain disease remission and as an acceptable alternative until RAIA becomes an option. Dabrafenib was successfully used as prolonged systemic therapy in BRAF + metastatic PTC resistant to RAI to induce and maintain disease remission and to reactivate NIS allowing for eventual use of RAIA.
Thyroid Hormone Action Friday Poster Basic
X. Liang, Y. Xia, M. Lee, K. Phillips
Molecular & Cellular Biology, Baylor College of Medicine, Houston, TX
Beiging of white adipose tissue (WAT) has shown promise as a non-invasive treatment towards combating diabetes and metabolic diseases. Thermogenic programs to dissipate excess energy via fatty acid metabolism and UCP1 is normally found in brown adipocytes (BAT) as well as beige adipocytes. Modern agonists target the beta-adrenergic receptor (b-AR) to turn on this program. Here we show an alternative target in the thyroid receptor (TR) with the thyroid agonist, GC1. Adipocytes derived from stromal vascular fraction (SVF) of inguinal WAT (Iwat) or gonadal WAT (Gwat) and 3T3-L1 were treated with TR agonist GC1 or b-AR agonist CL316243 for 7-9 days. Beiging was detected by western blot, qPCR, and immunofluorescence.GC1 induced beiging in iWAT culture more effectively than CL316243. To our surprise, GC1 also induced significant beiging in gWAT and 3T3-L1 cells. In addition, GC1-induced beiging was still present even in b-AR knocked out cells, but dramatically attenuated after knockdown of TR. Our data suggest that TR activation is sufficient to induce beiging and using novel mechanisms independent of b-AR signaling. Hence, TR agonists may be important tools in assessing the therapeutic potential of beige fat activation to treat diabetes and metabolic disease.
Thyroid Hormone Action Friday Poster Basic
T3 is essential to the central nervous system; signaling depends on intracellular T3 concentration that is determined by transporters (MCTs, LATs and OATPs) and local conversion of T4 to T3 by deiodinases. The combined action of transporters and deiodinases defines adequate supply of T3 that binds to nuclear receptors (TR) and modifies gene expression. We asked whether T3 signaling in the human brain (i) can be studied via the expression of T3-responsive genes and (ii) correlates to the expression of transporters and/or deiodinases. This was done analyzing gene expression profile obtained through microarray analyses of 15 postmortem human cerebral cortex samples (Brodmann 38 region). Cause of death was limited to accident or sudden death. The mRNA expression level of 15 positively regulated genes was used to create an index of T3-signaling (T3s+) and with 15 negatively regulated genes (T3s-). These two indexes correlate with each other with a r2 = 0.30 (p < 0.04). Further analyzes revealed a positive correlation between thyroid hormone transporters and both indexes: MCT8 and T3s- (p < 0.02; r2 = 0.36) and T3s+ (p < 0.005; r2 = 0.48); MCT10 and T3s- (p < 0.003; r2 = 0.53) and T3s+ (p < 0.03; r2 = 0.33); LAT1 and T3s+ (p < 0.002; r2 = 0.40); LAT2 and T3s- (p < 0.02; r2 = 0.39) and T3s+ (p < 0.01; r2 = 0.42). Neither T3s- or T3s+ correlated with OATPs, Dio2 or Dio3. There was negative correlation between TRα expression and T3s+ (p < 0.01; r2 = 0.41) and TRβ expression and T3s- (p < 0.001; r2 = 0.57). TR co-regulators also correlated with T3 signaling indexes. The co-activator SRC-1 correlated negatively with T3s- (p < 0.02; r2 = 0.34) and positively T3s+ (p < 0.007; r2 = 0.45). The co-activator PGC-1a correlated positively with the T3s+ (p < 0.03; r2 = 0.33) and negatively with T3s- (p < 0.003; r2 = 0.65). The co-repressor RIP140 correlated positively with T3s+ (p < 0.009; r2 = 0.43) and negatively with T3s- (p < 0.01; r2 = 0.40).Taken together, these data suggest that there is normal variation in T3 signaling in the temporal cortex of euthyroid individuals that correlate with thyroid hormone transporters, TRα and Trβ, co-modulator SRC-1, SRC-3, PGC-1A, RIP140.
Thyroid Hormone Action Friday Poster Clinical
Levothyroxine (LT4) dosing following total thyroidectomy remains challenging, particularly in the obese. We hypothesized that obese patients given standard weight-based LT4 replacement following total thyroidectomy reach their TSH target range less often than normal weight patients. We performed a retrospective chart review of 236 patients undergoing total thyroidectomy at an academic hospital between 2012-2015. Patients were categorized into three groups based on NIH classification of body weight using body mass index (BMI): Normal BMI (BMI <25), Overweight (BMI 25-30), and Obese (BMI >30, range 30-61). Initial levothyroxine dose (mcg/kg/day), type of thyroid disease, and TSH level at 4-6 weeks postoperatively were collected. Target TSH range at first follow-up was set at 0.1-3 mIU/L. The Normal BMI group had 77 patients, and 77.9% had cancer. Median LT4 dose in mcg/kg/day was 1.79 (1.36-2.22). The Overweight group had 85 patients, and 68.2% had cancer. Median LT4 dose in mcg/kg/day was 1.65 (0.7-2.31), p > 0.001 compared to Normal. The Obese group had 74 patients, and 64.9% had cancer. Median LT4 dose in mcg/kg/day was 1.64 (0.9-3.3), p = 0.0003 compared to Normal.
45 patients (58.4%) in the Normal BMI group met the defined TSH target range. Of those patients that did not meet this range, 24 (31.2%) had a TSH above target, and 8 (10.4%) had a TSH below target. 59 patients (69.4%) in the Overweight group met the TSH target range (versus Normal, p = 0.14). Of those patients not meeting this range, 18 (21.2%) had a TSH above target (versus Normal, p = 0.14), and 8 (9.4%) had a TSH below target (versus Normal, p = 0.83). 47 patients (63.5%) in the Obese group met the TSH target range (versus Normal, p = 0.5). Of those patients not meeting the TSH target range, 14 (18.9%) had a TSH above target (versus Normal, p = 0.08), and 13 (17.6%) had a TSH below target (versus Normal, p = 0.2). We observed a trend that obese patients who do not reach the TSH target range are more frequently below the target (over-treated) than normal and overweight groups, despite being prescribed a significantly lower starting weight-based dose. Our results may support the use of lean body weight in calculating weight-based LT4 dosing in obese patients.
Thyroid Hormone Action Friday Poster Case Report
Thyrotoxic periodic paralysis (TTP) is a disorder characterized by thyrotoxicosis, hypokalemia, and progressive symmetrical muscle weakness. The condition may be fatal if respiratory failure or cardiac arrhythmia occurs. Although the pathophysiology is not well understood, TPP may develop when serum potassium levels are normal, a rare entity known as normokalemic TPP. We report a case of normokalemic TPP due to Graves' disease. A 32-year-old obese Asian male presented with sudden onset of weakness in the lower extremities upon awakening. No history of fever, chills, upper respiratory infection, or spinal trauma. A similar episode two weeks previously was less severe and rapidly resolved. The patient reported insignificant weight loss, but denied palpitations, irritability, heat intolerance or distal extremity tremor.
Physical examination revealed proximal muscle weakness of the lower extremities (2/5 RLE and 3/5 LLE) with intact deep tendon reflexes and sensation. Cranial nerve examination was normal. Electrolyte analysis showed normal potassium 3.7 mEq (3.5-5.1) and magnesium 1.7 mg/dl (1.6-1.9) but elevated phosphorus 5.0 mg/dL (2.5-4.5), Thyroid function tests revealed hyperthyroidism TSH 0.015 mIU/ml (0.47-4.68), T3 4.18 ng/dl (0.7-1.9), T4 4.15 ng/dl (0.78-2.19).
The patient was diagnosed with TPP. Potassium chloride and propranolol were administered with marked improvement and continued along with methimazole upon discharge. No further episodes of weakness were reported. Thyroid-stimulating immunoglobulin level 551 (<140); thyroid peroxidase antibody 92 (<9). Neck ultrasonography showed diffusely heterogeneous and moderately hyperemic thyroid gland. TPP is a rare presentation of thyrotoxicosis, most commonly described among young Asian men. Although hypokalemia is one of the hallmarks for TPP, normokalemia cannot exclude the diagnosis. Our patient had hyperphosphatemia as well which is not commonly seen in patients with TPP; However, several studies suggest thyroxine and triiodothyronine directly influence renal tubular phosphate reabsorption. Increased awareness of atypical presentations of TPP will result in early diagnosis and appropriate treatment of the underlying thyrotoxic state.
Thyroid Imaging Friday Poster Basic
Thyroid nodules are common clinical problems with prevalence of palpable thyroid nodules to be approximately 5% in women and 1% in men living in iodine-sufficient parts of the world. Thyroid Image Reporting and Data System is a classification system advocated for risk stratification of thyroid lesions. It is still difficult to decide which lesions should undergo fine needle aspiration biopsy because of different guidelines. Scope included all thyroid nodules who had undergone thyroid ultrasound, Thyroidectomy and histopathology done in VRPMC last 2014-2017, ages 21-70 years old and Filipino. This is a retrospective descriptive analytical study that aims to determine the diagnostic accuracy of gray-scale ultrasound findings of thyroid nodules (based on TI-RADS) in predicting the risk of malignancy among Filipinos managed in Victor R. Potenciano Medical Center from 2014 to 2017.
There were 84 thyroidectomies (21 patients with histopathology and ultrasound results in VRPMC). TIRADS category for each nodule was determined. Diagnostic accuracy was determined for Korean, French and American College of Radiology TI-RADS. Significant difference between age groups was determined with Analysis of Variance and T-test to determine the significant difference between genders. TI-RADS has good diagnostic accuracy. French TI-RADS had the best diagnostic accuracy (Sn 88%, Sp 92%). Benign lesions were more in ages 40-49 years and least in 20-29 years. Malignant lesions were more in ages 30-39 and least on 20-29 and 50-59. All thyroid nodules were more in female gender.
This study proves that using gray-scale ultrasound imaging features of TI-RADS may therefore decrease the rate of inadvertent thyroid biopsy and has high accuracy in predicting which thyroid nodules are ominous.
Thyroid Imaging Friday Poster Case Report
Differentiating between type I and type II amiodarone-induced thyrotoxicosis (AIT) can be extremely challenging, in part because of the cold iodine saturation of the thyroid gland due to amiodarone. 99m Tc-sestaMIBI has been proposed as an alternate imaging isotope to radioactive iodine and 99m TcO4, as it is taken up into cells with increased mitochondrial content, and appears to be unaffected by iodine loads.
Patient 1:
28 year old man with hx of syncope due to NSVT requiring ICD on amiodarone was admitted for worsening shortness of breath. HR: 102. TSH <0.03, Ft4 3.98, Tt3 165, TSI 172 (<140). US showed heterogeneous gland, no increased Doppler flow to suggest Graves'. Technetium pertechnetate scan showed no uptake, which could be falsely low due to amiodarone's iodine content. Thyroid sestamibi scan with decreased uptake. Diagnosed with AIT type II. Started on prednisone with normalization of Tt3 in 4 days and eventual improvement in 3 months to TSH <0.03, Ft4 1.71, Tt3 96.
Patient 2:
61 year old man with iCMP h/o VF arrest, atrial fibrillation, on amiodarone, who presented with worsening dyspnea on exertion. HR 113. TSH <0.03, Ft4 4.47, Tt3 194. US showed heterogeneous gland, no increased doppler flow. Technetium 99m sestamibi scan with decreased uptake. TFT's improved in 10 days TSH <0.03, Ft4 3.25, Tt3 120 on prednisone.
Patient 3:
47 yo man with Vtach on amiodarone who presented with diverticulitis. HR 82. TSH <0.03, FT4 > 6.0, TT3 288, TSI 22 with symptoms of mild proptosis on exam suggesting possible Graves' disease. US showed a diffusely enlarged heterogenous gland, decreased vascularity. Thyroid sestamibi scan with decreased uptake. TFT's improved in 2 weeks to TSH <0.03, FT4 4.28, TT3 140 on prednisone.
We followed 3 patients who were admitted for hyperthyroidism. Their clinical course proved that they all did have type 2 amiodarone induced hyperthyroidism with improvement on steroid therapy alone which correlated with the scan results. Although no gold-standard diagnostic test is available, 99m Tc-sestaMIBIcan be an accurate tool for differentiating subtypes of AIT.
Thyroid Nodules & Goiter Friday Poster Clinical
Fine needle aspiration (FNA) biopsy is a critical procedure in the management of thyroid nodules. Although, the efficacy of surgeon-performed thyroid FNAs has been demonstrated in the literature, there are insufficient data regarding the learning curve and how to establish an efficient program with a low insufficiency rate. An endocrine surgery thyroid FNA program was established in 2000 by one surgeon, with training of additional partners during fellowship and upon recruitment. Outcomes were periodically reviewed to determine the best practice for adoption, as part of a continuous quality improvement process. The results of this practice within 18 years were analyzed. The FNAs were performed by endocrine surgeons under ultrasound and without on site pathologic review. A total of 6141 FNAs performed by 8 endocrine surgeons. The total number of FNAs performed by each surgeon varied between 298-1391. Overall, insufficiency rate was 4.6%, with individual surgeon rates ranging between 2.7% and 8.1%. A typical learning curve was not observed for each surgeon, suggesting that this task was mastered in fellowship training. The insufficiency rate was consistently below 5% when examined in 5-year blocks for the whole team over the course of the study. The technique associated with the least insufficiency rate involved FNAs performed in 2 passes using 22-gauge needles under constant suction. This study shows that an establishment of a highly efficient thyroid FNA program with multiple surgeons is possible with a structured endocrine surgical training and adoption of a standard technique. The maintenance of efficiency requires a periodic quality review of outcomes and abortion of techniques resulting in deviations of sufficiency rates.
Thyroid Nodules & Goiter Friday Poster Clinical
The different approaches of endoscopic thyroid surgery has shown clear cosmetic advantage. The transorovestibular approach (TOVA) is the shortest route to reach thyroid and totally scar free surgery with high cosmetic outcome. In this current study of 12 patients we are going to highlight the benefits of 3DHD endoscopic technology in the management of multinodular goiter or solitary thyroid nodule through TOVA. From June 2017 to May 2018 patients having solitary thyroid nodules ≤6cm were enrolled in this study. Total 12 patients underwent this procedure through TOVA using 3DHD endoscopic system (Viking, USA). Out of 12 patients 10 were female and two were male who underwent hemithyroidectomy. The mean duration of goiter was 9.67 ± 11.08 months, the mean thyroid nodule size was 4.5 ± .91cm. all were benign, the mean TSH was 2.68 ± 1.34 IU/ml, the mean operation time was 120.42 ± 21.69 min, The mean hospital stay was 2.42 ± .79 days, most patient discharged on 3rd post operative day except one male patient discharged on 4th post operative day due to prolong drain output. On univariate analysis the duration of goiter and size of goiter was not correlated significantly similarly the size of goiter and duration of surgery was not correlated significantly (p = 0.012). The mean cost of therapy was 25283.42 ± 533 8.11 INR. On follow up there was no RLN or mental Nerve Palsy. The TOVA is shortest route to reach thyroid, 3DHD endoscopy provide excellent depth perception and magnification which helps in identification and preservation of recurrent laryngeal nerve, parathyroid gland and vital vessels.
Thyroid Nodules & Goiter Friday Poster Clinical
F18-Fluorodeoxyglose Positron Emission Tomography (PET) avid thyroid nodules carry an estimated cancer risk of 34%. The performance of Afirma molecular diagnostic in indeterminate thyroid nodule (ITN) with PET avidity is not known. This is a retrospective study at The Ohio State University, approved by the institutional review board, of all patients with ITN (Bethesda III/IV), PET imaging and Afirma testing from 12/2011 to 12/2017. There were 34 ITNs identified that had Afirma testing and FDG PET performed. Afirma testing was performed with the Gene Expression Classifier (GEC) in all nodules. PET positivity [median SUV: 7.0 (range: 2.9-72.6)] was noted in 21/34 nodules. Of the 21 PET-positive nodules, 14 had “suspicious” GEC results; 12 underwent surgery. Surgical pathology was benign in 8, thyroid cancer in two and non-invasive follicular thyroid neoplasm with papillary-like nuclear Features (NIFTP) in two. Excluding GEC suspicious non-operated nodules and assuming all benign GEC nodules are truly benign, the positive predictive value (PPV) (for malignancy or NIFTP), negative predictive value (NPV), sensitivity and specificity were 33%, 100%, 100% and 47% respectively. The PPV was higher for Bethesda IV than III (60% versus 14%, p = 0.055). There were 13 nodules that did not demonstrate PET avidity (PET -) five of which were suspicious on GEC and underwent surgery revealing one cancer. Assuming all PET- nodules with benign GEC are truly benign, the PPV, NPV, sensitivity and specificity were 20%, 100%, 100% and 67% respectively. There were no statistically significant differences in PPV (p = 0.69) or specificity (p = 0.17) between (PET +) versus (PET -) ITN. The benign call rate in (PET +) nodules was 33% versus 62% in (PET -) nodules (p = 0.11). In PET positive ITN, Afirma GEC benign call rate and the PPV were not statistically significant from PET negative ITN in this retrospective cohort study.
Thyroid Nodules & Goiter Friday Poster Clinical
The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) characterizes thyroid FNAC into one of six diagnostic categories, each with a corresponding rate of malignancy (ROM) that may be influenced by factors such as the nodule risk stratification pathway, technical and cytopathology experience, statistical method used to calculate malignancy rates, and duration of follow up. The aim of this study is to establish the local ROM for TBSRTC categories in order to guide clinical decision making in Southern Alberta. We reviewed 5868 consecutive thyroid FNAC and the available surgical pathology follow up till March 2017, for FNAC performed between 2010 and 2014 in Southern Alberta (1.5 million inhabitants). We calculated the proportion and ROM of each Bethesda diagnostic category, as well as the performance characteristics of thyroid FNAC in our cohort. The distribution of TBSRTC categories for 5868 thyroid FNAC was: 1211 (19%) nondiagnostic (ND), 3324 (57%) benign, 873 (15%) atypia of undetermined significance/ follicular lesion of undetermined significance (AUS/FLUS), 156 (3%) follicular neoplasm/ suspicious for follicular neoplasm (FN/SFN), 89 (2%) suspicious for malignancy (SM), and 305 (5%) malignant. The overall surgical resection rate was 16% (937 of 5868), and of the resected nodules 456 were malignant. By TBSRTC category, the surgical resection rate was 7% of ND, 7% of benign, 21% of AUS/FLUS, 56% of FN/SFN, 90% of SM, and 94% of the malignant. The ROM in resected nodules was 9% in ND, 11% in benign, 26% in AUS/FLUS, 43% in FN/SFN, 80% in SM, and 96% in the malignant. We observed a true positive rate of 93%, false positive rate of 7%, true negative rate of 89%, and false negative rate of 11%. We calculated a sensitivity of 90%, specificity of 93%, positive predictive value of 93%, and negative predictive value of 90%. We observed higher rates of ND and AUS/FLUS compared to the targets recommended in recent literature. While the ROM by TBSRTC category in our study was comparable to the range reported in the literature, the benign cytology category had a ROM of 11% (expected rate <3%). This may be a result of selection bias for nodules triaged for surgery in a category with a low resection rate.
Thyroid Nodules & Goiter Friday Poster Clinical
Parathyroid neoplasms share cytological features similar those of thyroid neoplasms. They can be intra-thyroidal, making them difficult to distinguish using FNAB alone. Diagnosis is often confirmed with intra-operative frozen section analysis. This study sought to identify cytomorphological or immuno-histochemical features that could be useful in differentiating thyroid from parathyroid lesions in the preoperative stage. A retrospective chart review of 11 patients diagnosed with a thyroid neoplasm on FNAB was performed. The control group consisted of 6 patients with an intra-operative diagnosis of benign thyroid neoplasm. The study group consisted of 5 patients with an intra-operative diagnosis of parathyroid adenoma/carcinoma. Cytology from FNAB and surgical pathology were independently reviewed by a pathologist who was blinded to the diagnoses. All patients had nodules in or near the thyroid gland that met criteria for FNAB. Ten had pre-operative diagnoses suspicious for follicular or Hurthle cell neoplasm, and one was parathyroid carcinoma. On surgical pathology, four were parathyroid adenomas and one was parathyroid carcinoma.
Cellularity, absent colloid, and macrofollicles were common cytolopathological findings in parathyroid and thyroid lesions. Nuclear atypia was present in the parathyroid carcinoma, one follicular adenoma, and one Hurthle cell adenoma. Growth patterns were similar between both groups. PTH washout was useful in distinguishing parathyroid and thyroid adenomas. Serum calcium levels were not reliably elevated in parathyroid adenomas or carcinoma.FNAB cytological features are insufficient for differentiating thyroid and parathyroid lesions. PTH staining is a helpful tool, but determining the appropriate clinical setting for its use can be challenging. Additional investigation into methods for accurately distinguishing parathyroid and thyroid neoplasms in the pre-operative stage is needed to better guide surgical managment of these lesions.
Thyroid Nodules & Goiter Friday Poster Clinical
The Afirma Gene Expression Classifier (GEC) is commonly used to manage indeterminate nodules and to avoid unnecessary surgery. We report our experience with 49 GEC results and correlate with ultrasound characteristics and final surgical pathological diagnosis. Retrospective analysis of data on patients with indeterminate fine needle aspiration (FNA) results and subsequent GEC testing from 01/01/2014 to 12/31/2017. Ninety eight patients (89% women) with a mean age 57.1 ± 1.2 years with 104 indeterminate nodules were included in the analysis. Of the 58 atypia of undetermined significance (AUS) at the first biopsy, repeat FNA was non-diagnostic in 4 (ND; 7%), 28 were benign (48%), 24 were AUS (41%), and one each was follicular neoplasm (FN; 2%) and malignant (2%). Of the 28 FN on the first biopsy, repeat FNA was ND in 2 (7%), 9 were benign (32%), 16 AUS (57%), and 1 FN (4%). Of the 49/104 (47%) who had GEC testing, 17 (35%) were benign and was suspicious in 32 (65%).
Surgery was ultimately performed in 18 of the 49 GEC tested patients. The final pathology was benign in 6 (33%), 1 follicular thyroid cancer (FTC; 6%), 7 follicular variant of papillary thyroid cancer (FVPTC; 39%), and 4 non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) (22%). The most common cancer was FVPTC.
Three of the 6 benign nodules (50%) had low or very low suspicious features of ATA sonographic pattern, while 8/12 (67%) malignant nodules had intermediate or high suspicious ATA features. The prevalence of malignancy in GEC suspicious nodules was 44% without and 66% with NIFTP. ATA ultrasound features would have avoided surgery in 6 benign nodules, but would miss 4 cancers. GEC avoided surgery in 17/49 (34%) patients. Bethesda-III nodules harbored low risk thyroid cancers, a conservative approach of these nodules with serial neck ultrasound assessment seems reasonable. We lack long term outcome data of GEC benign nodules, such patients should be monitored closely.
Thyroid Nodules & Goiter Friday Poster Clinical
Ultrasonography (US)-guided Ethanol ablation (EA) is suggested first-line treatment for benign cystic and predominantly cystic thyroid nodules. However, additional treatment has been recommended in case of recurrence is suspected. Thus, reasonable definition of recurrence is important to minimize unnecessary additional treatment. We reviewed and validated previously suggested recommendations of recurrence and additional treatment for ethanol ablated benign thyroid nodules. From January 2014 to August 2017, total 154 patients with cystic or predominantly cystic benign thyroid nodules who underwent US-guided EA only once were enrolled. Follow up US examination was done at 1,6, and 12 months after US-guided EA. All patients were divided into therapeutic success (volume reduction ratio ≥50%) and therapeutic failure (volume reduction ratio <50%) groups at final follow up. We applied our data to previously suggested recommendations for additional treatment and compared final post-treatment results. The volume of treated nodules decreased significantly at 1-month and last follow-up after US-guided EA (3.9 ± 1.4 vs. 2.3 ± 4.2, p < 0.0001, and 1.5 ± 1.0 p < 0.0001). The clinical problems also improved significantly at 1-month and last follow-up. However vascularity of ethanol ablated nodules increased at 1-month follow-up (0.5 ± 0.8 vs. 0.7 ± 0.9, p = 0.05), and 84.2% of therapeutic failure patients showed vascularity at 1-month follow up. When we re-evaluated our patient group (ethanol ablated thyroid nodules) applying previously suggested additional treatment criteria such as nodules with remnant fluid more than 1 ml, volume reduction less than 50%, or demonstration of solid component with vascularity at 1-month follow up US, additional treatment was unnecessary in 70 ∼ 81% of the ethanol ablated thyroid nodules.EA was effective for treating benign thyroid nodules. Simple observation without additional treatment was enough to achieve the therapeutic success in case recurrence is suspected. Therefore additional treatment should be decided carefully by combining actual clinical problems and US features. Understanding of this concept will be useful for doctors who perform US-guided EA to minimize unnecessary additional procedures.
Thyroid Nodules & Goiter Friday Poster Case Report
Thyroid nodules are uncommon and are especially rare in patients with Graves' disease regardless of age. When present in the pediatric population, the concern for malignancy leads to more extensive workup and intervention. It may be difficult to differentiate non-thyroidal etiologies from thyroid nodules. We present a case of a thyroid nodule found via ultrasound in an adolescent patient with Graves' disease for whom surgical pathology revealed a non-thyroidal etiology. An 18 year old female with hyperthyroidism presented to the emergency room with chest pain, palpitations, fevers, and diarrhea. She was diagnosed with hyperthyroidism two months prior and started on methimazole but was nonadherent. Family history was significant for multiple members with cancer, including thyroid. Her vital signs and physical exam were consistent with hyperthyroidism, and labs confirmed Graves' disease. A thyroid ultrasound showed a 1.7 cm ill-defined abnormally echogenic nodule containing linear echogenicities. Repeat ultrasounds at follow up visits showed no significant change in size or sonographic pattern. A fine needle aspiration was performed and showed Bethesda II cytology. Due to concern for malignancy and desire for definitive treatment for uncontrolled Graves' disease, she underwent total thyroidectomy. Surgical pathology of the suspicious nodule revealed foci of Hassall corpuscles with calcifications consistent with intrathyroidal thymic tissue. Intrathyroidal thymic tissue is due to maldescent of the thymus during embryogenesis and typically involutes with the thymus during puberty. There are rare reports of this entity in older patients and its typical ultrasound appearance of a “starry sky” makes it difficult to distinguish it from a thyroid nodule with calcifications. Our patient exhibits a unique presentation of intrathyroidal thymic tissue in a postpubertal patient with Graves' disease. Thymic hyperplasia is associated with Graves' disease, and may explain the continued presence of thymic tissue in the thyroid after the expected age of involution. It is important to consider intrathyroidal thymic tissue in individuals with Graves' disease, regardless of age, who have a thyroid nodule with a “starry sky” appearance.
Saturday, October 6, 2018
Thyroid Cancer Saturday Oral Translational
The understanding of the mechanisms underlying thyroid cancer immune escape can lead to the identification of new molecular targets and/or efficacy biomarkers. For this purpose, we performed immune expression profiling in thyroid cancers to obtain a comprehensive view on immune mechanisms activated during cancer progression. The study was conducted retrospectively in 25 papillary thyroid carcinomas (PTC), 14 poorly differentiated thyroid carcinomas (PDTC), 13 anaplastic thyroid carcinomas (ATC) and 7 normal thyroid tissue samples (NT). DNA and RNA were purified from FFPE tissues. An extensive genotyping was carried out by Sequenome MassARRAY System on DNA samples. Conversely, gene expression profiling was obtained on RNA samples using the Nanostring platform and its nCounter PanCancer Immune Profiling Panel. Unsupervised hierarchical clustering of the normalized expression data indicated a very strong separation according to the histotype descriptors. Conversely, no association could be detected with the genetic descriptors (WT, BRAFV600E, RAS mutation, TERT mutation, RET/PTC rearrangements, BRAF+TERT, RAS+TERT). Gene expression comparison of ATC, PTC and PDTC vs NT showed high number of regulated genes in the cancer samples. In detail, immune-related gene sets were significantly up-regulated (ATC > PTC >> PDTC). ATC and a great part of PTC showed a microenvironment heavily infiltrated by macrophages and T-cells of the CD8+ effector phenotype, part of which appeared to be functionally exhausted. Conversely, PDTC, as NT samples, as a minority of PTC, displayed a poor infiltration by immune cells. Interestingly, an up-regulation of inhibitory immune checkpoint mediators, including PD-L1, PD-L2, PD1, MHCII, LAG-3, PVR and TIGIT, could be detected in ATC and PTC. These data indicated that immunotherapeutic approaches for ATC and part of PTC should foresee combination of inhibitory immune checkpoint disruptors and eventually measures to dampen TAMs. Conversely, PDTC, as a subgroup of PTC, are not expected to respond to the treatment with inhibitory immune checkpoint disruptors alone.
Thyroid Hormone Action Saturday Oral Basic
This study was to investigate whether thyroid hormones could affect reproductive and metabolic function by interacting with TRβ in Kiss-1 neurons through the central pathway. In this study, we used the CRISPR/Cas9 principle and the Cre-loxP approach to construct the mice which were conditional TRβ-deleted in Kiss-1 neurons.(1) In 2-month-old females, serum FSH levels in Kiss1-TRβ KO group were significantly decreased compared with that in WT group (P < 0.05). Meanwhile, the serum levels of LH and E2 in Kiss1-TRβ KO group were also decreased compared with that in WT group. (2) Serum AMH levels in Kiss1-TRβ KO group were significantly decreased compared with that in WT group (P < 0.05) in 6-month-old females. (3) It was worth noting that though there was no difference in serum T levels between KO and WT groups in 2-month-old males, serum T levels in Kiss1-TRβ KO group were significantly decreased compared with that in WT group (P < 0.05) in 6-month-old males. Our present findings indicate that the interaction of thyroid hormones with TRβ in Kiss-1 neurons is involved in the regulation of hypothalamus maintaining HPG axis and the regulation of ovary maintaining reserve function.
Thyroid Hormone Action Saturday Oral Basic
Thyroid hormone (TH), acting through thyroid hormone receptors (TR), plays critical roles in development. Cone photoreceptors, the light-sensitive neurons that mediate color vision and daylight vision, are amongst the most sensitive target cells for TH signaling. Our lab had previously shown that thyroid hormone receptor TRβ2 is essential for expression of the medium-wavelength (M) opsin and graded distribution of short-wavelength (S) opsin visual pigments in cones. Similarly, hypothyroidism or excessive TH in mice leads to cone abnormalities. However, little is known as to how circulating TH gains access to cones in the retina. Evidence suggests that specific plasma membrane transporter(s) are involved in certain tissues. Monocarboxylate transporter 8 (MCT8) is of particular interest as mutations in the MCT8 gene in humans lead to X-linked Allan-Herndon-Dudley-Syndrome (AHDS), distinguished by neurodevelopmental retardation and congenital hypotonia, although little is known about visual impairment in these patients.MCT8 expression in the mouse eye is determined by X-gal staining in MCT8-LacZ mice. Immunostaining for M- and S-Opsin on eye sections from MCT8 mutant vs. wild-type mice is performed to determine Opsin distribution. Staining for Arrestin 3 is used to monitor cone nuclear migration. Electroretinogram (ERG) analysis is performed to evaluate cone function.MCT8 is expressed in the retinal pigment epithelium, the ciliary body, Muller glia and choroid blood vessels in the mouse eye, forming a possible route for TH entry from the bloodstream into the retina. Furthermore, mice deficient in MCT8 display cone nuclear migration defects, disturbed cone Opsin gradients and defective function of cone photoreceptors. Some of the defects can be partially rescued by administration of the active TH, triiodothyronine (T3). MCT8 plays a pivotal role in cone photoreceptor differentiation in murine retina and may therefore mediate local TH accessibility to cone cells.
Thyroid Hormone Action Saturday Oral Basic
Amphibians undergo dramatic morphological changes during metamorphosis, a period mimicking the neonatal period in mammals, which are difficult to study due to the maternal dependence of mammalian embryos and neonates for survival. One of the most dramatic changes is the complete regression of the tail. Here, we used IIIumina RNA sequencing (RNA-Seq) corrected with single-molecule real-time (SMRT) sequencing for transcriptome assembly and gene expression analysis during tail resorption program in a novel amphibian model system. Twenty-four tail samples from the eight stages (Stages S18, S19, S21, S28, S39, S40, S41and S43) were subjected to RNA extraction, respectively. 17 tissues, containing adult heart, liver, spleen, lung, kidney, skin, ovary, testis, tails (S38, S40, S41, S43) and back muscle (S36, S43, S45) were homogenized and total RNA were isolated respectively. Mixed cDNA sequencing libraries (1-2, 2-3, >3 kb) were prepared and performed on the PacBioRS II. We obtained 67,939 transcripts and discovered 4,555 differentially expressed transcripts (DETs) and functionally classified these DETs by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). These analyses revealed 712 significantly enriched GO categories and 27 significantly enriched KEGG pathways which related to tight junction, cardiac muscle contraction, ECM-receptor and some disease pathways like Parkinson, Alzheimer etc. Further analyses of the gene expression profiles and function and regulation of the selected genes should help to understand the mechanisms of amphibian tail resorption and adaptive evolution from aquatic to terrestrial life. Between S39 and S40 when tail resorption has not begun, the upregulated genes were enriched with GO terms for muscle organ and structure development, suggesting continued tail development between the two stages. Oxidation-reduction process (TCA) and oxidoreductase activity (succinate dehydrogenase, fumarate hydratase) changed between S40 and S41, which mayimportant and can help initiate apoptosis process. Dramatic changes appearing at S43, there are total 2,864 DETs between S41 and S43, and numerous apoptotic cells were present in the notochord (especially the elastic membrane).
Thyroid Hormone Action Saturday Oral Basic
The thyroid hormone (TH), T3, is critical for human development and adult life. The genomic effects of T3 are mediated by three known T3-binding nuclear receptors (TRs), TRa1, TRb1 and TRb2, encoded by two T3 receptor genes (THRA and THRB). Recent discovery of a number of patients carrying heterozygous mutations in the THRA gene revealed a strong phenotype. Of particular interest is that such patients have constipation, suggesting intestinal defects due to THRA mutations. While the exact defects in the intestine remain unclear, earlier studies have provided strong evidence to support a role of T3 signaling in intestinal development and physiology. Weight and Size Measurements: Thra1PV/+ mice's body, small intestine and colon were weighed and the length were measured after euthanization. Villus and crypt's length were measured on the H&E staining intestine sections.
Immunohistochemistry: Ki67 antibody are used for detecting proliferative cells in small intestine and lysozyme antibody for Paneth cells.
TUNEL Assay was used for detection of intestine epithelium apoptosis.
Alcian blue staining for Goblet cells on intestine.Thra1PV/+ mice exhibit a constipation phenotype mimicking patients with mutations of the THRA gene.
Thra1PV/+ mice have longer small intestine relative to body length.
Thra1PV/+ mice reduced in the average length of intestinal villus.
Thra1PV/+ mice decreased cell death in the small intestinal epithelium and cell proliferation in the intestinal crypts.
Thra1PV/+ mice increased Goblet cells and Paneth cells in the crypt of the small intestine.Thra1PV/+ mice faithfully reproduces RTHα as shown in patients. In adult Thra1PV/+ mice, we observed constipation just like in patients with TRα mutations. Importantly, we discovered significant intestinal defects, including shorter villi, increased differentiated cells in the crypt, accompanied by reduced stem cell proliferation in the intestine. Our findings suggest that further analysis of this mouse model should help reveal the molecular and physiological defects in the human intestine caused by TRα mutations and to determine the underlying mechanisms.
Thyroid Hormone Metabolism & Regulation Saturday Oral Basic
Subclinical hypothyroidism (SCH) and T2DM are closely related and often cluster in individuals. However, this connection is still uncertain, as well as the underlying mechanism. Therefore, it is necessary to further investigate the relationship between SCH and glucose metabolism, which has not been fully elucidated. The National Health and Nutrition Examination Survey (NHANES) database (1999-2002) was re-analyzed and logistic regression was used to evaluate the risk for diabetes among subjects with SCH. Then, an SCH mouse model was established to explore the status of glucose metabolism and insulin resistance(IR) via OGTT and ITT. Hepatic endoplasmic reticulum(ER) stress was determined in SCH mice. Subsequently, glucose and IR status were re-evaluated after alleviating the ER stress by 4-phenylbutyrate. Plasma glucose levels in SCH patients was significantly higher than that in euthyroid controls. The proportion of hyperglycemic subjects in SCH patients was higher than that in euthyroid controls. And SCH was associated with a 2.29-time increased risk for diabetes. Similarly, both fasting glucose and insulin levels in SCH mice increased significantly. SCH mice presented higher HOMA-IR index and lower ISI index compared to control mice. Hepatic ERp29 and Bip, as well as IRE1α and XBP-1s were upregulated significantly in SCH state, which indicated hepatic ER stress was triggered. Interestingly, the expressions of ERp29, Bip, p-IRE1α and XBP-1s decreased in SCH mice after 4-phenylbutyrate treatment. Concurrently, abnormality in fasting glucose and insulin levels, as well as HOMA-IR and ISI indexes, in the 4-phenylbutyrate-treated SCH mice were alleviated by inhibiting ER stress. Our findings demonstrated that hepatic ER stress induced abnormal glucose metabolism and phenotypic IR in SCH status. And the IRE1α/XBP-1 pathway was predominately involved in the process. Ameliorating ER stress by using 4-phenylbutyrate may provide a beneficial strategy for the prevention and therapy of abnormal glucose metabolism and IR in SCH.
Thyroid Nodules & Goiter Saturday Oral Clinical
The 2015 Thyroid Guidelines recommend observation for most highly-suspicious thyroid nodules <1cm (Sc-HSTN) seen on thyroid ultrasound (thy-US). The recommendation that some Sc-HSTN may benefit from “close sonographic follow-up” rather than a FNA biopsy leads to confusion among physicians, emotional burden in patients and higher healthcare costs. Here, we aimed to ascertain how Sc-HSTN are followed-up at the Mayo Clinic upon initial diagnosis. The information obtained will help us delineate follow-up guidelines. Retrospective longitudinal study of patients with Sc-HSTN evaluated at our institution between 01/2015 and 07/2017.207 patients (75.8% women, 87.0% Caucasian, age 59.0 ± 13.8) had 242 Sc-HSTN. All nodules had ≥1 worrisome characteristics, the most common being calcifications (164/67.8%) and irregular margins (51/21.1%). 7.4% were associated with abnormal lymph nodes. 36.6% of the 41 nodules that had an indication for FNA biopsy, were biopsied. Recommendations upon initial diagnosis were repeat thy-US (43.4%, most commonly in 7-12 months) and FNA biopsy (31.0%); the rest (25.6%) did not receive any recommendations. Nodules called “suspicious” or “indeterminate” on the thy-US report were more likely to be biopsied (49.3% and 31.7%, respectively, vs 10.0% when called “Non-suspicious”, p < 0.0001). Endocrinologists made the initial decision in 36.4% of the cases. Observation was more likely to be recommended when patients were seen by an endocrinologist (51.7% vs. 30.1%, p = 0.0014). Conversely, patients not seen by an endocrinologist were more likely to receive no recommendations (36.6% vs 13.4%, p < 0.0001). From those who were recommended to undergo biopsy, only 22.7% had an indication. Most times FNA biopsies were done due to patient's preference. 41 patients underwent partial or total thyroidectomy. Only 17.1% of these patients had an indication for surgery. The significant heterogeneity in the management of Sc-HSTN at the Mayo Clinic mirrors the lack of adequate guidelines. Upon initial diagnosis, patient's preference, thy-US report and the specialty making the first decision play a pivotal role in the decision-making process. The majority of biopsies and thyroidectomies performed had no indication.
Thyroid Nodules & Goiter Saturday Oral Clinical
Afirma GSC utilizes RNA sequencing and machine-learning algorithms to classify cytologically indeterminate thyroid nodules into benign (B) and suspicious (S) categories. Detection of genomic variants and fusions was recently expanded beyond BRAF V600E and RET/PTC1&3 by the Xpression Atlas (XA), which identifies 761 nucleotide variants and 130 fusion gene pairs in 511 genes. Here we used XA to analyze the mutational spectrum of 190 Bethesda III/IV nodules with gold standard histologic diagnoses.190 nodules previously collected in a prospective multicenter blinded trial design were analyzed with the XA. Among the 145 histologically benign nodules, 35 (24%) contained a variant or fusion (XA+). In the 99 benign nodules with GSC-B results there were 15 (15%) with XA variants and none with a fusion. These variants were 7 TSHR, 3 SPOP, 2 EIF1AX, 1 PTEN, 1 TSHR + EZH1, and 1 GNAS. In the 46 benign nodules with GSC-S results, 18 (39%) harbored a variant and 2 (4%) a fusion. There were 9 NRAS, 6 HRAS, 2 TSHR, and 1 SPOP. Two had a PAX8/PPRARG fusion.
Among the 45 histologically malignant nodules (41 GSC-S; 91% sensitivity), 22 were XA+ (49% sensitivity). In the 41 malignant nodules with GSC-S results, there were 19 variants (46%) and 2 fusions (5%). The variants were 9 NRAS, 3 HRAS, 3 BRAF V600E, 1 SPOP, 1 KRAS + EIF1AX, 1 EIF1AX, and 1 BRAF K601E. Fusions were BRAF/MKRN1 and 1 ETV6/NTRK3. In the 4 GSC-B false negative nodules (2 PTC, 1 fvPTC, 1 HCC), only the HCC contained a variant (TSHR). In 190 thyroid nodules with definitive histology, malignant nodules were twice as likely to be XA+ than benign nodules (49% vs 24%, p = 0.003 [χ2]). Although GSC-S nodules were nearly 3 times more likely than GSC-B nodules to be XA+ (47% vs 16%, p < 0.0001), the PPV for malignancy did not differ among all GSC-S, GSC-S XA+, and GSC-S XA- nodules (47%, 51%, and 43%, respectively; p = 0.77). When XA+, GSC S nodules expressed mainly RAS variants, and GSC B nodules predominantly TSHR variants. Conversely, the NPV for XA was 83%. These findings support GSC as better than XA to rule-out cancer while the addition of XA to GSC-S nodules may provide additional insights into pathway activation and potential cancer treatment targets.
Thyroid Nodules & Goiter Saturday Oral Clinical
Thyroid nodules are more common in older individuals but are more likely to be malignant in younger individuals. Although the Bethesda System for Reporting Thyroid Cytopathology (BSRTC) is widely used to interpret fine-needle aspiration (FNA) cytology, it is unclear whether BSRTC diagnostic categories impart the same risk of malignancy in younger versus older patients. Thus, we sought to compare the performance of FNA cytology in a continuous cohort of clinically relevant thyroid nodules spanning pediatric and adult care, all evaluated by a single expert cytopathology group. We evaluated all consecutive patients who underwent FNA of a thyroid nodule ≥1 cm in diameter at the combined Boston Children's Hospital/Brigham and Women's Hospital between 1998-2016. All cytology was interpreted and reported by Brigham and Women's Hospital cytopathologists according to the BSRTC. Histologic malignancy rates were calculated among resected nodules and compared between pediatric (≤18 years) and adult (≥19 years) nodules by chi-square analysis.430 pediatric and 13,415 adult nodules were analyzed. Malignancy rates did not differ between children and adults among nodules with nondiagnostic (33% vs. 18%, p = 0.12) or benign cytology (8% vs. 7%). In nodules with atypical cells of undetermined significance (AUS), the malignancy rate was higher in children but did not reach statistical significance [12/23 (52%) vs. 199/530 (38%), p = 0.15]. When adult AUS nodules classified as benign by a gene expression classifier were considered histologically benign, the malignancy rate in AUS nodules was significantly higher in children [12/23 (52%) vs. 199/663 (30%), p = 0.02]. In nodules with cytology suspicious for a follicular neoplasm, the malignancy rate was higher in children [9/13 (69%) vs. 232/653 (36%), p = 0.02]. Malignancy rates did not differ in nodules that were cytologically suspicious for papillary carcinoma (73% vs. 73%) or malignant (100% vs. 99%). In children and adults with clinically relevant thyroid nodules, malignancy rates differ within indeterminate BSRTC categories defined by similar morphologic features. This finding likely reflects true differences in nodule biology rather than variation in cytological classification.
Thyroid Nodules & Goiter Saturday Oral Clinical
The Afirma GSC utilizes RNA sequencing and machine-learning algorithms to accurately classify indeterminate thyroid nodules into benign (B) and suspicious (S) categories. Accompanying the GSC are a BRAF V600E classifier and RET/PTC1&3 fusion reporting. Variant and fusion detection was expanded by the 511 gene Xpression Atlas (XA) which includes 761 nucleotide variants and 130 gene fusion pairs. Here we analyze all clinical samples with complete XA profiles from July 2017 to April 3, 2018.4,742 samples were de-identified and existing data files were reanalyzed with XA. Strikingly different mutational patterns across Bethesda and GSC categories were found. A majority of Bethesda III/IV (cyto-I) nodules with GSC-S results were negative for variants or fusions (56% XA-); the most common variants identified were RAS (26%) followed by BRAFV600E (8%). In contrast were cyto-I nodules with GSC-B results where 85% of samples were XA- and 10% had TSHR variants.
The most common variant identified in Bethesda V and VI nodules was BRAF V600E, at 48% and 83%, respectively. RAS gene variants were observed in 8% of Bethesda V and 6% of Bethesda VI nodules.
Overall, fusions were detected less frequently than variants across all categories. Fusions were present in 6% of 1636 cyto-I GSC-S, <1% of 2969 cyto-I GSC-B, 6% of 65 Bethesda V, and 1% of 72 Bethesda VI nodules. The most common fusions were PAX8/PPARG (34 cyto-I GSC-S, 6 cyto-I GSC-B), ETV6/NTRK3 (19 cyto-I GSC-S), RET/PTC1 (11 cyto-I GSC-S, 1 Bethesda V), and RET/PTC3 (10 cyto-I GSC-S, 1 Bethesda V).XA is commercially available for potential additional risk stratification among Bethesda III/IV nodules with GSC-S results and Bethesda V/VI nodules. The exclusion of XA reporting among GSC-B nodules is supported by this analysis, where they were mostly XA- or TSHR+ and lacked highly informative genomic alterations. Markedly different genomic insights were found between cohorts at increased risk of cancer: Bethesda III/IV GSC-S (mostly RAS+ or XA-), and Bethesda V/VI (mostly BRAF V600E+ or XA-). Together, the GSC and XA contribute substantial genomic content to advance pre-operative risk stratification.
Thyroid Nodules & Goiter Saturday Oral Clinical
Minimally invasive techniques are considered safe and effective treatments for benign thyroid nodules but comparative studies between each technique are still lacking. The aim of our study is to compare the efficacy and safety of three thermal ablation methods: radiofrequency (RFA), laser (LA) and high intensity focused ultrasound (HIFU). We conducted a bicentric retrospective study between October 2013 and January 2018. One hundred seventy-six patients with benign histology or cytology and who refused surgery were enrolled. Clinical, biological and ultrasound evaluation was performed before treatment. We compared volume and symptoms variation as well as side effects at 6 weeks and 12 months. Two hundred nodules (mean size 16.8 ± 16.6 mL, 165 (82.5%) palpable) were treated (RFA = 108 (54%), LA = 81 (40.5%) and HIFU = 11 (5.5%)) in 176 patients (80.7% women, mean age 51.0 years). Nodules' volume (mL) (RFA vs. LA) decreased significantly from 20.4 ± 18.6 vs. 13.6 ± 13.3 (baseline) to 10.7 ± 12.7 vs. 8.5 ± 8.7 (−51.5 ± 17.2% vs. −40.2 ± 17.8%) at 6 weeks, and 7.8 ± 9.4 vs. 4.6 ± 8.6 (−73.2 ± 13.1% vs. −74.3 ± 22.0%) at 12 months. Volume reduction between RFA and LA was significantly different at 6 weeks (p < 0.001) but not at 12 months. After adjustment on age, initial nodule volume, TiRADS score and vascularization, no significant difference was observed at 6 weeks and 12 months between RFA and HIFU (-66.5 ± 14.0% vs.-57.8 ± 25.8%), and between LA and HIFU (68.1 ± 19.1% vs. -57.8 ± 25.8%). Clinical symptoms were reduced in the three groups: discomfort −72%, aesthetic inconvenience −72%, dysphagia −26%, dysphonia −4%. We observed two transient recurrent laryngeal nerve palsy, one hematoma and two abscesses successfully drained and a spontaneously regressive Horner's syndrome. No hypothyroidism was diagnosed. After a 12 months follow-up, thermal ablation was efficient in reducing nodules size by 60 (HIFU) to 75% (RFA and LA), with no difference between techniques. Very few transient but potentially serious side effects were reported, which causes should be analyzed.
Thyroid Nodules & Goiter Saturday Oral Clinical
Molecular tests (MT) using gene expression and/or mutational analysis have been developed to reduce the need for diagnostic surgery for indeterminate (Bethesda III/IV) thyroid nodules. There have been few studies on the cost-effectiveness of MT compared to diagnostic lobectomy (DL), and none comparing the two most commonly utilized MT. The aim of this study is to assess cost-effectiveness of DL, the Afirma Gene Expression Classifier (GEC), and Thyroseq Next-Generation Sequencing version 3 (TSV3). A decision tree from the payor perspective was created using a base case of a 40-year-old euthyroid woman with a solitary Bethesda III or IV thyroid nodule (TreeAge Decision Analysis Software). In this hypothetical model, lobectomy was performed for all patients in the DL arm and with positive MT, while those with negative MT underwent 5 years of surveillance. The outcome of interest was correct diagnosis, defined as malignant histology after DL or 5 years of nodule stability after negative MT. Costs were obtained from CMS data and the literature, and probabilities were obtained from the literature and expert opinion if data was not available. Sensitivity analysis was performed for test cost, pre-test probability of malignancy, and performance parameters. The cost per diagnosis was $10,207 for TSV3, $15,927 for GEC, and $33,080 for DL. As DL was so costly, further analysis was performed to compare only TSV3 and GEC. One-way sensitivity analysis between TSV3 and GEC, demonstrated that only test costs impacted model results. However, when the cost of both tests was varied in two-way sensitivity analysis, the model preference resulting in lower costs for TSV3 remained robust. In analysis randomly altering the probabilities of variables for 10,000 iterations, TSV3 was preferred over GEC in 97.8% of cases. In deciding whether surgery versus observation is optimal for indeterminate (Bethesda III/IV) nodules, TSV3 was consistently more cost-effective than GEC. However, use of either MT adjunct was more cost-effective than diagnostic lobectomy even after considering the need for 5-year surveillance for MT-negative nodules. MT use should be strongly considered if patient-related variables warrant nodule surveillance.
Autoimmunity Saturday Poster Basic
Thyroglobulin antibody (TgAb) is a glycoprotein mainly of immunoglobulin G (IgG) class. TgAb can be detected in various thyroid diseases. IgG is divided into four subclasses with different biological functions. The distribution of TgAb IgG subclasses differ in different thyroid diseases. Our previous study showed aberrant glycosylation levels of TgAb IgG in HT patients. Owing to IgG1 and IgG4 are primary subclasses of TgAb, this study aimed to investigate the glycosylation of TgAb IgG1 and IgG4 subclasses and explore the possible roles of TgAb in the pathogenesis of different thyroid diseases. TgAb IgG was purified from serum of patients with Hashimoto's thyroiditis (HT, n = 16), Graves' disease (GD, n = 9), papillary thyroid carcinoma (PTC, n = 6) and healthy donors (CON, n = 10) by affinity chromatography; TgAb IgG1 and TgAb IgG4 concentrations were determined by enzyme linked immunosorbent assay; lectin microassay was used to compare the difference of glycosylation on TgAb IgG1 and TgAb IgG4 subclasses in patients with different thyroid diseases and healthy donors. In different thyroid diseases, glycosylation levels of TgAb IgG1of HT was similarwith that of PTC, showing the increase of mannose, sialic acid and Neu5Acα6Gal, which was significantly higher than that of GD group and CON group. The levels of mannose, galactose, and Neu5Acα6Gal oligosaccharides in TgAb IgG1 in HT patients were significantly higher than those in healthy individuals. The level of GlcNAc may be higher than that in healthy people. All the findings were consistent with the results of glycosylation of the TgAb IgG in our previous study except core fucose. There was no significant difference in the levels of glycosylation of TgAb IgG1 between GD group and CON group. Glycosylation levels of TgAb IgG4 showed no difference among the four groups. Glycosylation of TgAb IgG1 presents an aberrant higher level in HT. It might provide new clues that the glycosylation of TgAb IgG1 subclass may participate in the pathogenesis of HT.
Autoimmunity Saturday Poster Basic
Graves' disease (GD), characterized by autoantibodies targeting antigens specifically expressed in thyroid tissues causing hyperthyroidism, is triggered by a combination of genetic and environmental factors. About 25% to 50% of patients with GD also experience extrathyroidal manifestations such as Graves' ophthalmopathy (GO). GO is the most common organ-specific endocrine disease characterized by proptosis, strabismus, impairment of visual function, ocular surface inflammation and dry eye. The etiologic factors of GO remain unknown; however, GO is generally believed to be associated with genetic predispositions and environmental factors, including exposure to cigarette smoke, high dietary iodine intake, and stressful life events. However, only several GO susceptibility loci, such as HLA, CTLA-4 et al, were identified in various ethnic populations, and additional genetic determinants have to be detected.
In order to investigate the genetic architecture of GO, we carried out a two-stage genome-wide association study in a total of 1,927 GD patients with GO, 2,760 GD patients without GO and 2,997 healthy controls.
We identified two potential specific susceptibility loci for GO, one was on chromosome 3p26.1 in intergenic region of ARL8B and BHLHE40 (rs2671762: P combined = 2.75 × 10−5, odds ratio (OR) = 1.32) and the other was on 20q11.22 in EDEM2 (P combined = 1.12 × 10−6, OR = 1.5), both loci were associated with GO, but not with Graves' disease. Since all GO patients also had Graves' disease in our study, we validated the 34 reported GD susceptibility variants in our GO patients. Interestingly, we found 11 SNPs in seven GD susceptibility loci were also associated with GO at the GWAS significant level (P < 5 × 10−8).
This study identified nine risk loci for GO including two GO specific risk loci and seven shared risk loci with GD. It is the first time to identify GO specific susceptibility loci, shedding light on the potential mechanism underlying the pathogenesis of GD.
Autoimmunity Saturday Poster Clinical
Vitamin D deficiency or insufficiency has been suggested associated with increased TPOAb in several researches but whether the association is definitely confirmed, causal or its causal direction was uncertain. We aimed to explore the causal association between Vitamin D and thyroid peroxidase antibody (TPOAb). 10636 participants were finally included from the Survey on Prevalence in East China for Metabolic Diseases and Risk Factors (SPECT-China), which was performed in 23 sites in East China during 2014 to 2016. We genotyped four 25(OH)D-related and four TPOAb associated single nucleotide polymorphisms (SNPs), and created their genetic risk scores (GRS), respectively. Bi-directional mendelian randomization (MR) analysis was used.25(OH)D GRS was significantly associated with 25(OH)D (β −0.093, 95%CI -0.111, −0.074) and with TPOAb level (β 0.067, 95%CI 0.002, 0.132). TPOAb GRS was significantly associated with TPOAb concentration (β 0.345, 95%CI 0.135, 0.556), but not with 25(OH)D (β −0.030, 95%CI −0.091, 0.030). Using 25(OH)D_GRS as instrumental variable in the MR analysis, we demonstrated a causal relationship between genetically determined 25(OH)D and increased TPOAb concentration (β −0.720, 95%CI -1.429, −0.012). No association was observed for genetically instrumented TPOAb with 25(OH)D. Our results provide evidence supporting decreased vitamin D concentrations causally lead to increased concentrations of TPOAb.
Autoimmunity Saturday Poster Clinical
We performed a study to verify the possible association between hypovitaminosis D3 and thyroid diseases and if hypovitaminosis D3 correction could lead to a negativization of anti-thyroid antibodies(Abs). From 2016, Butterfly Onlus performed a study on 800 thyreopatic patients(pts);here we reported data about 42 thyreopatic pts:mean age 48,5 years(min14, max83);n.34 females(80,95%), n.8 males(19,05%);all without known non-thyroid autoimmune disease and/or post-surgical hypoparathyroidism. All 42 pts fulfilled a blood test including vitamine D3 (1,25(OH)2D), TSH, fT4, anti-TPO Abs and anti-Tg Abs at time zero(T0) and after 6-12 months(T1). All pts with abnormal TSH values were treated and achieved euthyroidism. At T0, n.40(95,24%) pts showed vitamine D3(VitD3) levels under normal values(<30ng/ml), n.2(4,76%) in normal range(≥30 ng/ml). We considered only the 40 pts with hypovitaminosis D3:n.15(37,50%) showed anti-TPO Abs and/or anti-Tg Abs levels above the normal value at T0, while n.25(62,50%) in the normal range. All 40 pts were treated with oral cholecalciferol administration (25.000-100.000UI/month). At the T1check, n.23(57,50%) of the 40 treated pts showed VitD3 levels under the normal values, while n.17(42,50%) in the normal range. We checked the 17 pts with normal VitD3 levels at T1 for anti-TPO Abs and/or anti-Tg Abs levels at T0 and after 6–12 months of cholecalciferol administration(T1):n.7(41,18%) showed Abs levels above the normal value at T0 and for n.4(57,14%) of them we demostrated a normalization in the Abs levels after 6-12 months; n.3(42,86%)pts showed persistent hight levels of Abs levels at T1.N.10 pts(58,82%) showed normal Abs levels both at T0 and T1.We concluded that normalization of blood VitD3 levels in pts with negative Abs levels does not affect the Abs status, while VitD3 normalization after 6–12 months cholecalciferol therapy in pts with initial Abs positivity is associated with a normalization of them in the57,14%of cases. Further studies are necessary in order to better evalute the correlation between VitD3 and thyroid autoimmune diseases, considering the limits of our study linked to the low number of pts, the short follow up and the possible interferring actions of other vitamine D forms(i.e. 25(OH)D).
Autoimmunity Saturday Poster Clinical
131I radioiodine therapy (RIT) has been applied for juvenile Graves' disease (GD) in the United States for a long time. However, RIT for juvenile GD has been avoided because of the potential risk of tumorigenesis in Japan. There have been few reports regarding RIT for juvenile GD in Japan. Therefore, we reviewed juvenile GD patients treated with RIT in our thyroid specialty clinic. We reviewed the medical records of 493 GD patients under the age of 19 who had visited our clinic between January 2000 and December 2016. Each RIT was performed as an outpatient treatment, and the maximum 131I dose was 481 MBq per treatment. One hundred and eleven juvenile GD patients (22 males and 89 females: 10 to 18 years old, median 16 years) underwent RIT. 131I administration was performed once in 83 patients, twice in 25 patients, and three times in 3 patients. The total 131I dose was 133-1,143 MBq (median 481 MBq). The duration of follow-up after the initial RIT ranged from 12–201 months (median 80 months). All patients were primarily treated with an anti-thyroid drug (ATD), and RIT was performed for one or more of the following reasons : adverse effects of ATD in 52 patients, desire for definitive therapy in 24, absence of remission during long-term ATD treatment in 16, large goiter in 12, non-adherence of ATD in 8, and relapse of hyperthyroidism after ATD discontinuation in 7. The thyroid volume decreased from 15–99 mL (median, 35 mL) to 2.0–13 mL (median 3.0 mL). At the latest follow-up, the patients' thyroid functions were hypothyroidism with LT4 replacement (92%), subclinical hypothyroidism (1%), normal (5%, 40–163 months after single 131I dose), or subclinical hyperthyroidism (2%, 51–57 months after a single 131I dose). Thyroid hypoechoic micro-nodular lesions were newly detected in 5 patients 4–13 years after RIT. However, none of the patients were diagnosed with thyroid cancer, leukemia, or other cancers during the follow-up period. It has been reconfirmed that RIT is effective and safe for juvenile GD with a median follow-up period of 80 months (follow-up; up to 201 months).
Autoimmunity Saturday Poster Clinical
Autoimmune thyroiditis is a frequent diagnosis in all medical clinics in the United States. Obesity, gender, genetics, other autoimmune disease, and age are a few risk factors that have been associated with autoimmune thyroiditis, but there has not been a study of association between environmental pollutants and autoimmune thyroiditis. The primary objective of this study is to investigate the correlation of environmental pollutants with the prevalence of thyroiditis. A retrospective chart review of 4930 patients was performed whose current or past problem list as of September 2016, contained a diagnosis of autoimmune thyroiditis, which included Hashimoto's and Graves' disease. All patients were seen at a large endocrinology office in York and Adams County, Pennsylvania. We mapped the prevalence of thyroiditis using each patient's ZIP code. The EPA (Environmental Protection Agency) ratings from 2016 provided statistics regarding water quality, air quality, and superfunds quality. Superfunds are responsible for cleaning up the nation's worst hazardous waste sites and responding to environmental emergencies. The areas of highest to lowest prevalence on a scale of 0-100, with 100 being the highest were identified. We analyzed the relationship between the prevalence of thyroiditis and EPA ratings using a Pearson correlation. The Pearson correlation for thyroiditis and Superfund quality was −0.47 (p = 0.001). Areas with a worse superfund quality had a higher prevalence of thyroiditis. The correlation between thyroiditis and water quality was 0.35 (p = 0.017). Areas with a higher water quality had a higher prevalence of thyroiditis. There was no correlation between the prevalence of thyroiditis and air quality. These findings show a correlation between environmental factors and the prevalence of thyroiditis. This study did not control for other known risk factors for thyroiditis. We also did not account for the duration of exposure to the pollutants and the timing of the diagnosis of thyroiditis.
Autoimmunity Saturday Poster Clinical
A remarkable complication of Graves' disease is ocular injures. The hemodynamics of several organs may change including those of the eye. The choroid, as the vascular layer of the eye, may change in Graves' disease patients. Choroidal thickness may be a new evaluation index of Graves' ophthalmopathy. The aim of our study was to observe changes in choroidal thickness in patients with Graves' disease. The right eyes of 36 patients with Graves' ophthalmopathy (GO) and those of 36 age-, gender- and diopter-level-matched healthy participants were evaluated in this observational, cross-sectional study. The patients' data were obtained within 3 months after the onset of Graves' disease (GD). Thyroid hormone levels and thyroid stimulating hormone receptor antibody (TRAb) levels were measured, and the degree of exophthalmos was measured in all patients. A horizontal scan centered on the fovea was performed in all participants. Five points of choroidal thickness was measured at the fovea (SFCT) and at 1500 μm nasal (N1500), 3000 μm nasal (N3000), 1500 μm temporal (T1500) and 3000 μm temporal (T3000) to the fovea. The CT measurements obtained were (mean ± SD) 313.47 ± 100.32 μm, 279.22 ± 85.80 μm, 214.64 ± 75.52 μm, 313.19 ± 80.36 μm and 298.14 ± 82.75 μm in patients with GO and were 256.33 ± 50.18 μm, 223.14 ± 59.61 μm, 176.69 ± 60.66 μm, 250.92 ± 52.184 μm and 239.47 ± 60.35 μm in the control group at the foveal, N1500, N3000, T1500 and T3000 measurement points, respectively. The CT in GO patients were significantly increased at all the points compared with the control group (P < 0.05). There was no relationship between the CT and CAS, the degree of exophthalmos, triiodothyronine (T3), tetraiodothyronine (T4), thyroid stimulating hormone (TSH), or TRAb levels in GO.CT was found to be increased in GO patients and had poor relationship with CAS, exophthalmos and thyroid function tests.
Autoimmunity Saturday Poster Case Report
Ipilimumab is an immunotherapeutic agent which targets CTLA-4 to upregulate T-cell activity to target tumor antigens and trigger cellular death of malignant cells. Ipilimumab belongs to a developing class of medications known as checkpoint inhibitors. Check point inhibitors have been associated with immune-related adverse events (IRAEs) that trigger various endocrinopathies. We report a case of a patient presenting with central hypothyroidism as the first manifestation of hypophysitis while receiving ipilimumab immunotherapy for melanoma. The patient is a 49 year old man with a history of stage IIIB melanoma and no previous history of thyroid disease. He had been diagnosed with melanoma and was started on ipilimumab therapy and two days after receiving his second cycle he started to develop cold intolerance, fatigue, and constipation. He was seen by his oncologist which led to thyroid function tests being drawn which were concerning for central hypothyroidism: TSH of 0.320 uIU/mL and Free T4 of 0.54 ng/dL. This prompted further evaluation for hypophysitis through evaluation of his pituitary function: Prolactin was 7.1 ng/mL, LH was 2.1 mIU/mL, FSH was 4.6 mIU/mL, Testosterone was 74 ng/dL, GH was 0.76 ng/mL, and a cosyntropin test raised only his cortisol to 7.9 ug/dL. MRI imaging showed increased size of the pituitary with heterogeneous enhancement and leftward deviation compatible with hypophysitis. He was started on levothyroxine 50 mcg daily and prednisone with resolution of his symptoms. Thyroid hormone levels normalized on therapy and testosterone levels returned to a normal range without therapy. Hypophysitis represents one of the most common IRAE related endocrinopathies. While the mechanism for development of hypophysitis remains unclear it has been postulated that binding of CTLA-4 antibodies to the CTLA-4 receptor on pituitary cells leads to activation of the classic complement cascade and leads to inflammation of the pituitary gland.IRAEs can resemble common complaints associated with malignancy and clinicians must be aware of this and screen pituitary function on a regular basis for those on check point inhibitors to help stave off morbidity and mortality through early diagnosis.
Disorders of Thyroid Function Saturday Poster Basic
Prior real-world studies found better TSH outcomes among hypothyroid (HT) patients treated with Synthroid versus generic levothyroxine (GL). The current analysis further explored and refined the research for comparative effectiveness of Synthroid vs. GL using the HealthCore Integrated Research Database (HIRD®). We conducted a retrospective cohort study including patients with ≥2 claims for HT diagnosis between 1/1/2006 and 12/31/2017 from the HIRD. Patients were required to be aged 18+ and have: ≥2 fills for either Synthroid or GL (first fill as index, on or after the first HT diagnosis), ≥6 months of pre-index (baseline) and ≥12 months of post-index (follow-up) health plan enrollment, ≥1 TSH lab result over follow-up, no baseline claim for a non-cohort-defining levothyroxine, no diagnosis for thyroid cancer or pregnancy, and persistence with the index therapy over 1-year follow-up. Cohorts of Synthroid vs. GL users were matched 1:1 using propensity scores, developed from their baseline demographic, clinical, and economic characteristics. Primary outcome was the proportion of patients for whom the last TSH lab result during the follow-up period was within the reference range (0.3-4.12 mIU/L). The proportion of patients within the reference range was compared between Synthroid and GL cohorts using Chi2 tests. Sensitivity analyses were also conducted. A total of 18,694 Synthroid and 60,446 GL users were selected. Matched cohorts included 18,382 pairs which were well balanced on baseline characteristics. Mean age was 53 years and 82% were female. The most common baseline comorbidities associated with HT were hyperlipidemia (39.9%), hypertension (31.4%), and goiter (13.2%). The mean (SD, median) TSH result at follow-up was 2.4 (3.77; 1.8) for Synthroid and 2.6 (3.94; 2.0) for GL users (p < 0.001). The proportion of patients within the reference range was 78.5% for Synthroid and 77.2% for GL users (p = 0.002). Using a narrower TSH range (0.4-4.0 mIU/L) in sensitivity analyses, the proportions were 75.2% and 73.9% (p = 0.003). Synthroid was associated with better TSH outcomes as compared with generic levothyroxine in a US managed care population, consistent with the previous findings using other real-world data sources.
Disorders of Thyroid Function Saturday Poster Basic
TSH lab outcomes have been commonly used to measure hypothyroidism (HT) treatment. Limited literature is available to quantify the economic benefits of achieving TSH goals. This study assessed the healthcare resource utilization (HCRU) and costs among persistent levothyroxine users who achieved TSH lab value within the reference range (0.3-4.12 mIU/L) versus those who did not achieve the goal. A retrospective cohort study was conducted, including patients with ≥2 claims for HT between 1/1/2006 and 12/31/2017 from the HealthCore Integrated Research Database. Patients were required to be aged 18+ and have: ≥2 fills for either Synthroid or generic levothyroxine (first fill as index, on or after the first HT diagnosis), ≥6 months of pre-index (baseline) and ≥12 months of post-index (follow-up) health plan enrollment, ≥1 TSH lab result over the follow-up period, no baseline claim for a non-cohort-defining levothyroxine, no diagnosis for thyroid cancer or pregnancy, and persistence with the index therapy over 1-year follow-up. Patients were grouped into two cohorts (Achievers, Non-achievers), based on whether their last TSH value over the follow-up was within the reference range. HT-related HCRU and costs (in 2017 US dollar) in the follow-up period were compared between TSH Achievers vs. Non-achievers using multivariable regression models.64,796 patients were selected (mean age 54, 74% female), including 49,916 Achievers and 14,880 Non-achievers. Compared to Non-achievers, Achievers were significantly less likely to have ≥1 HT-related inpatient stay (5.2% vs. 6.6%) and outpatient service (90.5% vs. 91.4%). The mean [SD] number of HT-related inpatient days (0.2[1.55] vs. 0.3[1.78]) and outpatient services (3.6[3.36] vs. 3.9[3.63]) were significantly fewer in Achievers. Achievers also consistently incurred less than Non-achievers in mean (SD) HT-related costs: $174 ($116) vs. $180 ($116) in pharmacy costs, $1,994 ($9,553) vs. $2,472 ($11,035) in medical costs, and $2,168 ($9,553) vs. $2,653 ($11,035) in total costs (p < 0.001 for all comparisons). The study results suggest that persistent levothyroxine users who achieved TSH goals are associated with less hypothyroidism related health resource utilization and costs.
Disorders of Thyroid Function Saturday Poster Clinical
Symptoms such as tiredness, constipation, depression, cold intolerance and weight gain, are often associated with hypothyroidism (HT). The Adelphi Disease Specific Program (DSP) is a large scale, real-world data generation study. The DSP collected data on 1,000 adult patients with a confirmed diagnosis of HT from 60 primary care physicians and 40 endocrinologists in the US in Jan-Apr 2018, and part of the data describes the symptoms associated with HT and HT management in the real world.
In addition to detailed data on disease (e.g., diagnosis, severity, history, comorbid conditions) and treatment from the physicians, both physicians and patients also independently provided information on the patient's current symptoms. Number of symptoms reported by physicians vs. by patients was compared at a significance level of 0.05. A Kappa statistic was calculated to assess the agreement level between patient and physician reporting on each symptom type. This analysis included 262 patients who had symptoms reported by themselves and symptoms documented by their physicians. The mean age was 48.7 (SD 15.7), 78% were female, 70% had overt HT, and 94% were receiving prescribed HT treatment. Mean number of symptoms reported by physicians was 4.0 (SD 3.8) compared to a mean of 7.2 (SD 7.9) symptoms reported by patients (p < 0.01). The most commonly-reported symptoms were weight gain (33% physician-reported and 40% patient-reported), inability to lose weight (34% and 31%), dry/flaky skin (26% and 26%), head hair loss (17% and 22%), brittle hair (15% and 20%), low energy/excessive tiredness (21% and 48%), constipation (15% and 30%), depression (14% and 24%) and cold extremities/cold intolerance (7% and 22%). Discordance of patient and physician symptom reporting was present (or observed) in the symptoms of cold intolerance, tiredness, weight gain, constipation and depression (all kappa statistic <0.40, indicating fair agreement). Symptoms were more often reported by HT patients than their physicians, most notably tiredness and cold intolerance. Further investigation is needed to determine the reasons for discordance and ways to improve it.
Disorders of Thyroid Function Saturday Poster Clinical
Patients with hypothyroidism (HT) often experience non-specific symptoms, causing a delay in seeking medical care. An in-depth assessment of the journey that patients experience from the onset of symptoms to a diagnosis (Dx) of HT has not been previously studied in the US.
This study included 60 primary care physicians (PCPs) and 40 endocrinologists (endos) and 1,000 of their adult patients with a Dx of HT. Data were collected in Jan-Apr 2018 from: 1) patients: e.g. symptoms leading to a doctor visit, time between symptom onset and consultation, and time to arrive at a HT Dx; 2) physicians: e.g. patient characteristics, diagnostic tests, type of HT, whether the patient had a different Dx before confirmed as HT. Among all patients, 75% were female, mean age 50.5 (SD = 16.1); 67% with overt HT. Prior to initial consultation, patients had symptoms for a mean of 16.0 weeks: 22% consulted physicians within 4 weeks of onset of symptoms, 40% in 5–13 weeks, 31% in 14-26 weeks and 5% in >26 weeks. 53% of initial consultations were initiated by patients themselves, while 33% were encouraged by others. The symptoms precipitating consultation were: weight gain/can't lose weight (40%/29%), constipation (33%), dry/flaky skin (31%), and low energy/excessive tiredness (both 30%). For endo-managed patients, 57% were diagnosed by an endo (42% self, 15% other endo), 41% by a PCP, 2% other. For PCP-managed patients, 89% were diagnosed by a PCP (50% self, 39% other PCP), 11% by an endo. Twenty nine percent of the patients reported they were diagnosed with HT at initial consultation, 49% in ≤4 weeks, 18% in 5–13 weeks, and 5% in ≥14 weeks. To establish the Dx, TSH was tested in 86% of patients, FT4 in 52%, and FT3 in 15%. Radiological studies were done in 25% of patients, with more use reported by PCPs than endos (e.g., ultrasound, radioactive iodine uptake and scans). Prior to a HT Dx, 3% of patients received an alternative Dx: the most common ones were depression, anemia and thyroiditis without HT. These data confirm the need to improve early recognition of symptoms by patients and a more efficient diagnostic process for physicians. Further education of patients and physicians should improve this process.
Disorders of Thyroid Function Saturday Poster Clinical
Deliberate intake of thyroid hormone for weight loss is not without risk. Excessive dosage of exogenous thyroid hormone can result in overt thyrotoxicosis, atrial fibrillation, venous thromboembolism (VTE) and sudden cardiac death. We describe a case of factitious thyrotoxicosis resulting from surreptitious consumption of liothyronine (T3) obtained from an on-line pharmacy presenting with acute pulmonary embolism (PE). A 34 year old man presented with a 3 week history of recent 30 lb weight loss and a one day history of left sided pleuritic chest pain. He reported he had followed a ketogenic diet for intentional weight loss. Additional symptoms included diaphoresis, increased stool frequency, fatigue and anxiety. Physical examination revealed high blood pressure, tachycardia, hand tremor and flushed, diaphoretic skin. There were no goiter, thyroid nodules or neck tenderness. The remainder of the examination was unremarkable. Laboratory findings included TSH <0.015 (0.4-4.7), FT4 0.4 (0.7-1.8) and FT3 > 22.8 (2.8-5.3). A CT angiogram revealed bilateral PEs. The patient initially denied taking any hormone supplements, however he eventually did admit that he has been taking T3 obtained from an internet source for 3 weeks (reported dose 50 μg daily). He denied of any other hormone consumption. He was treated with cholestyramine and propranolol; the FT3 dropped to 8.2 on the following day. The patient was discharged on oral anticoagulation. Thyrotoxicosis is associated with an increased risk of VTE as a result of endothelial dysfunction, decreased fibrinolytic activity, and increased coagulation factor levels (factors VIII, IX, von Willebrand factor, and endothelium-associated protein concentrations). Thyroid evaluation is recommended for patients with unprovoked VTE and individuals with severe thyrotoxicosis should be considered at high risk for VTE. In literature review, elevated FT4 levels were associated with the risk of unprovoked VTE. Our case demonstrates increased risk of VTE may be associated with high FT3 levels as well. This case highlights that the abuse potential of prescription medication obtained through an internet source can be life threatening.
Disorders of Thyroid Function Saturday Poster Clinical
Autoimmune thyroid disease (AITD) comprises of Grave's disease and Hashimoto's thyroiditis. Rheumatologic disorders (RDs) are characterized by chronic inflammation and multisystem involvement. Poly-autoimmunity has now been well documented in the literature. The aim of our study was to compare AITD among various RDs and to analyze the yearly trend of AITD in hospitalizations. We used National (Nationwide) Inpatient Sample (2000-2014) to identify hospitalizations ≥18 years with select autoimmune RDs and AITD based on ICD-9 codes. We studied the prevalence of AITD and analyzed yearly trends of AITD among hospitalizations with or without RDs, in terms of annual percentage change (APC), using Joinpoint regression analysis. We calculated odds of association of AITD with various RDs, controlling for age, sex and race. The presence of RDs doubled the adjusted odds of AITD prevalence [aOR 2.13 (95% CI 2.07 − 2.18), p < 0.0001]. AITD was noted to have an increasing trend, both among hospitalizations with and without RDs with APC (2000-2014) of 5.20 and 3.99, respectively. Compared to other RDs, the highest association was with Sjögrens disease [aOR 6.28 (95% CI 5.78 – 6.84), p < 0.0001], followed by Idiopathic inflammatory myositis (IIM) and SLE with aOR of 2.66 and 2.61, respectively. Sjögren's syndrome (SS) is characterized by lymphocytic infiltration and destruction of the exocrine glands, mainly lacrimal and sweat glands. In AITD, there is lymphocytic infiltration of the thyroid gland. Our study shows a higher prevalence of AITD in the presence of any RDs, but most notably in those with SS. Historically, higher rates of thyroid dysfunction and autoantibodies have been described in SLE and RA, however, with equivocal results. In the past two decades, co-existence of SS and AITD have been increasingly reported, likely explained by a shared pathogenetic mechanism of focal or diffuse T-lymphocytic infiltration.
The presence of 2 autoimmune conditions in the same patient may be missed due to overlapping symptoms including myalgia and fatigue. Based on our study findings, we suggest that AITD should be sought in hospitalizations with RDs, especially Sjögrens disease, so that appropriate treatment can be started early.
Disorders of Thyroid Function Saturday Poster Clinical
Levothyroxine absorption from the gut is enhanced by taking the medication on an empty stomach and waiting 30 minutes or longer before eating and drinking. Fasting during the holy month of Ramadan is associated with altered eating habits which may lead to reduced compliance with levothyroxine-taking instructions. While some studies have reported a significant decrease in thyroid hormone levels, other studies did not find a significant change in thyroid function tests in fasting subjects during Ramadan. The objective of this study is to assess the impact of fasting and altered eating habits during the month of Ramadan on thyroid function tests in hypothyroid patients on levothyroxine. In a retrospective chart review, the thyroid function tests of patients on levothyroxine before and after Ramadan were studied. We excluded patients with abnormal thyroid function tests before Ramadan, patients less than 18 years of age, pregnant women, patients who had a change in levothyroxine dose or brand and those who were commenced on iron or calcium supplements during the study period. There were 112 patients [89 females] who fulfilled the inclusion and exclusion criteria of the study. The mean age ± SE was 44.70 ± 1.36 years [range 19.0–79.0 years] and the mean levothyroxine dose was 82.71 ± 3.57 mg/day. The mean TSH within 3-months before Ramadan [median 41.50 days, IQR 25.00–73.00] was 1.809 ± 0.094 mIU/L while the mean TSH within 2-months post-Ramadan [median 27.50 days, IQR -14.00-42.00] was significantly higher at 3.072 ± 0.312 mIU/L [95% CI −1.907 to −0.619, P-value <0.001]. Although the mean TSH remained within the normal reference range [0.3–4.2 mIU/L], there were 36/112 patients outside of the normal range. There were no significant differences in the free-T4 levels before and after Ramadan [n = 64]. Altered eating habits during Ramadan are associated with a significant increase in plasma TSH with approximately one-third of patients having a TSH-value outside of the normal reference range post-Ramadan. Prospective studies are needed to further investigate this phenomenon and to determine the most appropriate time and method for taking levothyroxine during Ramadan.
Disorders of Thyroid Function Saturday Poster Clinical
Many studies about hypothyroidism, miscarriages, infertility and decreased baby's IQ as recently as May 18,2018 have debatable conclusions IF NORMAL TSH IS only 2.5.
In 2004, AACE member, Dr. S. Lee showed that TSH from 2.5 to 4.5 or higher with symptoms and signs may be hypothyroid and need treatment. AVERAGE TSH WAS ONLY 1.25. TSH levels DECREASE as BetaHCG climbs THROUGHOUT Pregnancy(6.) Ob/Gyns want TSH to be 0.5 to 1.8 for hypothyroid pregnancies(7.) Since 2004 110 patients (15 men and 95 women) with signs & symptoms of subclinical Hypothyroidism were treated for the best reduction of individual symptoms.
Only two patients stopped Levothyroxine therapy because they refused medicine generally. The critical control group of 12 women had infertility, 17 miscarriages and one + anti tpo antibodies.
The experimental study arm was these same 12 women who required indivualized Levothyroxine doses, right after missed menses with resulting 15 healthy normal babies.
The 12th mother had a hypothyroid mother, three miscarriages and one full term baby death at 2 weeks was sent 100 miles away to this endocrinologist. Levothyroxine produced a healthy son.
Two men are remarkable: A 38 year-old MD (TSH 4.0) had less brain fog, obesity, fatigue, coldness and constipation. The 38-year old Fireman (TSH 3.5) improved obesity, fatigue, depression & WEAKNESS. After T4, and high doses of vitamin D, he was able to start a second job. These remakable results differ from published articles in that:
Levothyroxine therapy is required immediately after missed menses (at 2 weeks, not 12 weeks in one study.)
All women get titrated up rather quickly to dose that decreases most symptoms and keeps TSH in 0.5 to 1.8 range. Few patients are on 0.05 mg Levothyroxine (one study has most patients on that dose.)
T4 doses can be adjusted but never stopped.
Disorders of Thyroid Function Saturday Poster Clinical
The incidence of thyroid dysfunction among Irish women with sub fertility is unknown, nor is it clear if these women have less successful outcomes after fertility treatment. We conducted a retrospective, observational, anonymized review of case records of 239 women attending with subfertility over a 2 year period. Mean age 37.9 ± 4 years. TSH was available for 216 patients. The patients were divided into following sub groups by TSH; Group 1: < LLN, Group 2: LLN-2.5 (euthyroid), Group 3: 2.5-ULN which -suboptimal to proceed with IVF, Group 4: TSH > ULN (SCH) Group 5: known hypothyroidism with TSH <2.5 ; Group 6: known hypothyroidism with TSH >2.5mU/l. All patients with TSH >2.5 were treated with thyroxine to achieve a target TSH <2.5mU/L prior to their Embryo transfers. TSH ref range 0.35-4.94mIU/ml.
In total 43 (20%) patients had TSH values requiring correction before proceeding with fertility treatment. Overall, 60 patients (27.8%) had thyroid dysfunction, while 72.2% are euthyroid. While outcome data is limited; 76 (48.7%) of Group 2 had a positive HCG and combined other groups had a rate of 30 (50%) positive HCG (NS p = 0.866). Live birth occurred in 29/156 (18.6%) euthyroid patients vs 12/60 (20%) in all other groups (NS p = 0.812).
Disorders of Thyroid Function Saturday Poster Clinical
Advances in blood transfusion (BT) and efficient iron chelation therapy (CT) have lead to increased survival of thalassemia major (TM) patients. Repeated BT increases the total body iron resulting in deposition of iron in various tissues especially in endocrine glands, liver, and heart. Endocrine dysfunctions occur frequently in TM patients possibly because of iron deposition, free radical injuries and chelation toxicity. We studied the thyroid functions in adult TM (ATM) patients who were on regular BT and iron CT. Fifty ATM patients (29 males and 21females) with no personal or family history of thyroid disorder were recruited. Patients with HIV, hepatitis C and hepatitis B were excluded. FT3, FT4 and TSH measured in fasting state when sample was drawn for cross matching prior to BT. Anti TPO antibody estimation could not be done. The patients were in 18–33 years (mean 23 ± 3.2 yr), duration of BT 18-32.5 years (21.8 ± 3.09 yr), and serum ferritin was 788.5 – 5006.4 ng/ml (2746.31 ± 1247.5). Twelve patients had delayed or arrested puberty (7 males and 5 females). None of ATM had goiter and 7/50 (14%) ATM patients had secondary hypothyroidism (SH), 5/29 (17.24%) males and 2/21 (9.52%) females. None of ATM had evidence of primary hypothyroidism. We divided the patients in three age groups of 18–22, 23–27 & 28–32yr and analyzed the data of SH & S.ferritin according to age groups. SH was 1/28(3.57%), 3/16(18.75%) and 3/6(50%) & mean serum ferritin was 2473 ± 911, 2877 ± 591.5 and 3099 ± 289.8 ng/ml respectively. SH increases with increasing age and evidence of higher iron overload. Only SH was diagnosed in our study. It is concluded that pituitary thyrotroph cells are more vulnerable to iron toxicity than the thyroid follicles. Prevalence of SH increases with increasing age of the patients possibly because of increased duration of disease & higher iron overload
Disorders of Thyroid Function Saturday Poster Clinical
While the use of complementary and integrative medicine (CIM) by thyroid disease patients is common, allopathic physicians often lack familiarity about these modalities. Lack of knowledge about CIM use by surgical patients may negatively impact patient care and satisfaction. Our aim was to define the prevalence of scientific reporting on CIM for thyroid disease treatment and its implications for endocrine surgery. A PubMed bibliographic search was performed for studies evaluating CIM for benign and malignant thyroid disease. Studies were assessed for publication quality, author specialty, and treatment effects. A total of 522 records were identified. With 441 studies excluded after abstract screening and 30 after full-text assessment, 51 studies were eligible for final qualitative synthesis. Articles were published in 36 different journals, with most in Evidence Based Complementary and Alternative Medicine. The median impact factor of the represented journals was 1.89. The majority of first authors were MDs (31%) or PhDs (22%). Of the MDs, 35% were surgeons, 35% internists, and 24% endocrinologists. Articles included basic science studies (49%), case reports (14%), randomized control trials (14%), systematic reviews (6%), observational studies (6%), surveys (6%), literature reviews (4%), and clinical trials (2%). Conditions studied included hypothyroidism (n = 10), hyperthyroidism (n = 13), auto-immune thyroid disease (n = 13), goiter (n = 7), thyroid cancer (n = 11), and other thyroid diseases (n = 10). Forty-five studies assessed specific CIM treatment effects from natural products (64%), alternative medicine systems (27%), mind-body therapies (7%), or manipulative and body-based therapies (2%). Of these studies, 89% reported favorable effects. Only 21 of 51 studies addressed the absence or presence of adverse outcomes. No articles specifically studied surgical risk associated with CIM use. There is a paucity of data regarding CIM for thyroid disease treatment. There must be communication about CIM use between endocrine surgery patients and providers. This will not only facilitate patient care and satisfaction, but will also drive objective investigation with the hope of filling the current knowledge gap.
Disorders of Thyroid Function Saturday Poster Clinical
Familial dysalbuminaemic hyperthyroxinaemia (FDH) is a recognised cause of raised, circulating T4 (or rarely) T3 levels. Heterozygous ALB mutations (R218H, R218P, R218S; R222I), located in subdomain IIA of the protein, increase its affinity for iodothyronines. This subdomain also interacts with steroids in vitro.
Total serum cortisol (nmol/L) was also raised when measured by either immunoassay [Beckman >1489 (RR 140–690), Abbott >1650 (RR 101–536), Roche 1678 (RR 166–507), Centaur 2376 (RR 280–650)], or by mass spectrometry (1920, RR 280–650); however serum free cortisol (nmol/L), measured following equilibrium dialysis, was normal (16.7, RR 12.3–44.2), as was 24 hour urinary free cortisol (342 nmol/L, RR 99–378). Other circulating steroid measurements were also raised [17-hydroxyprogesterone (nmol/L) 12.55 (RR 1.9–6.5), Cortisone (nmol/L) 175 (RR 34–91), 11-deoxycorticosterone (nmol/L) 0.35 (<0.25)].
Radiolabeled T4 binding to patient's serum was markedly elevated (70%, RR 6–11%), prompting ALB sequencing and identification of a mutation (R218P). We have first documented interaction of R218P mutant albumin with steroids as well as iodothyronines in vivo, causing artefactual elevation of this hormone combination, with potential for misdiagnosis of an apparent, new, endocrine entity.
Disorders of Thyroid Function Saturday Poster Clinical
GO patients were divided according to administered therapy. Group 1 (n = 128) consisted of patients treated with low MMI dose (2.5–10 mg/day). Group 2 (n = 132) consisted of patients treated with RAI (15 millicuries) followed by L-thyroxine.
Disorders of Thyroid Function Saturday Poster Clinical
Long term amiodarone treatment can lead to thyroid dysfunction as well as hepatic toxicity. Amiodarone-induced thyroid dysfunction can occur in about 32% of treated patients. Thus, periodic monitoring of thyroid stimulating hormone (TSH) and liver function tests (SGPT and SGOT) is recommended. However, data is limited regarding rates of adherence to guidelines. Using an urban center population, we aimed to characterize the patient population with long-term amiodarone use and assess rates of adherence to current guidelines for TSH, SGPT and SGOT monitoring. All patients aged 18 years or older who were prescribed amiodarone for more than 1 year in Henry Ford Hospitals, Detroit and West Bloomfield, Michigan were retrospectively identified between January 2013 and December 2017. Patients younger than 18 years and those who had amiodarone prescribed for less than 3 months were excluded. The medical records were examined for patient's characteristics including age, gender and race. Patients prescribed amiodarone were also analyzed for adherence with established guidelines, defined as TSH measurement at time of amiodarone initiation and 3- 6 months after. Adherence to liver function tests monitoring was also monitored at time of initiation of treatment and 6months after. Indication of amiodarone use, prescribers of amiodarone and TSH, concomitant statin use were also analyzed. A total of 295 patients were included in the study. The majority of these patients were males (62%) and white (50%) with average age of 69.9. Amiodarone was prescribed for atrial fibrillation/flutter in 79% of the cases and ventricular arrhythmias in 19%. 73% of the patients used amiodarone concomitantly with statin. Amiodarone was prescribed mainly by cardiologists (75%) and TSH was prescribed by cardiologists (50%), primary care physicians (35%), cardiac surgeons (3%) and endocrinologists (3%). Baseline testing of TSH was done in 71% whereas baseline testing of SGPT and SGLT was at 12.5 %. At 3-6 months, only 51% had thyroid function tests and 9 % had liver function tests. Monitoring of thyroid and liver function tests in patients on amiodarone is less than optimal. This is probably due to lack of awareness of current guidelines.
Disorders of Thyroid Function Saturday Poster Clinical
In the treatment of primary hypothyroidism, routinely, levothyroxine dose depends on the body weight. But, some studies shown that the dose depending on the body weight vary with age, menopausal status and gender. Our aim was to study how age, gender, menopausal status, body weight(BW) and Ideal body weight(IBW) affected Levothyroxine (LT4) replacement doses in Patients with autoimmune thyroid disorders. It was cross sectional study involving patients of autoimmune primary hypothyroidism. Inclusion criteria was patients on levothyroxine with TSH in normal range for age. Patients on other medications that are known to interfere with levothyroxine absorption were excluded from the study. LT4 dose requirements were calculated for the BW and IBW. Logistic regression analysis was done to determine how gender, menstrual status and age affects LT4 dose for BW and IBW. Total 184 patients included in the study (170 females and 14 males). LT4 dose requirement based on BW (LT4/BW) was significantly higher in men as compared to pre-menopausal and post-menopausal women (1.50.4 vs 1.40.47 and 1.40.47 vs 1.10.41). Post-menopausal women had lower LT4/BW dose as compared to premenopausal (1.10.41 vs 1.40.47). In contrast, there was no significant difference in LT4 dose based on IBW (LT4/IBW) between the groups {men and pre-menopausal women (1.70.49 vs 1.80.57), men and post-menopausal women (1.80.57 vs 1.70.51), pre-menopausal women vs post-menopausal women (1.70.51 vs 1.70.51)}. On logistic regression analysis, LT4/BW was significantly affected by age, gender and menopausal status, whereas LT4/IBW was not affected by these factors. We propose that the single LT4 dosing based on IBW (1.7ug/kg) can be used for the treatment of primary hypothyroidism instead of BW.
Disorders of Thyroid Function Saturday Poster Clinical
Despite published guidelines for hypothyroidism and osteoporosis, variability in clinical practice is expected. In some cases, deviation from established guidelines may adversely impact patient outcomes and increase costs. This study aimed to assess practice variability among endocrinologists at a large urban tertiary and quaternary U.S. academic medical center.
Chart review was conducted in the first 200 patients consecutively seen for hypothyroidism (n = 100) or osteoporosis/osteopenia (n = 100) in calendar year 2017. Data were collected regarding disease diagnosis, initial treatment, and follow up management practices. The majority of patients were seen in follow-up for treatment of hypothyroidism (72%) or bone health (62%). Most (99%) patients with hypothyroidism (84% women, 62% Caucasian, mean age 52.6 ± 16.7 [SD] years) had a serum TSH concentration measured at or near the time of the visit, but other serum thyroid indices measured and fraction of patients included TT4 (10%), FT4 (82%), FT4I (6%), TT3 (9%), FT3 (12%), and thyroid antibodies (48%). Of the one-third of patients who had a thyroid ultrasound done previously, or at the current visit, the indication for imaging was unclear in 27% of this subgroup. For patients with osteoporosis (87% women, 73% Caucasian, mean age 69.0 ± 11.5 [SD] years), 64% had >1 DXA scan recorded; the median interval between consecutive DXA scans was 25 months (range, 6 months-9.9 years). Sixty-eight percent of the patients had bone turnover markers assessed within seven months of the visit.
The indications for obtaining serum thyroid tests, other than TSH and antibodies, as well as thyroid ultrasound, were unclear among some patients managed for hypothyroidism. Similarly, in patients with osteoporosis/osteopenia, inconsistencies were observed in the intervals of DXA testing and in whether bone turnover markers were assessed. Although practice variability among providers is a well-established phenomenon in clinical medicine, these findings demonstrate that there may be opportunities for increased standardization of care, particularly regarding laboratory testing and radiologic studies, that may improve clinical care and utilization of healthcare resources.
Disorders of Thyroid Function Saturday Poster Clinical
Treatment options for Graves' disease (GD) include: antithyroid drugs (ATD), radioactive iodine (RAI) and thyroidectomy. Uncertainty regarding the comparative effectiveness of these treatments exists, as the evidence is limited by referral bias and small samples. We aimed to characterize their efficacy and safety. We performed a retrospective analysis (2005–2013) of administrative claims from a US database, the OptumLabs Data Warehouse (includes >100 million privately insured individuals and Medicare Advantage enrollees). Adults who received initial treatment for GD were included.
For patients treated with ATD for >60 days, treatment failure was defined as (1)receiving RAI or surgery, or (2)a break of >90 days in ATD use followed by re-initiation of ATD. ATD use for >24 months was not considered failure. Failure in the RAI and surgical group was defined by the need for further treatment.
Multivariable Cox proportional hazard models were used to assess predictors of treatment failure. We report hazard ratios (HR) and 95% confidence intervals (95% CI). We identified 4661 patients treated for GD with a mean age 48 years. Most were white (63%) and female (80%). Patients were initially treated with ATD, 2817 (60%), RAI, 1549 (33%) and surgery, 295 (6%). The mean length of follow up was 4.5 years. About 12% of patients receiving ATD continued therapy for >24 months.
Surgery was most effective (99%), followed by RAI (93%), and ATD (50%). Women were at lower risk of failing therapy with RAI (HR 0.54, CI 95% 0.36-0.83). Patients >55 and <65 years had a lower risk of failing ATD therapy compared to those <35 years (HR 0.77, CI 95% 0.64-0.92) and black patients had a higher risk compared to white patients (HR 1.2, CI 95% 1.07-1.42). Adverse events were more common with surgery (24%) compared to ATD (12%) and RAI (6%).
Our results are limited by the insufficient granularity of the data and use of administrative claims. We found lower failure rates with RAI and thyroidectomy when compared with ATD and different side effects profiles. ATD was the most common initial treatment option and was used as long-term therapy (>24 months) by 12% of patients. Physicians can use these findings when discussing treatment options for GD.
Disorders of Thyroid Function Saturday Poster Clinical
Thyroid disorders have a life-time prevalence rate of 12.5% in female, though less common among male. Colorectal cancer is one of the most common malignancies in both sexes. While many studies, mostly involving Caucasian populations, have found some controversial relationships between thyroid disorders and breast cancer, however, very few have explored the association between thyroid disorders and colorectal cancer.
In this case-control study, we utilized the Taiwanese National Health Insurance Research Database (NHIRD), one of the largest administrative health care databases around the world, to analyze the epidemiological evidence whether or not a history of thyroid disorder would alter the colorectal cancer risk within the Asian population. Patients with newly diagnosed primary colorectal (colon or rectal) cancer without a previous cancer history were identified from the NHIRD (2008-2013). People with no cancer diagnosis prior to the index date were age and gender matched as controls. Diagnosis of hyperthyroidism or hypothyroidism prior to the diagnosis of colorectal cancer or the same index date was identified. A total of 139,426 patients were enrolled in our study, 69,713 in each group. A history of hypothyroidism, despite treatment, was found to be protective for the development of rectal cancer among those aged > = 50 years (adjusted OR 0.54, p < 0.001). A history of hyperthyroidism may have protective effects in developing colon cancer in all ages (adjusted OR 0.74, p < 0.001), stronger effect was seen when ages <50 years (adjusted OR 0.55, p = 0.007). The analysis was adjusted for sex, age, aspirin use, histories of inflammatory bowel disease, obesity, benign polyps, diabetes, radioactive iodine treatment, hormone replacement treatment and colonoscopy within 10 years. Our case-control study utilizing the Taiwanese nationwide database suggests that a history of hypothyroidism has a protective effect against developing rectal cancer while a history of hyperthyroidism has a protective effect against colon cancer development.
Disorders of Thyroid Function Saturday Poster Clinical
Thyroid insufficiency and thyroid peroxidase antibody (TPOAb) positivity are common in women of childbearing age. Reports addressing the impacts of mild TSH elevation [2.5 to the upper limit of the pregnancy-specific reference range (ULRR)] combined with thyroid autoimmunity on pregnancy outcomes are conflicting. The aim of our study was to assess the effects of mild thyroid dysfunction combined with TPOAb status in the first trimester on pregnancy complications. A total of 3549 singleton pregnant women with TSH, FT4 and TPOAb examinations during the first trimester and without levothyroxine or anti-thyroid drugs during pregnancy were retrospectively analyzed in Peking University First Hospital from September 2013 to September 2014. Subjects were divided into four groups: Group A (n = 52): 4.08<TSH <10 mIU/L, TPOAb positivity or negativity; Group B (n = 52): 2.5≤TSH ≤4.08 mIU/L, TPOAb positivity; Group C (n = 535): 2.5≤TSH ≤4.08 mIU/L, TPOAb negativity; and Group D (n = 2995): 0.23≤TSH <2.5 mIU/L, TPOAb positivity or negativity. Maternal and fetal complications were compared among groups. For maternal complications, Group A had a higher risk of placental abruption [OR 11.6 (95% confidence interval (CI) 2.48-54.31), P = 0.002] than Group D. Group B had a higher odds ratio for oligohydramnios [OR 4.89 (95% CI 1.46–16.41), P = 0.01] than Group D. No significant differences in single or composite maternal complications were found between Groups B and C. For fetal complications, higher risks of fetal distress were found in Groups A [OR 1.75 (95% CI 1.01–3.06), P = 0.048] and B [OR 1.88 (95% CI 1.08–3.27), P = 0.025] than in Group D. A higher risk of composite fetal complications was found in Group B [OR 2.18 (95% CI 1.25–3.78), P = 0.006] than in Group D. Group B had approximately two times the risk of fetal distress [OR 1.8 (95% CI 1.01–3.20), P = 0.047] and composite fetal complications [OR 2.08 (95% CI 1.17–3.69), P = 0.013] as Group C. Our study suggests that mild TSH elevations (within the ULRR) combined with TPOAb positivity during early pregnancy may predict more adverse pregnancy complications than TSH levels <2.5 mIU/L (whether TPOAb positive or negative).
Disorders of Thyroid Function Saturday Poster Case Report
Moyamoya disease (MMD) is an idiopathic cerebrovascular disorder characterized by bilateral progressive stenosis/occlusion of terminal portions of the internal carotid artery (ICA) with prominent collaterals most commonly seen in patients of Asian descent. Moyamoya syndrome (MMS) describes cases with similar cerebrovascular features associated with certain medical conditions such as Graves' Disease (GD). We are presenting a rare case of MMS associated with GD in an African American (AA) patient.A 43 year old AA female with GD, non-compliant with medications, presented complaining of 2 days of right arm paralysis. Examination showed right upper extremity flaccid paralysis and a small goiter. Brain imaging including MRI and CT angiography demonstrated acute infarcts in bilateral anterior and middle cerebral artery watershed areas, a subacute infarct in the left caudate nucleus, and diffuse narrowing of bilateral ICAs; a patent anterior communicating artery was also seen, with most of the left anterior circulation being supplied by the diseased right ICA, all findings consistent with MMS. Admission thyroid function tests showed an undetectable TSH <0.01 mcIU/ML, total T3 125 ng/dL and free T4 1.7 ng/dL. Methimazole and Propranolol were restarted along with Aspirin. The patient made remarkable neurological recovery with medical management only without requiring any interventions. This is an unusual case as MMS has been mostly reported in patients of Asian descent and only a few cases have been described in patients of AA descent. The exact etiology of the association between MMS and GD remains unknown; some studies have shown an increased incidence of MMS in the presence of autoimmune diseases suggesting a possible autoimmune component to the pathogenesis. Other studies have suggested that the thyrotoxic state itself can alter vascular tone and cause cerebrovascular hemodynamic changes, exacerbating the ischemia. Our patient improved with the reintroduction of her thyroid medications supporting this theory. Further studies are needed to elucidate the underlying pathogenesis of this association. Compliance with thyroid medications is crucial in these patients to avoid further episodes of ischemia.
Disorders of Thyroid Function Saturday Poster Case Report
Thyroid storm (TS) is a rare and potentially fatal condition. Its treatment includes the use of medications that block the synthesis and release of thyroid hormone, symptomatic control of the hyper-adrenergic response, and the identification and treatment of the triggering factor. We present a case of TS in a patient with contraindications to the use of anti-thyroid drugs and its treatment with therapeutic plasma exchange (TPE). A 44 year-old male, with history of polysubstance abuse, presented with palpitations and excessive sweating of 1 day's duration. He was in atrial fibrillation (rate 170–180 bpm). Work-up significant for undetectable TSH (<0.03 mIU/L), high free T4 (fT4) 4.41 ng/dL (0.6-1.2), and total T3 276 ng/dL (87–178). TSI resulted later and was elevated. Serum ethyl alcohol level was elevated and urine drug screen was positive for cocaine. Thyroid ultrasound showed heterogeneous gland with increased vascularity suggestive of diffuse thyroiditis.
Patient was treated with stress doses of steroids, propylthiouracil (PTU), and iodine solution with mild improvement in fT4. However, on day 2 of admission, patient went into severe delirium tremens necessitating sedation and intubation. He became hypotensive and required pressors with resultant acute renal failure and shock liver. Liver function tests (LFTs) became severely elevated (ALT 1357 IU/L and AST 1972 IU/L). At that point, PTU was stopped.
Given the contraindication to the use of anti-thyroid drugs in the setting of acute liver injury, hematology was consulted for TPE. Patient had one session of TPE with resultant significant improvement in fT4 and T3 levels, a trend which persisted for about a week until LFTs improved and methimazole was started. Unfortunately, patient passed away from septic shock.TS in our patient was confounded by alcohol withdrawal and cocaine use, and its treatment limited by his complicated hospital course, including respiratory failure and cardiogenic/septic shock. Although TPE has a grade C recommendation for the treatment of TS based on the apheresis guidelines, it has been reported to be a successful treatment option when pharmacologic therapies are contraindicated and single pass albumin dialysis is not available.
Disorders of Thyroid Function Saturday Poster Case Report
Myxedema crisis is a rare illness that develops insidiously in uncontrolled hypothyroidism. The disease process is life-threatening and requires prompt diagnosis and treatment.57-year-old male presented to the Emergency Department (ED) with worsening generalized swelling and lethargy. Medical history included morbid obesity, hypothyroidism, and dyslipidemia. Patient's mother reported that her son was non-adherent with medications for months.
Initial vital signs were significant for hypoxia to mid-60s on room air, otherwise normal. Physical exam revealed an obese, grossly edematous, somnolent male. He had dry oral mucosa, macroglossia, and enlarged palatine tonsils that were obstructing the posterior pharynx from view. Cardiopulmonary exam significant for decreased breath sounds in bilateral lung fields. Labs notable for elevated TSH of 71.3 uIU/mL and low thyroid hormone levels: free T4 0.16 ng/dL, T3 29 ng/dL. Serum sodium, glucose, and random cortisol were within normal limits. ECG showed sinus rhythm with low voltage. Arterial blood gas showed pH 7.27, PCO2 81 mmHg, PO2 70 mmHg on 50 percent FiO2 hi-flow nasal cannula. Patient was intubated for respiratory failure and airway protection.
After intubation, the patient became hypotensive requiring vasopressor support. Bedside ultrasound revealed a large circumferential pericardial effusion concerning for tamponade physiology. Pericardiocentesis was performed with 900 milliliters of fibrinous fluid removed.
CT imaging revealed severe swelling of the tongue and tissue of oral cavity, which likely contributed to airway compromise. Patient was treated with high dose intravenous levothyroxine and hydrocortisone for myxedema crisis. He was successfully extubated three days into hospital stay with concurrent improvement in thyroid function tests. This case illustrates the importance of early recognition of uncontrolled hypothyroidism. Cardiac imaging via ultrasound helped direct and guide patient care in a timely fashion. Pericardial effusions are known to be associated with myxedema crisis and are important to investigate in the appropriate clinical setting-especially given high utility and cost effectiveness of bedside ultrasonography.
Disorders of Thyroid Function Saturday Poster Case Report
Described ia a rare presentation of thyrotoxicosis from a TSH-secreting macroadenoma.A 33-year-old male, biological father of 4, presented to the emergency room with progressive edema and exertional dyspnea. He noted 2 years of unintended 90lb weight and muscle loss. In 2015 he described a 1-2 week decline in his libido achievement of erections and climax. He denied palpitations, heat intolerance, hypoglycemia, or tremors. His laboratory data included TSH 29.91 uIU/mL (0.35–4.9), free T4 index 5.5 (1.0–4.0), free T4 3.55 ng/dL (0.6–1.8), T3 303 ng/dL (83–160), FSH 0.8 MIU/mL (1.0–12.0), LH 1.0 MIU/mL (0.6–12.1), total testosterone 20 ng/dL (250–1100), and a prolactin of 1.0 ng/mL (3.5-19.4). Physical exam he was cachectic appearing well virulized with a normal thyroid exam and small testicles. Transthoracic ultrasound noted a severely dilated left ventricle with an EF 30%. Pituitary protocol MRI visualized a 2.2cm sellar mass. Labs revealed and normal alpha subunit of 0.5 ng/mL (0.1-0.5). He was treated symptomatically with methimazole 30mg daily, metoprolol sucinate 50mg daily and has received one octreotide injection 30mg IM. 2 weeks after treatment his tumor measured 1.7cm and his TSH and FT4 improved to 12.39 and 2.9, respectively. T3 trended to 314.TSH-secreting adenomas represent less than 1% of all hyperthyroid cases with a population study from Sweden; incidence of 2.8 per 1 million. A case series of 43 patients with a confirmed a TSH-secreting adenoma, two presented with symptoms of severe thyrotoxicosis; noted to be cardiac failure and atrial fibrillation. Interestingly this patient's alpha-subunit was normal. A review by Beck-Peccoz and Persani suggested that spontaneous marked decreases in TSH and alpha-subunit might herald a tumor becoming less differentiated and more invasive. Presented is a case of a TSH-secreting pituitary adenoma with rare presentation of severe thyrotoxicosis and interestingly a normal alpha-subunit with a macroadenoma. This experience demonstrates the heterogeneity of signs, symptoms and laboratory data present in this rare entity. This experience also highlights the response to treatment of just a single dose of octreotide.
Disorders of Thyroid Function Saturday Poster Case Report
Takotsubo's cardiomyopathy, characterized by transient systolic dysfunction with angiographic absence of obstructive coronary artery disease, is a rare syndrome occurring in one percent of troponin-positive suspected acute coronary syndrome. Only a few cases describe thyroid storm as a possible precipitant of Takotsubo's, and our case is the first to our knowledge to occur in a patient who had undergone prior radioactive iodine (RAI) ablation.A 36 year-old female with Grave's disease who received 10.3 mCi RAI treatment six months prior was admitted for abdominal pain, nausea, vomiting, and malnutrition. She had persistent hyperthyroidism after RAI ablation requiring treatment with methimazole. Two weeks prior to admission, methimazole dose was lowered due to iatrogenic hypothyroidism. Medical history was notable for roux-en-y gastric bypass, recurrent pancreatitis, and anasarca from poor nutritional status. Several days into admission, the patient became minimally responsive, febrile to 100.8, heart rate 150's, blood pressure 103/60, and oxygen saturation 100% on room air. Physical exam was notable for jugular vein distention, diffuse non-nodular thyromegaly, bibasilar pulmonary crackles, and 2+ bilateral lower extremity pitting edema. EKG revealed ST elevation in V2-V4, and echocardiogram showed ejection fraction (EF) of 24% (decreased from 75% on admission). Troponin was elevated at 0.33. The patient was intubated for subsequent hypoxic respiratory failure. Thyroid function tests revealed TSH <0.04 mcu/ml, free T4 3.0 ng/dl, free T3 5.6 pg/ml, and total T3 164 ng/dl. She was treated for thyroid storm with high doses of propylthioruacil (PTU), dexamethasone, saturated solution of potassium iodide, and esmolol drip. Cardiac catheterization after adequate treatment with PTU revealed no coronary artery disease. The patient regained mental status in one week, normalization of TFT's in 9 days, and EF returned to 60% in 2 weeks. She was discharged with plans for future thyroidectomy. Though the pathophysiology of Takotsubo's remains uncertain, our case highlights the role of thyroid hormone in myocardial contractility and contribution towards the hyperadrenergic state that characterizes stress cardiomyopathy.
Disorders of Thyroid Function Saturday Poster Case Report
Thyrotoxicosis can manifest with a wide spectrum of symptoms. In its severest form, it can result in life threatening hemodynamic instability. Thyrotoxicosis is well known to cause atrial arrhythmias including atrial fibrillation/flutter. However, ventricular arrhythmia caused by thyrotoxicosis more rare.A 37-year-old female with past medical history Graves' Disease, hypertension, and no other cardiac history presents to hospital after cardiac arrest. Patient was known to be non-compliant with her methimazole (MMI). EMS reports indicated ventricular fibrillation (Vfib) arrest on rhythm strips. She subsequently had return of spontaneous circulation. Upon arrival at hospital, initial vitals were temperature 36.1C, heart rate 115, blood pressure 173/101. Initial labs were notable for undetectable TSH, free T3 725, free T4 1.9. Patient emergently underwent cardiac catheterization, which revealed normal coronaries. However, echocardiogram showed ejection fraction was depressed at <20%. Patient was started on MMI, stress does hydrocortisone, iopanoic acid, and beta blockade for thyrotoxicosis. Iopanoic acid and steroids were tapered off 5 days after admission. Over the course of the next 2 weeks, patient's MMI dose was gradually decreased. 12 days after admission MMI had been titrated down to 5mg daily as TFTs had decreased to TSH 0.06 and free T4 0.6. Cardiac electrophysiology followed patient throughout the hospitalization and concluded ventricular fibrillation was likely due to thyrotoxicosis. Cardiac MRI did not reveal arrhythmogenic right ventricular cardiomyopathy, scar, or infiltrative processes. PET/CT did not reveal sarcoid or inflammatory processes. EKG and telemetry review also did not reveal any underlying arrhythmia as cause for Vfib arrest. Patient ultimately underwent ICD placement prior to discharge. Thyroid hormone plays an essential role in the cardiovascular system. Thyrotoxicosis can be associated with life threatening cardiac rhythm abnormalities, particularly atrial arrhythmias. Ventricular arrhythmia caused by thyrotoxicosis without hypokalemia is more rare. Early recognition that thyrotoxicosis can indeed cause ventricular arrhythmias will lead to prompt treatment and improved outcomes.
Disorders of Thyroid Function Saturday Poster Case Report
Takotsubo is a rare acute cardiomyopathy that is seen in the setting of acute emotional or physiologic stress. It is uncommon, especially secondary to thyroid dysfunction. In a systematic review of 1109 patients diagnosed with Takotsubo, it was found that only 63 cases (6%) were due to a thyroid disorder.A 55-year-old woman who had a medical history significant for several years of hyperthyroidism secondary to Graves' presented to the emergency room complaining of chest and shoulder pains. Her methimazole had been held for the past 4 weeks due to hypothyroidism. Labs showed thyrotoxicosis, and she had atrial fibrillation with rapid ventricular response and acute systolic heart failure. Echocardiography showed reduced ejection fraction, mildly dilated right atrium, and areas of severe hypokinesis consistent with Takotsubo cardiomyopathy. This was also confirmed with cardiac catheterization showing no coronary disease. Interestingly, on follow-up several months after her thyrotoxicosis was treated, she had complete resolution of her cardiomyopathy confirmed by echocardiography.Takotsubo tends to affect post-menopausal women. In a review study, 86% of cases were in women. It is thought that estrogen deficiency may be a predisposing factor. The exact mechanism of Takotsubo is not currently known, but it is thought to occur with a catecholamine surge or exaggerated response to catecholamines. Thyroid hormone has a net effect of increasing cardiac output by causing an exaggerated response to catecholamines and therefore exaggerated inotropic and chronotropic effect. It is likely that our patient's extreme excess of thyroid hormone made her more susceptible to Takotsubo from an extreme response to catecholamines. It is worth noting that hypothyroidism has also been implicated in Takotsubo, but likely through a different mechanism. Since opposite disorders of the same gland may cause this uncommon cardiomyopathy, albeit by different mechanisms, it is clear that disordered thyroid function can have a profound effect on cardiac function. Diagnosis has prognostic value, since after the thyroid disorder is treated heart function usually returns to normal, as was the case with our patient.
Disorders of Thyroid Function Saturday Poster Case Report
A patient with newly diagnosed hyperthyroidism started on methimazole with subsequent elevated liver enzymes.A 52-year-old female with hypertension presented with palpitations. Her symptoms were associated with chest pain and dyspnea over the past month. She denied dysphagia, weight changes, and cold/heat intolerance. Vital signs and physical examination were unremarkable. CTA was negative for pulmonary embolism.
Initial investigation revealed a TSH below assay (0.36–3.74 m[IU]/L) and FT4 2.80 ng/dL (0.76 – 1.46 ng/dL). Additional labs including CBC and CMP were unremarkable.
Endocrinology was consulted for newly diagnosed moderately severe hyperthyroidism possibly due to Grave's Thyrotoxicosis. She denied history of thyroid problems or radiation exposure. Her mother had history of Graves' disease. We recommended starting methimazole 20 mg BID and switching metoprolol to propranolol. Further labs including TSH Receptor Antibodies (TRab) and Thyroid Peroxidase Antibodies (TPO) were ordered. Overall, she clinically improved and was discharged with endocrine follow up.
At the visit, she had remained symptom free. Her antibodies resulted with a negative TRab and an elevated TPO of 172.7 IU/mL (0.0 – 9.0 IU/mL). She developed abdominal pain, and AST and ALT values increased from 15 to 60 and 43 to 122 IU/L respectively. She had taken methimazole for a total of 18 days before it was discontinued and dexamethasone was started.
In 3 weeks, her LFTs normalized. Repeat labs showed a TSH 6.35 m[IU]/L and FT4 0.4 ng/dL indicating a hypothyroid phase of thyroiditis, or instead of recovery, thyroid failure in light of elevated TPO, but she was asymptomatic.
One month later, she had fatigue and weight gain and levothyroxine was started. Current belief is that drug induced liver injury from methimazole is from its metabolites and subsequent immunologic reactions that occur. Furthermore, analysis of cases suggests that age and increase dosage are risk factors for hepatotoxicity. Although methimazole is widely used in the treatment of hyperthyroidism, hepatotoxicity is a rare (<0.5%) serious side effect for which monitoring is recommended. In doing so, it will allow for timely identification of abnormalities and prompt treatment.
Iodine Uptake & Metabolism Saturday Poster Basic
The Na+/I– symporter (NIS), a basolateral plasma membrane glycoprotein, mediates I– accumulation for thyroid hormonogenesis and radioiodide therapy for thyroid cancer. Differentiated thyroid tumors often presents as cold nodules exhibiting reduced (or even undetectable) I− accumulation. However, most benign and malignant cold nodules showed normal to increase intracellular NIS expression, suggesting the presence of plasma membrane transport abnormalities. A thorough comprehension of the mechanisms that regulate NIS expression at the plasma membrane would have multiple implications for radioiodide therapy. In vitro functional experiments were performed in non-polarized or polarized MDCK-II cells stably expressing NIS variants. Structural modellings were performed using crystal structures deposited in the Protein Data Bank. We generated a NIS homology model based on the crystal structure of the benzyl-hydantoin transporter to characterize the location of the intracellularly facing NIS carboxy-terminus. We showed that the intracellularly facing carboxy-terminus of NIS is required for the transport of the protein to the plasma membrane. We revealed that the proximal segment of the carboxy-terminus contains an uncharacterized endoplasmic reticulum export signal, whereas the distal segment is dispensable for plasma membrane expression. We identified a highly conserved monoleucine-based sorting motif that determines NIS basolateral expression. Such monoleucine-based sorting motif confers dominant basolateral information. Moreover, in clathrin adaptor protein (AP)-1B-deficient cells, NIS sorting to the basolateral plasma membrane is compromised, leading to substantial NIS missorting to the apical plasma membrane. Computer simulations provided preliminary evidence supporting that the AP-1B hemicomplex γ-σ1 recognizes NIS monoleucine-based basolateral sorting motif, thus mediating NIS sorting to the basolateral plasma membrane. Although the molecular mechanisms that determine NIS intracellular retention in thyroid cancer remain elusive, our findings uncovering NIS basolateral sorting might open new avenues to identify new molecular targets to treat radioiodide-refractory thyroid cancer.
Iodine Uptake & Metabolism Saturday Poster Case Report
This case is that of a young girl suffering from hypothyroidism as a consequence of severe iodine deficiency, despite living in an iodine-replete area. A thirteen-year-old girl attended paediatric services in 2015 for assessment of a goitre with low free T4 6.8 pmol/L (Range: 12.6–21.0 pmol/L), inappropriately normal TSH 3.08 mIU/L (Range: 0.51–4.30 mIU/L), and T3 3.25 nmol/L (1.71–3.20 nmol/L) [Roche Assay]. She had a history of eczema and multiple food allergies. Assay interference was excluded using the Abbott Assay. Ultrasound thyroid showed multiple small cystic nodules. She represented in 2017 with worsening fatigue and persistent goitre. Her TFTs showed T4 5.5 pmol/L, TSH 2.37mIU/L and T3 2.95 mIU/L. Pituitary profile, MRI pituitary, anti-TTG and anti-TPO antibodies were normal. Morning cortisol was 326 nmol/L (6–10am: 166–507 nmol/L). Vitamin B12 was <125 pg/ml (187 –883) and Vitamin D 65 nmol/L. She was treated with Eltroxin, vitamin B12 and vitamin D supplements. Urinary iodine was measured [Iodine: Creatinine ratio 6.10 nmol/mmol (50–360 nmol/mmol)]. A diagnosis of hypothyroidism due to severe iodine deficiency was made. On further questioning, the patient had a diet that excluded eggs, dairy, fish, and nuts since early childhood. She was diagnosed with allergies to several food products as an infant, when she underwent allergy testing to identify food allergens that could be potentially exacerbating her eczema. Iodine intake was encouraged with dietician input and Eltroxin was continued. Repeat TFTs five months post treatment showed T4 15.6 pmol/L and TSH 0.62 mIU/L. Iodine plays a key role in thyroid hormone synthesis and is obtained from diet (milk, iodisied salt, seafood) and the environment (seaweed produces gaseous iodine, absorbed through the lungs). Iodine deficiency is endemic in certain areas; 53% of 14–15 year old girls in Galway are iodine deficient with a urinary iodine excretion <100ug/L, however severe iodine deficiency (urinary iodine <20ug/L) is very rare (<1%). This case highlights the importance of considering iodine deficiency in patients with incongruous TFTs.
Iodine Uptake & Metabolism Saturday Poster Case Report
The recommended daily dose of iodine is 150-200 mcg in nonpregnant adults1. The Wolff-Chaikoff effect describes the hypothyroidism result of excess iodine. In euthyroid individuals, escape from the Wolff-Chaikoff effect occurs when the iodine is stopped. Normal function is restored in 2-3 weeks2. A 73 year old female with a past medical history of hyperthyroidism, no history of radioactive iodine (RAI) or surgery, presented to the ED with weakness and change in mental status. Family members endorse a history of mild cognitive impairment. Her only medications are iodine supplements (225 mcg, 3 times a day) given by family with intent to treat her hyperthyroidism in place of RAI. On exam, patient is oriented only to self, found to be bradycardic to 50s, breathing at 10 breaths per minute, and hypothermic at 95°C. Physical exam is notable for facial and periorbital edema. Labs were remarkable for TSH of 85.42 uIU/mL, freeT4 < 0.1ng/dL, hypokalemia, metabolic alkalosis, and elevated creatinine kinase. The presumed diagnosis was hypothyroid secondary to failure to escape from Wolff- Chaikoff as a consequence of extended high dose iodine. The patient was given 100 mcg of IV synthroid and hydrocortisone and significantly improved. Myxedema coma describes severe hypothyroidism which presents with myopathy, bradycardia, altered level of consciousness, hypothermia, and hypoventilation. After iodine is ingested it binds to serum proteins and is taken up by the sodium iodine symporter in thyroid follicular cells to produce thyroxine3. When exposed to high iodine loads, the normal response is inhibition of thyroid hormone synthesis. Iodine is a necessary element and international organizations have mandated inclusion into various foods. However, many over the counter supplements contain 2-3 times the recommended daily dose4. When exogenous iodine is stopped, euthyroid patients escape from the Wolff-Chaikoff effect. However, this patient failed to escape from Wolff Chaikoff and progressed to myxedema coma. While iodine is necessary, it is important to educate patients regarding the supplementation as it can have devastating consequences. Patients should know that contrary to popular belief, more is not better.
Thyroid & Development Saturday Poster Basic
Thyroid disorders are common in India, with an estimated 42 million affected by either hypothyroidism or hyperthyroidism. 1/3rd of patients with hypothyroidism remain undiagnosed due to lack of clinical awareness. Primary care physicians (PCPs) play an important role in the screening, initial evaluation and initiation of therapy in these patients. In India and other LMICs, an understaffed and overburdened tertiary care system along with an ill-equipped and poorly skilled primary care system remains the unaddressed concern. This gap can be bridged through capacity building of PCPs. Public Health Foundation of India successfully implemented a comprehensive training initiative “Certificate Course in Management of Thyroid Disorders (CCMTD)”, with the support from Chellaram Diabetes Institute (academic partner), GSK Pharmaceuticals (educational grant partner) and a panel of 15 national experts. This 4 modular course covered various aspects of management of thyroid disorders, comprising a mix of theory, case studies, activities and videos, and was delivered once a month on weekends by 49 regional faculty (endocrinologists) across three cycles at various centres in India. An integrated monitoring mechanism by public health experts assured training quality. Around 2500 participants were trained over the three cycles. They represent 382 districts with centres spread over 41 cities of the country; 45% were post graduates and 31% from the government sector. The success rate as measured by an exit exam conducted at the end of the course was 89.9%. CCMTD has been accredited by the South Asian Federation of Endocrine Societies (2016-2017) and endorsed by the Asia and Oceania Thyroid Association (2016-2025). Seeing the success of the course in private sector, 2 States have also adopted this course for the training of their doctors. This course is unique since it is probably the only national level thyroid disease training program to be undertaken in the country. High enrolment and compliance rate reveal an acceptability by the physician community from India in education on thyroid disease management. Following successful run in India, the course has been adopted by DEAN for the training of their doctors in Nepal.
Thyroid & Development Saturday Poster Clinical
Fetal growth is influenced by maternal thyroid function during pregnancy. It is unknown, however, whether maternal thyrotropin (TSH) and free thyroxin (FT4) levels in early pregnancy are associated with fetal crown-rump length (CRL) and whether these associations are modified by thyroperoxidase antibodies (TPOAb) or fetal sex. The study comprised 46186 mothers who provided early pregnancy serum samples for analyses of thyroid function. Data were available on maternal age, parity, ethnicity, maternal anthropometrics, fetal gender, hCG, TSH, FT4, TPOAb and CRL.Maternal TSH levels were negatively correlated with CRL in early pregnancy while FT4 levels were positively correlated with CRL, particularly in male fetuses. The association of FT4 with CRL was significant in TPOAb-negative pregnant women, but not in TPOAb-positive pregnant women.CRL is closely related with maternal thyroid function in early pregnancy, particularly in male fetuses.
Thyroid & Development Saturday Poster Clinical
Thyroid hormone are essential for normal growth and development of the fetus. Previous investigation of the impact of thyroid function on birth weight have focused on the first trimester or the first half of pregnancy. This study was to translate the interactive effects between early and late pregnant maternal thyroid function with fetal outcome within a large Chinese population in Shanghai. We also examined the relationship between thyroid hormones and birth weight, SGA and LGA in TPOAb positive or negative pregnant women. All pregnant women living in the city of Shanghai with expected delivery date between January 2013 and December 2016 were enrolled in this study. In total 52,027 pregnant women were enrolled during the early pregnancy, of whom TSH and FT4 concentrations were measured during first (9th-13th weeks) and third (32nd-36thweeks) trimester pregnancy. Associations between these thyroid hormones and fetal growth were analyzed in TPOAb positive and negative women. Early and late maternal FT4 levels were inversely associated with birth weight, for both TPOAb positive and negative women. TSH levels were associated with birth weight and SGA in third trimester for TPOAb negative women. Furthermore, maternal FT4 levels in first and third trimester had interactive effects for the risk of LGA. Maternal thyroid function during early and late pregnancy had interactive effects, which was associated with Birth Weight.
Thyroid Cancer Saturday Poster Basic
Sex is a known factor affecting prognosis in patients with thyroid cancer. Computational analysis of the Cancer Genome Atlas data identified thyroid cancer as a malignancy with strong sex-biased molecular traits. The results of this computational analysis were not yet experimentally validated.
Thyroid Cancer Saturday Poster Clinical
While thyroid cancer generally has a favorable prognosis, 6-20% of patients develop distant metastases, and one third loose the ability to concentrate RAI, thus becoming radioactive iodine refractory (RAIR). Available targeted therapies have not led to survival benefit and are associated with toxicities.
Thyroid Cancer Saturday Poster Basic
Thyroid cancer morbidity is increasing more rapidly than any other malignancy in the United States, tripling in incidence over the past 3 decades. Analyzing this problem, some scientists have recently identified this epidemic of thyroid cancer as “overdiagnosis.” On the other hand, overall incidence-based mortality for thyroid cancer in USA from 1994 to 2013 substantially increased (1.1% per year). These findings are consistent with a true increase in the occurrence of thyroid cancer. The experience of studying pediatric radiation induced thyroid cancer in Belarus after the Chernobyl accident indicates that the synergistic influence of radiation and nitrates may lead to an increased risk for thyroid cancer. The aim of our work was to evaluate the nitrates impact on the prevalence of thyroid cancer among the children who were born before and after Chernobyl in Belarus according to type of residence (rural vs. urban). We used data from the Children Cancer Sub-Registry of Belarus on children with thyroid cancer (1,090 born before Chernobyl and 306 born after Chernobyl). The prevalence of pediatric thyroid cancer among rural residents who were born before Chernobyl of most contaminated areas with higher thyroid doses (Gomel, Brest, Mogilev) was significantly higher compared with urban (P < 0,001). Thyroid doses in Brest and Mogilev oblasts were about the same, however the prevalence of thyroid cancer in Brest residents was significantly higher than in Mogilev (p < 0.05). Higher concentration of nitrates in drinking water from open wells of Brest oblast (exceeding the Maximum Contaminated Level by 4.0 times) may be linked to these discrepancies, since the level of nitrates in the Mogilev region was within the norm. The difference in the prevalence of thyroid cancer of urban and rural children who were born after the Chernobyl disaster in all oblasts has not been identified. Combined influence of radiation and nitrates in rural residents at the time of Chernobyl accident can lead to increased risk for thyroid cancer. Further cohort or case-control studies with individual exposure estimates are required to quantify the effect of nitrate on thyroid cancer risk.
Thyroid Cancer Saturday Poster Basic
The anaplastic thyroid carcinoma (ATC) is the least common but most aggressive type of all thyroid cancers with a median survival of approximately 4 months. It is clinically presented by rapid tumor mass gain, accompanied by systemic metastasis to distant organs and insensitivity to common treatments. Thus there is still a lack of effective treatment options. By transcriptome profiling via Total RNA-Sequencing of primary ATCs we confirm a highly aggressive phenotype characterized by a severe trans-differentiation including the loss of typical thyroid marker expression and epithelial cell characteristics. This is associated with a strong upregulation of mesenchymal and stemness-promoting factors. As novelty, with this new data we were able to identify differentially expressed RNA-binding proteins (RBPs), which received a strong increase of interest as keyplayers in highly aggressive cancers. The most severely upregulated mRBP transcript in ATCs encodes the oncofetal RNA-binding protein IGF2BP1 (Insulin like growth factor II mRNA-binding protein 1). It belongs to a family of conserved oncofetal RNA-binding proteins modulating the cytoplasmic fate of various mRNAs. In cancer, IGF2BP1 was shown to promote the oncogenic potential of tumor-derived cells by various means. In agreement, we observe that IGF2BP1 depletion respectively overexpression significantly affects viability, invasiveness and self-renewal potential of ATC-derived cells in vitro and the growth of Xenografts in nude mice. Aiming to reveal the up- as well as downstream effectors of IGF2BP1 in ATCs, we identify an epigenetic switch responsible for the de novo synthesis of IGF2BP1 in ATCs as well as several novel targeted mRNAs. The latter encode various oncogenic factors including AURKB and LIMK1. By interfering with the degradation of these target transcripts, IGF2BP1 promotes the proliferative, self-renewal and invasive potential of ATC-derived tumor cells. In conclusion our findings indicate that IGF2BP1 is a potent molecular marker unambiguously distinguishing ATCs from other thyroid cancers and that targeting IGF2BP1-dependent oncogenic networks by epigenetic drugs may provide new hubs for ATC-treatment.
Thyroid Cancer Saturday Poster Basic
Non-medullary thyroid cancer (NMTC) is the most common endocrine malignancy. The combination of surgery and radioactive iodine treatment cures ninety-five percent of all differentiated thyroid malignancies. One of the prevalent recurrent subtypes is oncocytic (Hürthle-cell) follicular carcinomas (FTC-OV). It was demonstrated that FTC-OV is dominated by whole-chromosome losses during tumour progression leading to a near homozygous genome (NHG). Subsequent genome doubling of the entire NHG genome is often seen. The stepwise loss of whole-chromosomes as a result of lagging chromosomes during mitosis was recently attributed to high levels of ROS with subsequent CHK2 activation. Using quantitative NMR spectroscopy, we searched for overlapping metabolic features, that characterize the two thyroid cell lines with NHG [XTC.UC1 (oncocytic) and FTC-236 (follicular)] in comparison with the thyroid cell lines SW579 [follicular] and BHP2-7 [papillary] not showing NHG. Cells were grown in glucose-enriched or galactose-enriched medium, the latter to increase respiratory stress. All four cell lines have unique metabolic profiles. XTC.UC1 was found to have a unique metabolic profile where cellular metabolism has completely shifted to the production of aspartate. Distinct levels of metabolites linked to ROS scavenging were seen pointing to a relative excess of ROS in the two NHG cell lines. An increased dependency on amino acids and one-carbon metabolism identified the metabolic pathways of all cell lines tested.
Thyroid Cancer Saturday Poster Basic
Anaplastic thyroid cancer (ATC) is a rare and extremely malignant tumor that accounts for 1-3 % of all thyroid cancer incidence. The genetic events leading to this aggressive tumor type have not yet been fully explored. Moreover, genomic studies are limited by the availability of fresh frozen tissue sample. However, recent advances in next generation sequencing have enabled whole exome sequencing (WES) and RNA sequencing (RNA-seq) of formalin-fixed paraffin-embedded (FFPE) samples. The aim of the present study was to investigate mutations, fusions genes and copy number events that are involved in ATC tumorigenesis.16 FFPE and 1 fresh frozen sample, obtained prior to chemo or radiotherapy, were investigated by WES and RNA-seq. DNA and RNA libraries were constructed using the TruSeq DNA Exome library kit and the TruSeq RNA Access library kit. Constructed libraries were sequenced on Illumina Nextseq500. In the 11 matched tumor/normal pairs, somatic variants with a median of 40 (range 10-5885) per case were detected. Regarding mutations, 30% had mutations in TP53, 18% in NRAS and 9% in BRAF. In addition, a novel recurrent mutation was identified in SMARCAD1; a gene involved in restoration of epigenetic signatures in heterochromatin regions following replication. Hotspot mutations in the TERT promoter were seen in 20% of cases. A total of twenty-eight fusion genes were detected by RNA-seq; none of which was recurrent. Copy number analysis revealed frequent polyploidy and many breakpoints in near-centromeric regions, indicating genomic instability.WES and RNA-seq of primary ATC tumor samples revealed genomic complexity in ATC. ATC harbored multiple fusion genes and recurrent point mutations in TP53, NRAS, TERT and SMARCAD1. Our findings increase our understanding of the complex genetic events in ATC.
Thyroid Cancer Saturday Poster Translational
Struma ovarii are benign thyroid ovarian neoplasms. Although nearly all struma ovarii remain confined to the ovary (IOS), some can spread to extraovarian sites (EOS) while maintaining an innocuous appearance; these lesions are exceedingly rare and have been called highly differentiated follicular thyroid carcinoma of ovarian origin and peritoneal strumosis. Among pathologists, there is debate on whether EOS lesions represent benign or malignant tumors. Starting with a remarkable index case of EOS to the mandible and intra-atrial septum, we explore the molecular nature of IOS and EOS tumors for the first time. Peripheral blood, normal thyroid tissue, mandibular and cardiac tumor tissue were obtained from the index patient. Additional EOS tumors (n = 2) and IOS tumors (n = 7) were identified. Isolated DNA was analyzed using the Applied Biosystems TMOncoScan Microarray system. We performed whole exome sequencing and RNASeq on EOS tumors. The OncoScanTM SNP microarray analyses demonstrated normal heterozygosity of the index case peripheral blood and thyroid gland but complete whole genome homozygosity (WG-HMZ) in her cardiac and mandibular tumors. The atrial tumor, which was not invasive and only adherent to the atrial wall, demonstrated WG-HMZ only, whereas the aggressively behaving mandibular tumor showed both WG-HMZ plus a 13.8 Mb deletion of chr7p15.3p14.1 (the tumor's second hit).
Two EOS samples and seven IOS samples demonstrated similar degrees of segmental WG-HMZ interspersed with segments of heterozgosity. WG-HMZ was the primary genomic abnormality; none of the tumors harbored typical thyroid cancer gene mutations or fusions, although one EOS tumor had a second hit (chromosomal gains) and behaved aggressively.
OncoScanTM microarray demonstrated that all IOS and EOS tumors have similar molecular profiles, most commonly segmental WG-HMZ and less commonly complete WG-HMZ. Both WG-HMZ profiles stem from errors in meiosis I and /or II. We present the first comprehensive molecular analysis of both EOS and IOS tumors. Our data suggests that EOS tumors appear molecularly identical to IOS tumors until they receive second hits, whereby they behave more aggressively as cancer.
Thyroid Cancer Saturday Poster Translational
Current staging systems do not always accurately predict papillary thyroid cancer (PTC) behavior. As a result, most thyroid cancer patients undergo lifelong surveillance for tumor recurrence. We are the first group to detect up-regulation of the thyroid stimulating hormone receptor (TSHR) in thyroid cancer as a strong predictor of cancer recurrence. We analyzed fresh frozen classical PTC tissue and paired normal tissue from 16 patients; another 4 frozen PTC tumors were analyzed. WES and RNASeq were used for comprehensive genetic mutation and fusion analysis. Proteomic analysis by parallel reaction monitoring (PRM) was performed. LC/MS-MS was performed using a Q-Exactive HF Hybrid Quadruple-Orbitrap Mass Spectrometer coupled with a Dionex Ultimate 3000 nano-UPLC system interfaced with a Nanospray Flex Ion Source (Thermo Scientific). A retrospective chart review was performed. All patients had classical PTC with logoregional or distant metastatic disease (T1a: 25%, T1b: 75%, M1:15%). Most tumors were histologically aggressive with lymphovascular invasion (70.6%), capsular invasion (73.3%), and extrathyroidal extension (66.4%). Eight patients had gross soft tissue extension (44.4%). Ten patients had thyroid cancer recurrence (52.6%) at a median of 28 months of follow-up (IQR 14.75-33.25). TSHR RNA was similar among paired normal thyroid tissue and tumor tissue, whereas tumor samples had significantly higher TSHR protein expression by LC/MS-MS (p = 1.5043E-10). TSHR protein expression was positively associated with number of positive lymph nodes (p = 0.0786). TSHR mRNA and downstream FOXE1 mRNA expression was lower in tumors that recurred (p = 0.0384 and p = 0.0264) whereas TSHR protein expression was significantly higher (p = 0.0066). We are the first to demonstrate overexpression of the TSHR protein in papillary thyroid carcinoma by LC/MS-MS novel methods. Tumors that more highly express TSHR are associated with increased likelihood of recurrence. TSHR protein expression seems to be independent of mRNA expression, suggesting abberrant tumor signaling or reduced endocytosis of TSHR. Our findings raise the question of whether novel TSHR modulators may work better to prevent tumor recurrence.
Thyroid Cancer Saturday Poster Translational
Several molecular tests for thyroid cytology have been developed to support the diagnosis of indeterminate nodules. Some of these showed a great potential, but their real effectiveness is still under debate.
The aim of the present study is to develop a new gene expression-based molecular test for the differential diagnosis of indeterminate thyroid nodules. A 126-gene panel (nanoString Technologies) was tested on RNA purified from 45 fine-needle aspiration stained smears. All smears had Bethesda III or IV cytology; on histology 12 nodules were follicular adenoma (FA), 16 were follicular variant of papillary thyroid carcinoma (FVPTC) and 17 were noninvasive follicular neoplasm with papillary-like nuclear features (NIFTP). Samples were clustered by Pearson's correlation, and then classified by random forest algorithm as malignant or benign according to their expression profile. A bootstrap resampling (n = 1000) was used to assess the performance of the classifier. The clustering analysis showed a clear separation of samples into two groups. One included 15 FVPTC, 6 NIFTP and 1 FA; the other one included 1 FVPTC, 11 NIFTP and 11 FA. The classification algorithm classified samples as benign or malignant with 96.3% sensitivity, 40.6% specificity, and AUC 85.0%. In conclusion, the 126-gene-based classifier showed a good performance in discriminating benign from malignant lesions. In this setting NIFTP were considered as malignant since they need surgical treatment; however, clustering analysis confirmed their molecular heterogeneity by grouping them with either FA or FVPTC. Our approach has the advantage to work directly on cytology stained smears and, although these data are preliminary, the performance of this model proved at least as good as the currently available gene expression-based tests. Indeed a prospective validation is warranted to confirm the usefulness of this 126-gene classifier.
Thyroid Cancer Saturday Poster Translational
Thyroid cancer patients presenting with distant metastases have poor prognosis. The identification of driver molecular alterations in thyroid cancer distant metastases is critical for the development of targeted therapies. The objective of this study was to determine specific molecular alterations, and to identify the possible therapeutic targets in a patient-derived xenograft (PDX) model of thyroid cancer lung metastases.A PDX model was developed from the lung metastases of a poorly differentiated thyroid cancer. The multiplex PCR (Ion AmpliSeq) NGS panels were used to characterize genomic alterations. DNA and RNA libraries were generated using the Ion AmpliSeq Library Kits, and data analysis was performed using Torrent Suite software. Gene expression profiling was performed by Cancer Pathfinder RT-PCR array, and protein expression was examined by immunostaining. Morphological features of the PDX model were consistent with the morphology of poorly differentiated thyroid cancer. Detection of TG, PAX8 and TTF1 mRNAs, as well as anti-thyroglobulin immunostaining confirmed the thyroid origin of this PDX. Cancer cells were characterized by overexpression of Cyclin D1, CDK4, CDC20 and MKi67, therefore indicating high proliferative activities. BRAF and TERT mutations were not detected in PDX. Analysis of PDX-derived DNA identified activating mutation in PI3CA. Assessment of PDX-derived RNA revealed RNA-splicing–based skipping of MET exon 14. The skipping of MET exon 14 leads to inhibition of MET degradation, increases MET stability, and prolongs activation of MET kinase upon stimulation. Consistent with these observations, immunostaining with anti-MET showed high level of MET protein in epithelial cancer cells, but not in tumor associated fibroblasts. Analysis of PI3CA downstream signaling showed high levels of p-AKT. Together these results demonstrate that survival and propagation of thyroid cancer cells in lung metastases could be associated with activation of MET and PI3CA signaling. These data suggest that concomitant targeting of MET and PI3K signaling could represent a therapeutic option for thyroid cancer patients with distant metastases.
Thyroid Cancer Saturday Poster Translational
The differential diagnosis of thyroid lesions using fine needle aspiration (FNA) is a challenge. The increased worldwide incidence of thyroid cancer and the indications of FNAs have resulted in a large number of patients that undergo diagnostic surgery and, in many cases, this procedure is not necessary. Molecular tests for the detection of epigenetic changes associated with malignancy are a potential tool for the diagnosis of thyroid carcinomas. We aimed to develop a diagnostic method for thyroid cancer using DNA methylation analysis. We used a large-scale DNA methylation data previously generated by our group (Illumina 450k). The epigenomic profile of papillary (PTC = 60) and follicular (FTC = 10) carcinomas were compared with normal thyroid tissues (NT = 50) and benign thyroid lesions (BTL = 17). The findings were confirmed using a cross-validation analysis with public databases (GEO and TCGA). Two classifiers (Support Vector Machine method) were constructed to differentiate FTC and PTC. Aiming to increase the applicability of the method, selected differentially methylated CpGs were evaluated by pyrosequencing after DNA bisulfite conversion (PYRO-BIS) in 143 tumors (86 microarray-independent) and 58 BTL samples (array-independent). Differentially methylated CpGs were identified in PTC (2,130 probes) and FTC (21 probes) compared with NT and BTL. Three probes for each thyroid malignancy (FTC and PTC) were confirmed by external data with the highest diagnostic potential (large areas under the ROC curve). These probes were further selected to train the FTC/PTC-classifier, whose combination achieved 92.9% sensitivity (65/70 FTC+PTC) and 82.4% specificity (14/17 BTL). The PYRO-BIS analysis was executed, confirming a similar performance (90.9% sensitivity and 79.3% specificity). A thyroid cancer diagnostic tool based on DNA methylation was developed with great applicability and performance.
Thyroid Cancer Saturday Poster Translational
The cribriform morular variant of papillary thyroid carcinoma (CMV-PTC) is a subtype of familial non-medullary thyroid neoplasia. The objective of the present study is to elucidate the clinicopathologic and genomic hallmarks of CMV-PTC.Clinicopathologic and immunohistochemical data from CMV-PTCs were analyzed. The landscape of clinically-relevant solid tumor genomic alterations (gain-of-function or loss-of-function mutations and copy number alterations) was evaluated by targeted next-generation DNA sequencing (DNAseq) using the Oncomine Comprehensive Panel and DNA extracted from macrodissected formalin-fixed paraffin-embedded tissue. Variable tumor morphology was observed and metaplastic squamous morulae were variably present. Nuclear β-catenin accumulation and LEF-1 staining was identified in all tumors. In addition, tumor cells expressed pan-cytokeratin, CK19, TTF-1, and ER but were negative for thyroglobulin and p63 expression. In contrast, when present, the squamous morulae were only positive for pan-cytokeratin staining. Among tumors, the Ki-67 proliferative index varied from 1% to 30%. Five tumors demonstrated bi-allelic APC inactivation via loss-of-function mutation and/or copy number loss. Two of the tumors with bi-allelic APC inactivation had concomitant ATM mutations, although one was an N-terminal splice variant with variant fraction of 0.49 (i.e., possible germline variant). None of the tumors showed conventional PTC oncogenic mutations (i.e., BRAF, NRAS, HRAS, etc.), and no CTNNB1 mutations were identified.Squamous morulae may or may not be present in CMV-PTC. The genomic hallmarks of CMV-PTC are different from conventional PTC. Bi-allelic APC inactivation via loss-of-function mutation and/or copy number loss is common in CMV-PTC, which, coupled with the presence of nuclear β-catenin accumulation and LEF-1 staining, confirms the central role for Wnt pathway dysregulation in these tumors. Interestingly, despite unequivocal nuclear β-catenin accumulation and LEF-1 staining, tumors without bi-allelic APC inactivation did not show evidence of CTNNB1 mutation, suggesting the possibility of alternative mechanisms for Wnt pathway dysregulation in these tumors.
Thyroid Cancer Saturday Poster Translational
Glucose metabolism plays a pivotal role in cellular proliferation and maintenance in normal as well as cancer cells. Various metabolic alterations are observed in cancer cells, and cell-to-cell interactions may alter the process. We assessed the glucose uptake and expression of various isotypes of hexokinase in normal thyroid follicular epithelial cells and thyroid cancer cells and examined how they differ. Normal (Nthy ori 3–1) and thyroid cancer (BCPAP, FTC133, 8505c) cell lines were cultured separately in single cell condition, and they were also co-cultured with one of the cancer cell lines seeded in the bottom chamber and the normal cell lines in the upper chamber. Then, 18F-FDG uptake was measured. The expressions of Hexokinase type I, II, and III of each cell lines were analyzed by Western blot analysis. Cancer cell lines showed a decreased 18F-FDG uptake compared to Nthy ori 3–1 cell line in a single culture condition but an increased uptake when co-cultured with normal follicular cells. Furthermore, the expressions of hexokinase I was upregulated in BCPCP cell line while hexokinase II was upregulated in FTC133 and 8505c cell lines, and hexokinase III expression was increased in BCPAP cells when co-cultured with normal cells compared to single cell culture conditions. Expression patterns of hexokinase isotypes differed in each cancer cell lines, but they correlated well with the increased 18F-FDG uptake. Thyroid cancer cells showed increased glucose consumption and altered hexokinase expressions compared to normal follicular cells in co-culture conditions, and the explanation warrants a further study.
Thyroid Cancer Saturday Poster Translational
Glycyl-tRNA synthetase (GARS) exhibits remarkable functional versatility in protein synthesis, and it's non-canonical functions have been pathologically linked to tumorigenesis. In this study, we compared GARS gene expression patterns in PTCs to determine the clinical significance of GARS gene expression in PTC. We analyzed GARS messenger RNA expression counts using data from The Cancer Genome Atlas (TCGA).GARS gene expression was significantly higher in 59 PTC tissues than in paired normal thyroid tissues (mean 873.401 vs. 571.611). In univariate regression analysis, GARS expression was higher in patients with more than 2cm size, BRAF V600E mutation, Extrathyroid extension, higher MACIS Score, advanced T stage, and death. In multivariate regression analysis, GARS expression was higher in patients with BRAF V600E mutation, T stage (T2, T4), and M1 stage.
GARS expression has no significant association with overall survival and recurrence-free survival in survival analysis. In correlation study, GARS expression has the positive correlation with BRAF and NRAS. Higher GARS expression was associated with aggressive prognostic factors and worse overall survival in PTC patients. Our results suggest that GARS can be used as a marker to predict patient's prognosis and subgroup.
Thyroid Cancer Saturday Poster Translational
The identification of molecular alterations in cancer is required for selection of appropriate targeted therapy. Genetic profiling of formalin-fixed paraffin embedded (FFPE) cancer tissue samples by targeted next-generation sequencing (NGS) is becoming a routine in oncology clinical research.
The DNA was extracted from FFPE samples from 30 patients with MTCs using Thermo Fisher Scientific King Fisher Duo Prime Purification System. DNA library was generated from 10 ng of DNA using the Ion AmpliSeq Library Kit. Genomic alterations were determined using the Ion AmpliSeq NGS Oncomine 5.6 panel that covers hotspot mutations of 52 genes; and data analysis was performed using Torrent Suite software. The activation of downstream signaling pathways was assessed by immunostaining.
Single nucleotide variants (SNVs) or insertion/deletions (INDELs) were identified in 21/30 (70%) of examined MTCs. The most common genomic alterations were in RET proto-oncogene. RET mutations were detected in 14/30 cases (46%), and included RET 918, RET634, RET768, RET620 and RET 632-633 deletion. Mutations in RAS oncogene were detected in 6 cases (20%), and included 4 cases with KRAS and 2 cases with HRAS mutations. In addition, we identified an MTC that harbored mutation in FGFR3. RET and RAS mutations were mutually exclusive. In two RET-positive MTCs, SNVs in MET and ERBB3 were identified. Tumor harboring RET and ERBBR3 exhibited aggressive pathological features including extra-thyroidal extension and widespread lymph nodes metastases.
The NGS Oncomine panel allowed an identification of genomic aberrations in FFPE samples from patients with MTCs. These tumors may be responsive to targeted therapy, and assessment of genomic abnormalities in MTCs using targeted NGS approach may help to optimize a therapeutic strategy.
Thyroid Cancer Saturday Poster Clinical
Acquisition of cancer-associated mutational change is fundamental to thyroid carcinogenesis however up to 30% of thyroid follicular lining cell malignancies can lack detection of mutational change. Our study uses a combined mutation detection and microRNA (miRNA) classifier determination to evaluate the role of mutational heterogeneity in thyroid nodules. Cytologically indeterminate thyroid nodules (n = 48) from aspirates or microdissected cytology slides underwent molecular testing (oncogene point mutation/fusion detection [ThyGenX] and miRNA profiling using a 10 marker algorithmic classifier determination as well as pair-wise analysis of individual miRNA expression differences [ThyraMIR]). Malignant outcome was based on surgical pathology. Mutation variant content ranged from 2– 47.5% in malignant nodules (mean 19.3% (SD 13.7) for BRAF V600E (n = 21) and 19.3% (SD 11.8%) for RAS mutations (n = 19)). No nodules showed 100% mutated cell content. Pair-wise miRNA marker analysis yielded distinct miRNA profiles and differences between BRAF V600E vs RAS mutated nodules enabling these two forms of thyroid follicular lining cell neoplasia to be identified. 6/8 (75%) of mutation-negative nodules, with high 10 marker microRNA classifier levels indicative of malignancy, showed BRAF V600E and RAS mutated profiles predicted by pair-wise miRNA analysis supporting mutational heterogeneity as causally responsible for the lack of mutation detection. Thyroid cancers in cytologically indeterminate nodules are composed of a chimeric mixture of mutated and non-mutated cells with respect to common mutational genotypes (BRAF V600E, RAS). While the topographic distribution of mutated cells can be heterogeneous, the more homogeneous character of the miRNA profile can confirm the acquisition of common forms of mutational change. This work supports the concept that the mutated cell subset is able to recruit non-mutated cells to be phenotypically malignant, a function ideally suited to miRNA serving as a complementary component of combined molecular testing.
Thyroid Cancer Saturday Poster Clinical
Follicular patterned thyroid neoplasms with papillary carcinoma nuclear features, with or without invasion, are increasingly recognized as a diverse group of neoplastic processes. NIFTP is unlikely to undergo metastatic spread and thus treated by lobectomy. However, iEFVPTC, reflecting neoplastic progression with microscopic evidence of capsular invasion, is regarded as malignant. Mutational findings between these two closely related states cannot be used to discriminate. Using well characterized cohorts of these two entities, we show in microdissected tissue that microRNA (miRNA) profiling can effectively differentiate these entities. Unstained FFPE tissue sections of known NIFTP (n = 10), encapsulated follicular variant of PTC with invasion (iEFVPTC) (n = 10), with positive malignant usual PTC (n = 12) and negative benign (n = 21) controls, were microdissected. Mutational analysis included common oncogene point mutation/fusion detection (ThyGenX). miRNA profiling included a 10 marker algorithmic classifier determination in addition to pair-wise analysis of individual miRNA expression differences (ThyraMIR). Significant differences in overall classifier and individual pair-wise miRNA expression were searched between NIFTP vs iEFVPTC.Mutational status (N, H, K RAS, PAX8/PPAR fusion) did not differentiate NIFTP vs iEFVPTC. NIFTP and iEFVPTC did not show strong mutational changes (BRAF V600E) or high level algorithmic 10 marker miRNA levels as detected in positive controls. While the classifier status was not significantly different between these two entities, individual pair-wise differences in specific miRNA were capable of distinguishing between NIFTP vs iEFVPTC. miR-375, miR-204 and miR-139 were particularly discriminating. The NIFTP vs iEFVPTC challenge highlights the need for molecular approaches to differentiate between closely related entities that straddle the continuum from benign and malignant states. The addition of miRNA profiling can provide sets of specific pair-wise markers that meet the molecular diagnostic need to separate NIFTP vs iEFVPTC. This panel of profiling markers is suitable for further testing using preoperative thyroid nodule needle aspirates.
Thyroid Cancer Saturday Poster Clinical
A variety of benign entities produce thyroid nodular disease, the two most common being nodular hyperplasia (NH) and follicular adenoma (FA). NH is non-neoplastic, not requiring surgical excision unless symptomatic. FA, considered neoplastic, can justify local resection when viewed as a precursor for progression to cancer. Current molecular testing based solely on mutational analysis or RNA classifier does not differentiate between these or other benign states limiting surgery decision-making. We show that microRNA (miRNA) profiling can discriminate NH from FA with high accuracy for more informed molecular assessment of cytology indeterminate nodular disease. Cytologically indeterminate thyroid nodules underwent molecular testing (oncogene point mutation/fusion detection [ThyGenX] and miRNA profiling using a 10 marker panel algorithmic classifier determination as well as pair-wise analysis of individual miRNA expression differences [ThyraMIR]), performed either directly on the needle aspirates or via microdissection of cytology slides. Histopathology review of combined testing outcome yielded 24 cases of NH and 20 cases of FA.Benign nodules were shown to lack strong driver mutations or high miRNA classifier levels thereby excluding malignant status. Bethesda Diagnostic Classification of aspirates did not show differences between NH vs FA. While the classifier discriminated between benign vs malignant states with high accuracy, the overall algorithm could not differentiate between NH vs FA. Multiple pair-wise differences among specific miRNA panel markers were capable of distinguishing between NH vs FA with high accuracy (p < .0001). Differential expression of miR-138 in relationship to other miRNAs was most discriminating. A major objective of molecular testing of thyroid nodules is accurate preoperative diagnosis of thyroid nodule states, both benign and malignant. Benign entities are diverse and cannot be discriminated based solely by lack of detectable mutational change. We show that the two most common benign lesions are associated with objective miRNA profiling differences enabling the separation of NH and FA preoperatively optimizing individual patient care.
Thyroid Cancer Saturday Poster Clinical
Anaplastic cancer is a rare variant of thyroid cancer. It is one of the most aggressive and rapidly progressing malignant human neoplasms with a grave prognosis. An aggressive treatment may be attempted for tumors at an early stage, but the optimal management of this disease remains controversial especially for cancer at advanced stage with distant metastasis. In this study, we report the outcome of multi-modality treatment in 74 cases of ATCs over a 14-year period. From January 2003 to December 2017, 74 patients of ATC who were treated at the Thyroid Cancer Center, Gangnam Severance Hospital, Yonsei University College of Medicine were enrolled in this study. These patient's records were retrospectively analyzed with respect to clinical manifestations, extent of disease, distant metastasis, treatment modality and cause of death.74 patients (48 females, 26 males, mean age 63.4 years) with histologically proven ATCs were enrolled. Most of the patients (61.3%) presented with a growing mass at the point of diagnosis, followed by hoarseness (23.0%) and pain (23.0%). In 47 patients (63.5%), metastasis was observed with lung metastasis being the most frequently seen. As treatment modalities, surgery (44 patients 59.5%), chemotherapy (46, 62.2%), targeted therapy (21, 28.4%) and radiotherapy (51, 83.1%) was performed, whereas combination therapy was observed in 47 patients. Multimodality treatment showed better survival than single treatment (p < 0.005), with the longest median survival of radical surgery and chemoradiation of 36.3 months (range 1.1-51.8 months). ATC is an aggressive cancer with advanced stage at time of presentation. Active multimodality treatment may be considered to prolong survival in T4b and M1 cases.
Thyroid Cancer Saturday Poster Clinical
Kinase inhibitors are recommended for treating radioactive iodine (RAI)-refractory differentiated thyroid cancer patients with metastatic, rapidly progressive, symptomatic, and/or imminently threatening disease that is not otherwise amenable to local control using alternative approaches. Although associated with a significant progression-free survival improvement as compared to placebo in a large Phase III study, the benefit of TKIs needs to be proved in the context of associated moderate to severe toxicities that require frequent dose reduction and delays. Retrospective cohort study of medical records of 71 patients treated with tyrosine kinase inhibitors lenvatinib and sorafenib for thyroid cancer at Gangnam Severance Hospital from July 2016 to December 2017 was conducted. Baseline clinical parameters, dosage and adverse effects from initiation of treatment were collected. As tyrosine kinase inhibitors, sorafenib (N = 48) and lenvatinib (N = 23) was used. Initial starting dose for lenvatinib was 20mg/per day in all of the 20 patients. Adverse effects occurred in 19 patients (82.6%), requiring dose reduction in 8 (34.8%) of patients and drug cessation in 1 patient (4.3%). For patients using sorafenib, the initial starting dose was £400mg daily in 12 patients (25.0%), 600mg in 16 patients (33.3%) and 800mg daily in 20 patients (41.7%). Dose reduction was needed for adverse effects in 27 patients (56.3%), and drug cessation was necessary in 4 patients (8.3%). When most common adverse effect was compared between sorafenib and lenvatinib, hand-foot-syndrome was significantly more frequent in patient using sorafenib (42 (87.5%) vs 13 (56.2%), p = 0.003).
Both of the TKIs showed high rate of adverse effect. Adverse effect was more observed in sorafenib patients, which needed more often drug cessation.
Thyroid Cancer Saturday Poster Clinical
The incidence of differentiated thyroid cancer (DTC) in Belarus is constantly increasing in the last 25 years. Our previous results suggest possible role of 25(OH)D status in progression of DTC in patients living in Belarus. This study aimed to evaluate the potential role of vitamin D signal reception variations (on the basis of SNPs panel) in patients with thyroid carcinoma. Analysis of VDR ApaI (rs7975232), BsmI (rs1544410), TaqI (rs731236), Cdx2 (rs11568820) polymorphisms in DTC group (DTCG, 26 cases) compared to control group (CG, 64 cases). We applied qRT-PCR to detect VDR polymorphisms in peripheral blood leukocytes, all statistical analyses were performed using Shapiro-Wilk test, χ2 test, P < 0.05 was considered to indicate a statistically significant difference. Statistically significant association with DTC development was shown only for Cdx2 (rs11568820) polymorphism (p = 0.042) of VDR gene, whereas non-significant difference for ApaI (rs7975232) was p = 0.053, for BsmI (rs1544410) p = 0.079 and for TaqI (rs731236) p = 0.056. Serum levels of 25(OH)D were low-normal in CG without significant difference in mid-normal DTCG.
Genetic testing for these polymorphism can be performed the purpose of high-risk follow-up group forming. More research is required for creation of a complete risk-predictive model, taking into account results of additional risk factor analysis, including anamnesis, hereditary data and genetic tests for DTC susceptibility. This would help in optimizing cancer prevention policies under a personalized medicine perspective.
Thyroid Nodules & Goiter Saturday Poster Clinical
The incidence of thyroid nodular disease in Belarus is still among the highest reported. Ultrasound guided bipolar high-frequency ablation (USG-BHFA) shows up to be the promising present-day option for the benign thyroid lesions. Our study aimed to evaluate the therapeutic efficacy and safety of percutaneous USG-BHFA of benign thyroid nodules, using specially designed applicator needle - Thyrablator in prolonged follow-up clinical study. In clinical study 21 previously untreated patients with benign thyroid nodules were included. Informed consent was received prior to the inclusion in protocol. Benign cytology was proven by Fine-Needle Aspiration (Bethesda 2–3). Pre- and post-USG-BHFA ultrasonic (US) examinations were made using same US-scanner (SiemensAcusonAntares5.0) by two skilled radiologists, same specialists performed the USG-BHFA. Patients did not receive any specific anesthesia. Nodules were punctured the same way as in FNA under US-guidance and a power of 5–10 Watts with EMED-Spectrum electrosurgical unit (EMED, Poland) was applied for 30-60 seconds until a significant US visible hyperechoic formation inside the nodule was reached. Procedure was stopped in case of excessive pain or voice hoarseness. Ultrasonic control for possible hemorrhage, nodule edema or any other abnormalities was made in +1, +24 hours. Repeated visits were planned on day 10, and 30 after the USG-BHFA. Thyroid function was repeatedly assessed. During the procedure, none of the patients complained excessive pain. Two of 21 marked the feeling of heat equal to pain of 2/10 grades (by standard 10-point pain assessment scale). Thyroid function and Thyroglobulin levels didn't change significantly during the observation period.
Average volume of the nodules before the procedure was 2,09 ± 0,71ml. Mean residual volume of the nodules during the 30 days follow up was −62,81 ± 9,05%. No post-procedure complications were detected nor clinically, nor sonographically. Our results show effectiveness and safety of Thyrablator USG-BHFA needle on a small amount of power and exposition time driven to the nodules. Still a longer follow-up period required to prove same volume reduction velocity.
Thyroid Cancer Saturday Poster Clinical
Anaplastic thyroid cancer (ATC) is rare but fatal thyroid cancer responsible for majority of thyroid cancer related mortality. ATC may originate de novo or from preexisting differentiated thyroid cancer. Complex interaction between different gene mutation has been suggested to be the main causative factor for origin of ATC in both pathway. Mostly affected pathways are MAP kinase and PI3k kinase. Hence we decided to study the frequent alterations in both the pathways in ATC patients. Clinico-pathological data of 34 ATC patients were collected retrospectively and Formalin Fixed Paraffin Embedded (FFPE) blocks were taken out for genetic analysis. DNA was isolated from FFPE tissues. BRAF V600E mutations were screened by RFLP PCR method and confirmed by sequencing. RET/PTC, RAS and PI3CA mutations were screened by sequencingA total of 34 patients were studied: Mean age 58.6 + 11.6 years, F:M- 1.8:1, 60% had the history of previous goiter. Most common presenting symptom was rapidly growing thyroid mass followed by dyspnea, dysphagia and hoarseness of voice. Extent of disease was local, locoregional and metastatic in 32, 35 and 33% respectively. 57.6% were Euthyroid, 20.5 % were hyperthyroid while functional status were not available in 11.7%. FNAC was suggestive of ATC only in 52.9% cases. 15 (44%) were operated. BRAF V600E mutations were observed in 10/34 (29.4%). Interestingly, all three ATC patients with DTC components had BRAF V600E mutation, while BRAF was positive only in 7/31 (22.5%) of patients with no DTC component. Mean survival of 3.5 months in BRAF positive cases in comparison to 5.5 months in BRAF negative ATC. RAS mutations were found to be positive in 5.8%, and none had RET-PTC/PI3CA mutations. BRAF V600E was the commonest mutation of the four genes tested and more so common in patients with previous history of longstanding goiter or differentiated thyroid cancer. However the survival of BRAF +ve ATC patients were worse in comparison to BRAF -ve cases
Thyroid Imaging Saturday Poster Clinical
The prevalence of thyroid nodules is approximately 3- 8% in the general population but increases to almost 50% after 65 years of age. When a Solitary thyroid nodule (STN) is found, the most important clinical concern is to exclude malignancy (5-15%). We aimed to evaluate role of elastography in predicting malignancy in thyroid nodules. We included patients with euthyroid STN and excluded patients with purely cystic nodule and with associated comorbidities. Risk of malignancy was assessed before surgery based on ultrasonography and elastography characterstics of nodule. Elastography was done by endocrine surgery fellow using machine ESAOTE, my lab twice (EA720, SN- 21615085) under supervision of consultant radiologist. TIRADS scoring was done using standard ACR (American college of radiodiagnosis) criteria. Colorimetric score (CS) by modified Asteria criteria. Strain ratio(SR) more than 7 was taken as cutoff for malignancy. Bethesda system has been used for categorizing the cytopathology report. Total of 74 patients were studied on OPD basis. F:M-2.7:1, mean age-33.52 years. 49 patients were having purely solid nodule, 14 patients - predominantly solid and 11 patients - complex solid cystic nodule. In purely solid nodule, CS and SR on elastography was 91% sensitive and 85% specific in predicting the risk of malignancy. On combining the results of TIRADS with CS and SR specificity increased to 89.5% however the sensitivity remained 91%. The sensitivity and specificity of CS and SR in predominantly solid nodule and complex solid systic nodule were 73, 70, 49 and 44% respectively. On subgroup analysis, out of 49 patients of purely solid nodule 19 patients were having cytology reports of either FLUS or Follicular neoplasm (Bethesda 3/4/5). Combined results of TIRADS, CS and SR was 100% sensitive and specific in this subgroup.Ultrasound elastography is an easy, non-invasive and rapid technique that can be routinely used in thyroid US scans as an office procedure to predict the risk of malignancy in purely solid nodule with FNAC of Bethesda 3,4,5. The technique can be easily mastered by surgeon after a brief training under supervision of radiologist.
Thyroid Cancer Saturday Poster Clinical
Up to 30% of pts with thyroid cancer (TC) recur. Well planned re-surgery plays a critical role in management of recurrent/persistent disease. We aimed to investigate the effectiveness of radioguided occult lesion localization (ROLL) guided surgery in patients with recurrent TC. This study includes 32pts [F/M:24/8 age:43 ± 12 years (18-58)] with a diagnosis of TC[24 papillary (PTC), 2 follicular cancer (FTC) and 6 medullary thyroid cancer (MTC)]. Three (3/32) pts had also distant metastases in addition to their local disease. Before surgery all pts underwent ultrasonography (USG) guided mapping and intra-lesional radiolabeling with injection of 11 MBq, Tc-99m-labeled macroaggregate. Surgery was performed based on the excision of radiolabeled lesions by a gamma probe and non-radiolabeled tumor foci via USG-neck map. Post-operative Tg levels and neck-USG were used for the surgical success. Among thirty-two pts, 62 metastatic lesions were identified by USG (median size:10 ± 6.3mm (range:5-30). Sixty-nine percent (43/62) of these were radiolabeled for detection via gamma probe with a radiolabeling success of 98%. The remaining lesions were marked only on USG-map. Afrer surgery USG showed no evidence of disease (NED) in %97(31/32) of pts. In the follow-up, stimulated-Tg levels of pts with differentiated TC (DTC) and no distant metastases (23/32) were below 1 ng/ml in 78% (18/23) of pts and suppressed-Tg <0,2 ng/ml was achieved in 91% (21/23) of pts. In pts with DTC with structural incomplete response and no distant metastases, we dramatically changed the American thyroid association response category and achieved excellent response in 91% (21/23) of pts. Among pts with MTC, one had lung metastases and increasing calcitonin levels despite normal USG. At follow-up, 5/6 pts suffering from MTC without distant metastases had normal USG and calcitonin levels were reduced, 60-80% in 3/5 and >80% in 2/5 of the pts. ROLL-guided surgery with USG-mapping is an effective method in the treatment of recurrentTC. This method yielded NED rate of 97% (31/32 pts) in neck area and increased excellent response rates according to ATA guidelines. Further studies with larger pt groups and longer follow-up should be performed to confirm the efficacy of this surgery.
Thyroid Cancer Saturday Poster Clinical
Tyrosine kinase inhibitor is the therapy of choice in patients with progressive radioiodine refractory metastatic thyroid cancer (TC). Although patients initially respond to therapy, disease eventually progresses and optimal time for drug withdrawal is a matter of debate. Here we discuss a case with metastaticTC who progressed rapidly after cessation of tyrosine kinase inhibitor therapyA 75 year old man with a diagnosis of poorly differentiated TC had total thyroidectomy and central lymph node dissection. Despite of radioiodine ablation with 3.7 GBq I-131, he had persistent elvated serum thyroglobulin levels. FDG PET-CT was performed to rule out metastases. PET images showed multiple FDG avid pulmonary metastases. Patient had than received additional 7.4 GBq radioiodine therapy however post therapy scans were unable to show I-131 uptake in pulmonary metastases. He underwent surgery for a pulmonary metastases that invades right atrium. He had received retinoic acid therapy for a possible redifferentiation effect, Unfortonately second 7.4 GB after retinoic acid failed to show an uptake in pulmonary metastases. Additional liver metastaes were also detected in subsequent FDG PET-CT. Patient than received 2 years of sorafenib and his Tg levels remained stabil around 2,347 ng/ml despite a slowly progressing increase in tumor size at the end of second year of therapy. Sorefenib was stopped due to tumor progression according to RECIST criteria and his Tg levels was 11,272 ng/ml during cessation. He received temozolomide for 4 months after sorafenib but his Tg levels had rised rapidliy to 448,380 ng/ml in 4 months He had developed brain metastases which led to death of the patient 5 months after cessation of sorafenibAltough patent had progresed under sorafenib therapy, rapid progression after drug cessation shows an ongoing growth inhibitory effect of Sorafenib. Sorefenib provided stable disease for 2 years and slowly progressive disease afterwards. Tyrosine kinase inhibitors are routinely used in progressive radioiodine refractory metastaticTC. Rather than rapid cessastion of drug after disease progression adding another drug like mTOR inhibitors or chemotherapy must be considered to prevent rapid progression.
Thyroid Cancer Saturday Poster Clinical
Tumor sink effect(TSE) is an sequestration of radiopharmaceuticals in normal or malignant tissue which may lead to a significant decrease of uptake in other metastatic or healthy tissues. We aimed to investigate occurrence of this phenomenon in pts who received I-131 for metastatic thyroid cancer(TC). Out of 324 pts who received high dose I-131 for metastaticTC, 41 pts (F/M: 32/9median age: 65 range:18–79) were found to be eligible for TSE evaluation and analyzed in 2 subgroups. Group A (n:12)-Visualisation of the residual thyroid tissue but no uptake in known metastatic site in the first I-131 dose. Group B (n:29)-Uptake in the residual thyroid tissue and metastatic sites. After second therapeutic I-131 administration or diagnostic whole body I-131 scan(IWBS); a new I-131 avid lesion or significant increase in the uptake of existing I-131 avid lesions were accepted as a sign of TSE in the presence of decreasing thyroglobulin (Tg) levels. In group A;4 pts had pulmonary metastases (mts),7 pts had lymph node (LN) mts and 1 pt had both LN and pulmonary mts. All pts had high uptake in the residual thyroid tissue but none of them showed increased uptake in the 2nd therapeutic(n:4, 2 after retinoic acid) or diagnostic WBS (n:8). In groupB;11 pts had pulmonary mts, 9 pts had LN mts,4 had bone mts, 1 pt had both LN and pulmonary mts, 2 pt had bone and pulmonary mts and 2 had LN and bone mts. Among these, 15/29 pts had complete remission (CR), 12/29 had partial remission (PR) and 2/29 had progressive disease after I-131. One pt who had diffuse uptake in the lungs with faint uptake in the LN mets had prominent uptake in the LNs in the 2nd therapy scan. In one pt with multiple bone mets, a new foci in bone was observed, and in one pt with multiple bone mts and star artefact, a new foci in lung were detected in the 2nd I-131 dose. All of these pts had decreasing Tg values and intensity of existing I-131 avid lesions, despite visualization of new foci. Follow-up of these pts confirmed therapy response,2 had CR and 1 had PRThese results indicate that lesions with a high I-131 uptake may mask subtle lesions and TSE can be seen in pts receiving I-131 for TC. New I-131 avid foci with decrease in Tg valus with must be interpreted with caution.
Thyroid Cancer Saturday Poster Clinical
Papillary thyroid carcinoma (PTC) is generally an indolent disease, with a high cure rate in most patients. However, regional lymph node metastasis are found in 30-40 % of patients, recurrence disease occurs in up to 30% of cases. Surgical PTC management, especially regarding need of central lymph node dissection (CLND), remains controversial. Retrospective analysis of 97 cases with PTC T1-T2 by ultrasonography without central lymph node metastasis (CLNM) who underwent total thyroidectomy with CLND between March 2011 and March 2018. All surgeries were performed by the same surgical team. Eligible patients were categorized into three groups: PTC tumor size <1 cm (group I), >1 − <2 cm (group II), and >2 − <4 cm (group III); presence of CLNM was compared between groups. Patients with known clinical or ultrasonography CLNM diagnosis prior to surgery were excluded. Our general practice at Sanatorio Las Lomas is to evaluate the central compartment during surgery, getting a frozen section for enlarged or suspicious lymph nodes, adding a CLND when positive. The aim of the study is to evaluate relationship between tumor size and CLNM and determine the importance of performing CLND according to tumor size. Lymph node involment was present in 59% of the cases. CLNM in group I, II and III were 28%, 47% and 70% respectively. CLNM rates: 45% in males vs 41% in females. Tumor size rates: group I 43% in females vs 45% in males; group II 47% in females vs 45% in males; and Group III 10% in females vs. 10 % in males. Prophylactic CLND remains controverial. Surgeons wants to minimize complications, such hipoparatyhyrodisim and recurrent nerve injury. There is a group of patients who need more agressive surgery. In our experience the incidence of metastasis is remarcable above average of published reports. Tumor size correlates with presence of CLNM, this is due to patient selection for CLND. There is not a parallelism between not performing CLND and not evaluating central neck compartment.
Thyroid Cancer Saturday Poster Case Report
Adjuvant radioiodine (RAI) therapy for differentiated thyroid cancer is a standard procedure for treatment remnant thyroid tissue and iodine-avid metastases. RAI treatment in children and adolescents requires special precautions, thus individualized approach in this setting is reviewed.
The aims of this work is to determine the Maximum Tolerated Activity (MTA) that could be safely given to optimize dose regime effectiveness and tumor control.
A 12 year old boy was referred with hard central neck mass and lateral lymph nodes. Fine Needle Aspiration Biopsy confirmed Papillary Thyroid Carcinoma. He underwent total thyroidectomy, bilateral central neck dissection with left recurrent laryngeal nerve resection and bilateral modified neck dissection, for a diffuse sclerosing PTC variant with macroscopic extrathyroidal extension, vascular invasion and 63/85 lymphs nodes involved, with massive metastases and extranodal extension. There was no evidence of distant metastases. Internal Dosimetry was performed with recombinant human TSH using EANM SOPs protocol to estimate maximum therapeutic activity of 131I. Internal dosimetry with 123I whole body scan /SPECT images showed left neck paratracheal tissue.
Internal dosimetry with 123I: Full-body residence: 10.88 hs. Minimal activity to achieve 35 cGy in blood: 143 mCi (5291 MBq). Maximal activity to produce bone marrow Grade I toxicity was 280 mCi (10360 MBq). The maximal activity to achieve 160 cGy in blood was 640 mCi (23.680 MBq). Based on fast blood RAI clearance, 400 mCi of 131I (14800 MBq, equivalent to 98 cGy in blood) were administered, with previous rhTSH stimulation. Would body scan/ SPECT images showed left paratracheal and new retro-sternal tissue.
Although extensive surgery was performed, the suspected residual neck tissue and a unknown mediastinum tissue were treated with a tailored activity, with minimal bone marrow depression. Dosimetry is safe and useful to calculate MTA when tumor cells have greater radiosensitivity. Performing empiric activities, no ablation of normal remnants tissue would achieved.
Thyroid Cancer Saturday Poster Clinical
Whether radioactive iodine therapy (RAIT) should be routinely recommended for intermediate-risk papillary thyroid cancer (PTC) patients remains controversial. The response to therapy restaging system (RTRS) recommended by 2015 American Thyroid Association (ATA) is a dynamic evaluation strategy to assess the clinical status of a patient at any point during the follow-up. In this self pre- and post-RAIT control study, we innovatively used this RTRS to identify whether intermediate-risk PTC patients could benefit from the RAIT. Among the 1714 potentially eligible patients underwent total thyroidectomy and RAIT, 699intermediate-risk PTC patients were finally enrolled, whose initial and final response was assessed before and after the RAIT through thyroid hormone withdrawal (THW). Both biochemical and imaging results such as serum TSH, Tg, TgAb, neck ultrasonography and 131I whole body scan (131I-WBS) were obtained for identifying the initial and final response. After the RAIT, totally 28.18% of patients downgraded to low risk patients after the RAIT. Among the TgAb negative patients (n = 578), 53.15% (118/222) achieved the final ER in the initial IDR patients; 20% (20/100) achieved the final ER and 46% (46/100) improved to the final IDR in the initial BIR patients. For the TgAb positive patients(n = 121), 68.61% (82/121) achieved the final ER, and 90.1% (109/121) got falling levels of the final TgAb. After the RAIT, both the median level of stimulated Tg (s-Tg) and s-Tg/TSH decreased significantly (2.50ng/ml vs 0.43ng/ml, 0.025ng/uIU vs 0.005ng/uIU, both p < 0.001) in the TgAb negative patients, and the trends were similar in the subgroups of patients with initial IDR and BIR, even those with initial ER. For the TgAb positive patients, the median level of TgAb decreased from 280.70IU/ml to 54.51IU/ml (p < 0.001). The short-term final response of the intermediate risk PTC patients were improved after the RAIT, especially in the patients with initial IDR or BIR.
Thyroid Cancer Saturday Poster Clinical
Whether one more or empirical radioiodine therapy (E-RAIT) could improve the prognosis of papillary thyroid cancer (PTC) patients with undesirable short-term responseto initial RAI therapy (RAIT) remains controversial. This study aimed to explore the impact of E-RAIT on the long-term response in such patients. Totally 111 intermediate-risk PTC patients assessed as indeterminate (IDR) or biochemical incomplete response (BIR) to the initial RAIT were retrospectively enrolled. According to the times of RAIT, patients were divided into the single RAIT (S-RAIT) (n = 84) and the E-RAIT group (n = 27). Serum TSH, Thyroglobulin (Tg), TgAb and neck ultrasonography were measured every 6 months. The final outcome was reassessed as excellent response (ER) or non-ER (NER) with a median follow-up of 40.9 months. At the response assessment to the initial RAIT, the E-RAIT group patients presented with higher stimulated-Tg(s-Tg) and BIR rate compared with S-RAIT group (17.30ng/ml vs 2.40 ng/ml, 51.9% vs 11.9%, both p < 0.001). Capsule invasion and s-Tg above 10ng/ml were identified as risk factors predicting the final NER (OR:3.061, p = 0.041; OR:8.337, p = 0.001). By the final follow-up, the level of Tg was much reduced and the ER rate was much improved in patients who received E-RAIT, and no significant difference was observed between the two groups in terms of the level of Tg and ER rate (0.10ng/ml vs 0.18ng/ml, p = 0.1; 60.7% vs 55.6%, p = 0.635). For patients with indeterminate or biochemical incomplete response to the initial RAI therapy, especially those with higher s-Tg, an improved final prognosis could be achieved by one more RAI therapy.
Thyroid Cancer Saturday Poster Case Report
Papillary thyroid carcinoma (PTC) is the most common type of differentiated thyroid carcinoma. 46% to 88% of PTC patients harbor BRAFV600E mutation. Herein, we describe a case of radioiodine refractory (RAIR) PTC with positive BRAF and TERT promoter mutations and history of brain metastasis who responded quite well to apatinib, an oral anti-angiogenic tyrosine kinase inhibitor (TKI) against VEGFR-2. This was a 44-year-old male RAIR PTC patient with pulmonary and brain metastases. Right frontal-lobe tumor resection had been conducted to remove the brain metastasis. The primary tumor showed positive BRAFV600E and TERT promoter mutations. This RAIR PTC patient was treated with apatinib at an initial dose of 750 mg qd. A cycle was defined as 4 weeks. Compared with the baseline level, the Tg concentration was sharply decreased by 59.1% 2 weeks following apatinib (25.89 vs. 63.26 ng/ml) and continued to decline by 84.4% at 6 weeks (10.47 vs. 63.26 ng/ml). Partial response was achieved at cycle 2 and maintained to cycle 22. The progression free survival reached 22.1 months. Apatinib administration was interrupted for 3 times due to grade 3 hand-foot-skin reaction (HFSR) and left scapula fracture. Dose was reduced to 500 mg qd due to grade 3 HFSR after 16.7 months of apatinib administration. A total of 14 drug-related adverse events (DRAEs) occurred 36 times. Most of them were grade 1 or 2. The most common DRAEs of grade 3 were HFSR, hypocalcemia and hypertension. Gene mutation status are linked to the severity of disease, while, patients harboring BRAF mutation tend to have a good prognosis following TKI therapy. BRAF mutation in synergy with TERT promoter mutation is associated with more aggressive forms of thyroid cancer. Our report showed a quite good respond to apatinib in a patient harboring both two mutations. Nevertheless, whether these molecular alterations could be used as prognostic factors require further study. RAIR PTC patient with positive BRAF and TERT promoter mutations could also benefit from apatinib treatment, even after surgical resection for brain metastasis.
Thyroid Cancer Saturday Poster Clinical
Metastases of thyroid carcinomas to the choroid and orbit are rare, based on literature review, PTC with metastases to the choroid was found in 8 patients.
66 y/o AA male with a history of Lung and thyroid nodules, FNA of left thyroid nodule in 2011 showed numerous neutrophils and necrotic debris, consistent with an abscess. CT guided FNA of the lung nodule in 2015 showed a follicular variant of PTC, suggesting metastatic disease. He underwent total thyroidectomy, pathology showed papillary thyroid carcinoma, tall cell variant with aggressive histology.
He had RAI ablation with 192 mCri of I-131.
Post-therapy scan: 4 foci in the thyroid bed, 1 foci in the mediastinum, bilateral diffuse metastasis to lungs and left knee uptake.
Bone scan showed multiple bone metastases (ribs, manubrium, sternum, sacrum).
PETCT revealed mild FDG avid bilateral pulmonary metastases and destructive large sternal mass metastases status post External beam radiation therapy with 4000 Centigray.
In 2017 patient developed a blurry vision, MRI orbit showed a 0.6 cm choroidal enhancing lesion in the posterior chamber left ocular globe lateral to the optic disc, representing PTC metastasis. The plan was to start Tyrosine Kinase Inhibitors Therapy but the patient refused, so he underwent radioactive plaque radiotherapy of the Left choroidal metastatic lesion with an excellent clinical response. Treatment options for choroid metastasis include enucleation if a definitive loss of vision or persistent pain, radioactive plaque, External Beam Radiation Therapy, Iodine-131 therapy, chemotherapy.
Plaque radiotherapy provides more focused, targeted radiotherapy than External Beam Radiation Therapy resulting in good tumor control and fewer ocular complications. Shields et al. treated 36 patients with choroidal metastases with plaque radiotherapy and observed immediate regression in 100% of patients, with lasting regression in 94% over a mean follow-up period of 11 months. A stable or improved vision was achieved in 58%. No data exist describing the best and most effective treatment of PTC metastases to the choroidal, because of the limited number of cases. In our patient, Plaque radiotherapy achieved an excellent clinical response.
Thyroid Cancer Saturday Poster Clinical
The role of nodule growth in assessment and reassessment of thyroid nodules is not well understood. Current guidelines indicate that re-biopsy may be warranted if a nodule with low suspicion of malignancy undergoes significant nodule growth (>20% in 2 dimensions with minimal increase of 2 mm, or >49% increase in volume). There have been several recently conducted studies with conflicting evidence regarding the relationship between malignancy and nodule growth. This study hypothesizes that thyroid nodule growth is not a predictor of malignancy. Retrospective exploratory chart review of histopathologically-confirmed malignant thyroid nodules assessed at Kingston Health Sciences Centre between 2006–2016 and benign thyroid nodules assessed during 2016, at least 1cm in diameter and with two ultrasounds completed at least 30 days apart. The primary outcomes of this study are the proportion of malignant compared to benign thyroid nodules that grow significantly between the two imaging time points and comparison of doubling time.120 benign nodules and 57 malignant nodules were included. There were 40 male patients and 137 female patients. A higher proportion of malignant nodules had significant growth when assessed using the >20% in 2 directions parameters (29.8% vs 16.8%, p = 0.047), but not when using >49% total volume increase parameter (35.1% vs 23.5%, p = 0.107). Doubling time was shorter for malignant nodules compared to benign (median 463.2 days vs 1022.1 days, p = 0.036), indicating more rapid growth of malignant nodules. The results of this study suggest that thyroid nodule growth may be an indicator for malignancy and that growth is likely a reasonable indication for repeat biopsy. Statistical significance was demonstrated when assessing growth using the rule of 20% increase in 2 dimensions, but not when assessing total volume growth. Doubling time, although not commonly used in assessing thyroid nodules, indicated a statistically significant faster growth rate for malignant thyroid nodules.
Thyroid Cancer Saturday Poster Clinical
Lenvatinib is an oral multi-thyrosine kinase inhibitor (TKI) approved for the treatment of progressive radioiodine-refractory differentiated thyroid carcinoma (DTC). Primary endpoint was to confirm, in the clinical practice, the efficacy of Lenvatinib therapy in a series of patients (pts) followed in a single centre; secondary endpoint was to search for good prognostic factors of improved progression-free survival (PFS). We analyzed the data of 74 pts who, for progressive DTC according to RECIST 1.1, started Lenvatinib therapy. Median age at diagnosis was 65 years; male/female ratio was 1.05; 28% of pts was previously treated with other TKI; lymphnodes, lung, bone, and liver metastases were present in 82%, 89%, 46%, and 20% of pts, respectively. At first control, 2 months after Lenvatinib starting therapy, the disease control-rate was obtained in 100% of pts: 35% had a partial response (PR) and 65% had a stable disease (SD). After a mean of 16 months of follow-up, 31/74 (42%) pts was still being treated: 15/31 (48%) pts remained in PR; 12/31(39%) pts remained in SD, 4/31 (13%) had a slowly progressive disease (PD). The best radiological response was obtained after a mean of 4 months of therapy. The median PFS and overall survival were 38 and 22 months, respectively. The treatment-related adverse events (AE) occurred in 93% of pts. The most frequent AE were fatigue (78%), nausea and anorexia (75%), weight loss (67%), arterial hypertension (67%), dysgeusia (46%), diarrhea (32%) and proteinuria (28%). Regarding the AE severity, the majority of pts had grade1/2 according to the Common Terminology Criteria for Adverse Events (CTCAE). The occurrence of hypertension or nausea-anorexia or weight loss was significantly associated with a better PFS (45 vs 19 months, p = 0.03; 45 vs 7 months, p = 0.0002; 45 vs 7 months, p < 0.0001, respectively). These data confirmed that, in clinical practice, Lenvatinib therapy is effective and associated with a prolonged PFS. After 16 months of follow-up the clinical benefit rate was 42%. In our series the occurrence of AE of hypertension, nausea-anorexia and weight loss predicted a better response.
Thyroid Cancer Saturday Poster Clinical
Following thyroidectomy for differentiated thyroid cancer (DTC), thyrotropin (TSH)-suppressive therapy is sometimes indicated to decrease the risk of recurrence. The resulting hyperthyroidism may increase the risk of osteoporosis. The objective of this study is to evaluate if bone health is investigated by clinicians in DTC patients. Medical charts from patients with DTC operated in our center between 2011–2016 with at least 2 follow-ups were retrospectively evaluated.
We compiled information on bone mineral density (BMD) testing, vitamin D status and osteoporotic treatment as indicators of bone health evaluation performed in clinical practice. Charts were also reviewed to determine if BMD testing were indicated based on Osteoporosis Canada's recommendations. Patients were divided in two groups according to their median TSH: suppressed TSH (TSH ≤0.1) and non-suppressed TSH (TSH >0.1).278 DTC patients (206 women) with a mean age of 50 ± 15 years were followed for an average of 2.9 years.
The TSH suppressed group (n = 68) and non-suppressed group (n = 210) had no differences in bone health investigation. In the suppressed group, 4% of patients had a prior diagnosis of osteoporosis at baseline compared to 5% in the suppressed group (p = 0.9). Rates were similar for BMD testing (10% vs 9%, p = 0.75), vitamin D evaluation (65% vs 65%, p = 0.4) and both groups had comparable rates of osteoporosis treatment (7% vs 8%, p = 0.94) for the suppressed vs non-suppressed group, respectively.
For postmenopausal women with suppressed TSH (representing the highest risk group for osteoporosis) only 6/31 (19%) had BMD testing. Bone health is under-investigated in the follow-up of DTC patients. Even in the higher risk population for osteoporosis, bone health was not recognized as a priority. Clinicians should be sensitized to bone health in DTC patients as thyroid cancer incidence is rising in order to avoid increasing morbidity.
Thyroid Cancer Saturday Poster Clinical
There is still limited evidence of thyroid-stimulating hormone (TSH) suppression in low-intermediate risk papillary thyroid carcinoma (PTC), especially in patients treated with lobectomy. Patients who had lobectomy and TSH suppression post-operatively were retrospectively included into analysis. According to the American Thyroid Association (ATA), the proposed TSH suppression levels were 0.1–0.5 mIU/L, and 0.5-2 mIU/L for intermediate, and low-risk patients, respectively. Recurrence-free survival (RFS) was chosen as the primary end-point. A total of 160 patients were identified, of whom 65 were categorized as low risk, 95 as intermediate risk. The median follow-up time for the cohort was 120 months (range: 88-187 months). No death occurred during the follow-up period. Based on ATA recommendations, 84 patients did not meet the TSH suppression criteria upon TSH suppression treatment, among whom 16 were in the low risk group, 68 in the intermediate risk group. Survival analyses revealed that no RFS benefit was observed by strict TSH suppression in low (P = 0.331) and intermediate (P = 0.197) risk patients versus their counterparts.
Next, we divided the patients into two groups according to the pre-operative TSH level at the cut-off value of 2 mIU/L. For low pre-operative TSH patients with intermediate recurrence risk, no difference was detected in the TSH <0.5 mIU/L, 0.5-2 mIU/L and >2 mIU/L subgroups (P = 0.220). Similarly, TSH suppression <2 mIU/L would not benefit survival in low-risk patients.
When we limited the cohort into patients with pre-operative TSH ≥2 mIU/L, survival benefits were achieved by TSH suppression in intermediate risk patients (10-year RFS were 91.7%, 100% and 75.0% for the TSH <0.5 mIU/L, 0.5–2 mIU/L and >2 mIU/L subgroups, respectively, P = 0.024), as well as low risk patients (10-year RFS were 100% and 75.0% for the TSH <2 mIU/L and ≥2 mIU/L subgroups, P = 0.013). When treated with lobectomy, TSH suppression was beneficial for low-intermediate risk PTC patients whose pre-operative TSH ≥2 mIU/L; otherwise there is no need of TSH suppression.
Thyroid Cancer Saturday Poster Clinical
Recent studies reported the improvement of thyroid cancer survival. We evaluated the changes in the disease-specific survival (DSS) of differentiated thyroid cancer (DTC) in association with clinicopathological characteristics in Korea from 1996 to 2005. This is a retrospective, multi-center cohort study. A total of 4,398 DTC patients were included and classified according to the year of initial surgery: 1996–2000 (Period 1), 2001–2003 (Period 2), and 2004–2005 (Period 3). During the study period, the patient age and the proportion of papillary thyroid cancer was gradually increased. The primary tumor became smaller (2.3 ± 1.4 cm at Period 1 to 1.5 ± 1.2 cm at Period 3, P < 0.001). The proportion of high-volume lymph node metastases significantly decreased (20% at Period 1 to 13% at Period 3, P for trend <0.001). DSS differed significantly according to the period during the median 10 years of follow-up (P = 0.002). The 10-year DSS rates were 98.0%, 98.7%, and 99.2% in Period 1, 2, and 3, respectively. After adjusting for various characteristics, the disease-specific mortality risk was significantly lowered in Period 2 (Hazard ratio [HR] = 0.44, 95% confidence interval [CI] 0.23-0.83, P = 0.011) and Period 3 (HR = 0.40, 95% CI 0.20-0.78, P = 0.007) compared to that of Period 1. This trend was also significant in a subgroup analysis of low (I-II) and high (III-IV) TNM stages. The disease-specific mortality of DTC in Korea decreased over time. Earlier detection of small DTCs with less extensive disease, and treatment standardization may be associated with this phenomenon.
Thyroid Cancer Saturday Poster Clinical
The efficacy of radioiodine remnant ablation (RRA) for patients with differentiated thyroid carcinoma (DTC) with gross extrathyroidal extension (ETE) is well described. However, its role in gross ETE invading only strap muscles, T3b category in the newly proposed eighth edition of TNM staging system, is currently unknown. This study retrospectively analyzed 260 DTC patients with ETE invading only strap muscles who underwent thyroidectomy at a tertiary Korean hospital between 1994 and 2005. Cancer-specific survival (CSS) and recurrence-free survival (RFS) in the no RRA (n = 13), low RRA activity (<3.7 GBq, n = 80), and high RRA activity (≥3.7 GBq, n = 167) groups were studied. No significant differences were observed between low and high activity RRA groups in terms of 10-year CSS (97.3 % versus 99.3 %; HR 0.23, 95% CI 0.02-2.57; p = .235) and RFS (86.8% versus 88.8%; 0.90, 0.40-2.03; p = .804). In no RRA group, no patients died of cancer, and only one developed structural recurrence. In Cox regression analyses with inverse probability of treatment weighting adjusted for clinicopathologic risk factors, high activity RRA was not related to recurrence outcomes compared to low activity (HR 0.60, 95% CI 0.26-1.35; p = .214). Long term oncologic outcomes did not significantly differ between low versus high activity RRA groups, which suggests that low activity RRA might be sufficient in patients with DTC with gross ETE invading only strap muscles. Further studies are needed to clarify the optimal activity of RRA in these patients.
Thyroid Cancer Saturday Poster Clinical
An international group of experts recommended reclassifying non-invasive encapsulated follicular variant papillary thyroid cancers as ‘non-invasive follicular thyroid neoplasm with papillary-like nuclear features' (NIFTP) in 2016. The purpose of this study was to establish preoperative clinical, laboratory, ultrasonographic, and cytological variables, which can differentiate NIFTP from non-NIFTP follicular cancers. We conducted a retrospective chart review of patients from a single institution evaluated between 2012 and 2017. We identified 203 adult patients who underwent lobectomy or total thyroidectomy for a follicular variant of papillary thyroid cancer during that period. Each patient's medical chart was reviewed and information on preoperative variables was recorded. An expert pathologist reviewed all surgical specimens and reclassified the non-invasive encapsulated ones as NIFTP. Overall, 44 patients were included in the NIFTP group and 159 in the non-NIFTP group. Mean age was 50.1 years in the NITFP group and 50.7 in the non-NIFTP group. Most patients were female (86.4% in the NIFTP group vs 79.8% in the non-NIFTP). More patients underwent lobectomy in the NIFTP group (50% vs 16.4% in the non-NIFTP, p = <0.0001) Less patients received radioactive iodine in the NIFTP group (31.8% vs 52.2% in the non-NIFTP, p = 0.0177). Preoperative thyroglobulin levels were lower in NIFTP patients (Median 25.55 mcg/L ± 67.8 vs 76.06 mcg/L ± 119.8 in non-NIFTP, p = 0.0104). A cut-off value of 31.3 mcg/L had a sensitivity of 75% and a specificity of 62.5% to distinguish NIFTP lesions from non-NIFTP follicular cancers. NIFTP nodules were smaller (Mean size 22.97 mm ± 12.3 vs 25.88 mm ± 11.2 for non-NIFTP, p = 0.0448) and more often solid than non-NIFTP (93.2% vs 74.8% for non-NIFTP, p = 0.0067). Measures of diagnostic accuracy showed that 2017 ACR TIRADS category of 1-4 had a negative predictive value and a sensitivity of 100% for NIFTP. Lower preoperative thyroglobulin levels, smaller nodule size and solid texture as well as 2017 ACR TIRADS Category of 1-4 are more strongly associated with NITFP than non-NIFTP follicular cancers, can favour less invasive surgical options and avoid unnecessary radioactive iodine treatments.
Thyroid Cancer Saturday Poster Clinical
Many studies have proven that lymph node (LN) metastasis in papillary thyroid carcinomas (PTC) are related to the high recurrence rate, low disease-specific survival rate, and overall survival rate and are associated with a poor prognosis. Although there is increasing consensus on the value of total thyroidectomy, the ideal treatment for regional LN metastasis has remained a subject of debate. Determining the extent of neck dissection should be mainly based on the predictable pattern of spread of regional LN metastasis from PTC. In addition, if we can identify the predictive clinicopathologic factors of regional LN metastasis, we can make proper preoperative plans. We prospectively evaluated the pattern and predictive factors of LN metastasis of 411 patients with PTC who underwent total thyroidectomy and bilateral central LN dissection with or without therapeutic lateral LN dissection. The patients underwent preoperative ultrasonography and fine-needle aspiration cytologic study of primary tumors and palpable lateral neck nodes. There were 303 women and 108 men ranging in age from 14 to 84 years, with a mean of 49.41 years. The number of dissected and positive lymph nodes in the central compartment was 7.08 ± 7.13 and 2 ± 3.30 respectively (mean ± SD). Male sex was statistically significantly related to central LN metastasis (P = 0.16), and ipsilateral central LN metastasis was significantly related to lateral neck metastasis and recurrence (P = 0.24, <0.01). For lateral LN metastasis, Age (over 55) and multifocality were statistically significant (P = 0.16, 0.01). So central LN metastasis was significantly related to lateral LN metastasis. We identified the incidence and pattern of cervical lymph node metastasis. Central neck dissection is recommended for all PTC patients. Careful inspection for LN metastasis should be performed when evaluating male patient and Age (over55) with PTC, and if central LNs are involved, carefully inspect lateral LNs. Careful inspection for LN metastasis should be performed when evaluating male patients with PTC, and if central LNs are involved, carefully inspect lateral LNs and recurrence.
Thyroid Cancer Saturday Poster Clinical
Lenvatinib, a recently approved tyrosine kinase inhibitor (TKI) for radioactive iodine refractory differentiated thyroid cancer (DTC), has been shown to delay disease progression and have a meaningful benefit in overall survival. However, there is no predictive marker of response to lenvatinib yet. Herein, we comprehensively analyzed clinical and radiological parameters to predict response to lenvatinib in lesion-based assessments. Medical records and radiographs were collected from 11 referral hospitals in 66 patients treated with lenvatinib. Up to 96 measurable lesions were evaluated serially until a progressive disease and Time doubling time (TDT) was calculated from two CT scans at historical and at the beginning of the dose. Except for patients with only non-target lesions or treatment periods of less than one month, 57 patients were analyzed, and 34 women and 7 TKI naïve patients were included. The mean progression-free survival (PFS) was 5.1 months (95% confidence interval (CI) 4.4-9.5 months), the mean duration of response was 6.0 ± 4.4 months, and the objective response rate was 38%. In lesion-based assessments, 31 lesions (32.2%) with significant tumor shrinkage (complete or partial response) were classified as responders and the remaining 65 lesions (stable or progressive disease) were classified as nonresponders. The average TDT of responders and nonresponders were 11.5 months and 14.3 months, respectively. Rapidly progressive disease with a shorter initial TDT (<12 months) was more likely to respond to lenvatinib. Patients exposed to lenvatinib an average of 16 mg or more per day or never treated with TKI had a lower risk of progression but were not statistically significant (P value for daily dose = 0.067, and P value for TKI exposure = 0.086).TDT calculation at the beginning of treatment and lesion-based tumor assessment will help select the response group for lenvatinib therapy and predict therapeutic response.
Thyroid Cancer Saturday Poster Clinical
Although patients with papillary thyroid cancer (PTC) with synchronous distant metastases frequently experience poor clinical courses, their clinical prognostic factors have never been reported separately. This study aims to investigate prognostic factors in PTC with synchronous distant metastases. This retrospective cohort study included 63 patients with PTC with synchronous distant metastases who underwent total thyroidectomy. Progression-free survival (PFS) and cancer-specific survival (CSS) was assessed according various clinicopathologic characteristics including age, sex, histologic subtypes, degree of local advancement, sites of metastases, radioactive iodine avidity, the time when metastases were found, and surgical excision of metastatic lesions. During median follow up duration of 6.4 years, 20 cases of progression (10-years PFS = 62.3%) and 9 cases of cancer-specific death (10-years CSS = 84.5%) were observed. Male (Hazard ratio [HR] = 4.39, p = 0.011) and extensive extrathyroidal extension (ETE) beyond strap muscle (HR = 3.56, p = 0.033) were associated with shorter PFS in the multivariable Cox regression analysis. Additionally, male (p = 0.048), extensive ETE (p = 0.004), old age (>45 years; p = 0.016), and discovery of metastases at diagnosis were associated with shorter CSS using Kaplan-Meier curves with log-rank tests, and no patient with all of these four characteristics survived more than 5.8 years. Not only old age which is a traditional prognostic factor, but male sex and extensive ETE of primary lesion have important prognostic roles in PTC with synchronous distant metastases.
Thyroid Cancer Saturday Poster Clinical
Although differentiated thyroid cancer generally has great prognosis, early regional lymph node metastasis could be seen in 30-80% patients with PTC. Preoperative ultrasound plays an important role in the formulation of therapeutic regimen for patients with PTC. However, the sensitivity and specificity of ultrasound in predicting metastasis lymph nodes in PTC were only 65% and 72%, respectively. Many surgeons only take ultrasound findings as diagnosis basis. Therefore, mistakes may occur in the preoperative planning of patients with PTC.Data were retrospectively collected between September 2016 and February 2018 from the First Affiliated Hospital of Zhengzhou University in China. 286 lateral neck lymph nodes identified in 250 patients met the inclusion criteria. 108 lymph nodes have the cytology and Tg washout measurements simultaneously. Preoperative thyroid ultrasound examinations were performed using either a Aplio XG (TOSHIBA, Japan) or ARIETTA 70 (HITACHI, Japan) instrument equipped with a 10 MHz or 5–14 MHz linear-array transducer. Fine-needle aspirations were examined by Edge (SonoSite, USA) equipped with a 6-13 MHz liner-array transducer and a 22-Gauge needle (GALLINI, Italy). In this study, 252 (88.11%) had final diagnosis of malignancy and 34 (11.89%) were benign. Cystic change (OR: 3.78, 95% CI: 1.49-9.59), absence of fatty hilum (OR: 4.68, 95% CI: 1.77–12.37), peripheral vascularity (OR: 10.17, 95% CI: 2.01–51.39), mixed vascularity (OR: 7.22, 95% CI: 2.01–25.90) were significant predictors of malignant lateral neck lymph nodes. The area under curve (AUC) (95% CI) was 0.837 (0.76–0.92) for the combination of four features above. The combination of FNA cytology and thyroglobulin (Tg) washout measurement had sensitivity and specificity as 84.52% and 100%, respectively. X 2 showed significant difference between ultrasound and the combination of FNA (X 2 = 11.097, P = 0.001). Preoperative ultrasound can be used as a screening for patients with papillary thyroid carcinoma, however, once there is lymph node metastasis in the lateral neck area, an ultrasound guided FNA cytology and Tg washout measurement are needed to confirm the extent of surgery.
Thyroid Cancer Saturday Poster Clinical
Thyroid Cancer Saturday Poster Clinical
Current management guidelines for pediatric thyroid cancer are largely based on adult research despite the differences between pediatric and adult thyroid cancers. The North American Pediatric Thyroid Cancer Registry was established at Texas Children's Hospital in 2017 to advance the understanding of pediatric thyroid cancer. Patients less than 21 years of age with a diagnosis of pediatric thyroid cancer anywhere in North America are consented in person or via telephone. Clinical information is abstracted from medical records. Tumor tissue, blood or saliva samples from patients, and saliva samples from biological parents are banked for future research. Between February 2017 and March 2018, 21 patients were enrolled. Diagnoses include papillary thyroid carcinoma (18), papillary thyroid microcarcinoma (2) and minimally invasive follicular carcinoma (1). The median age at diagnosis was 15.71 years (range 9 – 18 years). Sixteen (76%) patients were female. Patients identified as White Hispanic (11), White non-Hispanic (3), Black (1), other (4), and 1 declined. Nine patients are ATA low- risk, 2 are intermediate-risk, and 10 are high-risk. Seventeen patients had a total thyroidectomy, 3 had a hemithyroidectomy, and surgery was deferred in one patient due to extensive disease. Twelve patients had central lymph node dissection (LND) and 8 had an additional lateral LND. Five (56%) ATA low-risk patients and 10 (83%) intermediate and high-risk patients received radioactive iodine. Two patients in the ATA-high risk group with extensive lung metastases received tyrosine kinase inhibitors. Three patients had a RET fusion. Two patients had a prior history of cancer (leukemia and Hodgkin lymphoma). Eighteen tumor samples and 17 blood/saliva samples were collected from patients. Twenty-four saliva samples were collected from parents. The Pediatric Thyroid Cancer Registry is a resource for clinical and basic science investigators interested in pediatric thyroid cancer. ATA members are encouraged to enroll their pediatric patients on the registry.
Thyroid Cancer Saturday Poster Clinical
Selective use of 131I was advocated by ATA guidelines for IR-DTC. The post-operative evaluation, 3-4 mths after total thyroidectomy, should be considered in the decision making to perform or not RRA. However, the available data on the impact of delayed RRA on the outcome of IR pts, are conflicting.
We retrospectively evaluated the data of 311 consecutive IR-DTC pts followed at our institution for a median of 5.9 yrs. All patients performed RRA with 30 mCi after rhTSH. We divided pts in Group-A (RRA <6 mths from surgery – 101 pts) and Group-B (RRA ≥6 mths from surgery – 210 pts).
The median time elapsed between surgery and RRA was 3.4 mths in Group-A and 7.3 mths in Group-B. The two Groups were similar for gender distribution (female 75.6 vs 67.6% − p = 0.17) and age (median 44.7 vs 47.1 yrs – p = 0.18). Classic variant PTC (43.6 vs 42.4%), follicular variant (10.9 vs 14.8%), FTC (5 vs 4.3%) and aggressive variants PTC (40.6 vs 38.6%) were similarly distributed in Group-A and B (p = 0.821), as well as tumor dimension (median 2.2 vs 2 cm – p = 0.5), multifocality (55.4 vs 53.3% - p = 0.73), lymphnode metastases at histology (26.7 vs 27.6% - p = 0.87). At the first control after RRA (median 7 mths), no difference in Excellent (58.2 vs 62.3%), Biochemical (7.1 vs 5.8%), Structural (6.1 vs 5.8%) and Indeterminate Response (28.6 vs 26.1%), were noted (p = 0.91). At the end of follow-up (median 5.9 yrs), there were no difference in Excellent (74.5 vs 76.9%), Biochemical (2 vs 2.4%), Structural (10.2 vs 7.7%) and Indeterminate Response (13.3 vs 13%) [p = 0.9], as far as in the number of repeated 131I courses performed during the follow-up [p = 0.67].
1) In IR-DTC pts, RRA performed <6 mths or ≥6 mths showed the same efficacy, both at the first control after ablation and at the end of follow-up; 2) No difference in the total number of 131I courses were noted between the two groups; 3) IR-DTC could critically and safely reassessed in the year following the surgery before deciding to perform RRA.
Thyroid Cancer Saturday Poster Clinical
Active surveillance (AS) is a debated management strategy for patients with low-risk papillary thyroid cancer (PTC). We aimed to examine factors that influence endocrinologists' and surgeons' recommendations for AS in patients with PTC. We conducted a web-based survey of members of the ATA, AAES, and AHNS and randomized respondents to receive or not receive evidence-based information about AS prior to completing the survey. Respondents indicated whether they would recommend AS or an alternative treatment for 11 case scenarios with varying patient and tumor characteristics. We also asked providers about their preferred treatment for themselves and beliefs about what influences patients' treatment decisions. We compared rates of recommending AS across the scenarios with Chi-square. To identify factors associated with providers' recommending AS for scenarios with a PTC ≤1cm, we used multivariable logistic regression. Respondents included 99 endocrinologists and 246 surgeons (n = 345). For the case of a 45-year-old woman with a very low-risk, solitary 8mm PTC, 41.8% of endocrinologists and 16.0% of surgeons recommended AS (p < 0.0001). Clinical factors that increased the likelihood of recommending AS on bivariate analysis included decreased tumor size (4mm) and increased age (75y) regardless of life expectancy (p < 0.05). Respondents were less likely to recommend AS for a younger patient (20y) or a >1cm PTC (p < 0.05). In the regression model, endocrinologists had greater odds of recommending AS (OR 2.91). Other factors associated with recommending AS included the respondents' preference for AS if they were diagnosed with an 8mm PTC (OR 7.53) and if the patient prefers AS (OR 7.50). Receipt of information about AS prior to the survey did increase the odds that providers recommended AS (OR 2.11). Providers recommendations for AS of PTC are associated with multiple factors including their own personal treatment preference and the patients' preference. Receipt of information about AS influenced provider responses, though the long-term effect is unknown. Educating both providers and patients about AS may increase utilization of AS.
Thyroid Cancer Saturday Poster Clinical
ATC is associated with variable sites of metastases. We report a case of a patient with BRAF V600E-mutated (BRAF+) ATC presenting with acute renal failure (ARF) and bilateral renal metastases responsive to dabrafenib. A 51-year-old man with papillary thyroid cancer with squamous differentiation, treated with thyroidectomy, chemoradiation and 1 year of pembrolizumab, presented with an enlarging right neck mass over 1 month not seen on recent PET-CT (PET). He reported fatigue, fever, difficulty breathing, right flank pain and decreased urine output (UOP). He was hypertensive with oliguric ARF (BUN 49 mg/dL, serum Cr 3.14 mg/dL, and eGFR 21 mL/min/1.73 m2) requiring hemodialysis (HD). Renal ultrasound showed enlarged kidneys with a diffusely infiltrative process replacing renal parenchyma. PET showed widespread metastatic disease in right levator scapulae/left trapezius muscles, left cricoid cartilage, lung, bones, right adrenal and increased uptake in bilateral kidneys. Right neck mass and renal biopsies confirmed BRAF V600E mutated ATC by NGS and IHC, respectively, excluding immunotherapy-related nephritis. He started reduced-dose dabrafenib 100 mg twice daily 10 days after presentation to our center. Two weeks later, he had regression of bilateral neck masses and increased UOP (> 1.2 L/day) with Cr 1.26 mg/dL. Last HD occurred 19 days after starting dabrafenib. Repeat PET 4 weeks later showed partial response with renal metastases regression and a large right perinephric hematoma. The patient transitioned gradually to full doses of dabrafenib, trametinib and pembrolizumab once the hematoma decreased and stabilized. He had grade 1 fatigue and fevers. After 103 days on therapy, the patient developed progressive disease. Liquid biopsy (cfDNA) revealed BRAF V600E and a new TERT promotor mutation. To our knowledge, this is the first reported case of ATC associated with renal metastases and ARF. Early initiation of anti-BRAF therapy led to clinical and radiologic significant responses sustained over 100 days and was well-tolerated. Rapid tissue diagnosis, mutational testing and initiating targeted therapy are essential to prevent morbidity and mortality in ATC.
Thyroid Cancer Saturday Poster Clinical
The AJCC recently released the 8th edition of the cancer staging manual and granted medullary thyroid carcinoma (MTC) unique staging for the first time. No designation is provided for tumors in which distant metastatic disease (DM) has not been formally assessed at the time of staging (MX), nor is preoperative calcitonin (Ctn) considered. This omission leaves clinicians to decide how to best categorize patients (pts) into the staging system to allow disease prognostication. We sought to determine the overall survival (OS) of pts classified with MX disease and whether Ctn level can guide staging.1,067 pts with complete staging data and MTC were retrospectively identified in a large institutional MTC registry. M stage at diagnosis was defined as: M0: pts with negative comprehensive imaging regardless of Ctn or described by clinician as M0; MX: pts in whom DM was not assessed; M: pts with documented evidence of DM. Kaplan Meier survival estimates were utilized to determine the OS of M0, MX and M1 pts. OS of the MX cohort was compared by preoperative Ctn levels. Multivariate Cox proportional hazards modelling analyzed the impact of preoperative Ctn levels by M stage on OS when controlling for T and N stages. This study included 332 (31%) MX pts, 612 (57%) M0 pts and 123 (12%) M1 pts. The median and 10-year OS by M status was 30.1 years and 82% for M0, 26.9 years and 67% for MX and 7.3 years and 41% for M1 disease, respectively (p < 0.001). When MX disease was included in the M0 category the median survival and overall survival for the M0 group decreased to 29.7 years and 77%, respectively. Preoperative Ctn level of 500 pg/mL did not impact the OS of the MX group in either univariate (p = 0.900) or multivariate analysis (HR 1.00, CI 0.99–1.00, p = 0.913) nor was any other Ctn cutoff found to be informative. In this large single-center MTC registry, MX patients had a median and 10-year OS that was significantly worse than M0 but better than M1 patients. Preoperative Ctn did not influence OS of the MX cohort suggesting it may not guide staging. When clinically appropriate, comprehensive imaging is needed to effectively stage patients with MTC to provide improved survival estimates.
Thyroid Cancer Saturday Poster Clinical
We aim to establish the risk for clinically relevant central lymph node metastasis (CRCM) on papillary thyroid cancer (PTC) patients with suspicious lateral lymph nodes on preoperative ultrasound (SLN) and non suspicious lymph nodes on the central compartment. Retrospective review of PTC patients with a preoperative staging US showing SLN who underwent lymph node resection at our institution between 2013 and 2017. We defined as suspicious lymph node, central or lateral, those with micro/coarse calcifications, cystic areas, hyperechoic spots, and hypervascularization with capsular vessels. We studied the risk for CRCM >2mm and ≥5mm on pathology and categorized our patients according to the central neck preoperative staging US on suspicious, uncertain and normal. We defined as “uncertain” those prominent central lymph nodes associated with Hashimoto's Thyroiditis, peri-istmic/infrathryoid, hypoechoic and with no hilum; or those accompanying an identified PTC that do not have typical suspicious characteristics. Finally, we studied other preoperative variables in order to assess their impact on the risk for CRCM. We reviewed 77 patients (65% women, median age 39 years). CRCM >2mm were present on 74% (57/77), whereas CRCM ≥5mm, on 45% (35/77). According to the evaluation of the central compartment on US, 36% (28/77) had a normal sonographic pattern: of them, 68% (19/28) had CRCM >2mm and 32% (9/28) had CRCM ≥5mm. An uncertain central US pattern was established on 21% (16/77): of them, 69% (11/16) had CRCM >2mm and 50% (8/16) CRCM ≥5mm. On the assessment of preoperative variables, presenting ≥3 SLN was significantly associated to an increased risk for CRCM >2mm (68% vs 97%, p = 0.002) and for CRCM ≥5mm (37% vs 68%, p = 0.014). A significant risk for CRCM exists on PTC with SLN on the staging preoperative US, which is maintained even for patients with normal central sonographic patterns. The risk increases for patients with uncertain central lymph nodes on the US. Larger number of SLN on US is significantly associated to a greater risk for central metastases. This information should be used to consider central lymph node dissection when SLN are detected on staging US, even in the absence of suspicious central LN.
Thyroid Cancer Saturday Poster Clinical
The reclassification of non-invasive forms of encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC) to NIFTP was done in an effort to reduce overtreatment of this entity considered as benign. Nevertheless, recent studies have reported adverse oncologic outcomes in patients with NIFTP, such as local neck recurrence or distant metastases. The aim of this study was to report the frequency, to describe clinical features and long-term outcomes of histologically confirmed cases of NIFTP. It was a retrospective study using data from french Marne-Ardennes thyroid cancers register between 1975 and 2015. Pathologic reports of follicular variant papillary thyroid cancers (FVPTC) were evaluated. Endocrine pathologists reviewed all specimens without infiltrative borders, tumor necrosis and/or psammoma bodies. Strict diagnostic criteria were used for the diagnosis of NIFTP. Among 2154 papillary thyroid cancer (PTC), 383 cases were FVPTC, 115 cases were reviewed histologically and finally 65 patients met the strict inclusion criteria of NIFTP. The frequency of NIFTP was 3% of PTC and 16.9% of FVPTC. 50 patients were women (76.9%) and median age was 47 years. Average size of NIFTP was 26.7 mm (range 4-60). 51 patients had total thyroidectomy with central and/or lateral neck dissection in 16 patients and 14 underwent lobectomy. There were no lymph node and no distant metastases at diagnosis. 46 patients (70.7%) received radioiodine. Median follow-up was 14.6 years (range 1.9-27.3) after initial treatment. No evolutive events were reported during follow-up and no death due to NIFTP was registred. Our study confirm the low frequency of NIFTP among PTC and the indolent course of this tumor.
Thyroid Cancer Saturday Poster Clinical
First-line treatment of low risk papillary thyroid cancer (PTC) generally includes immediate thyroid surgery. Active surveillance (AS) has been proposed as a strategy for management of very low risk PTC. Our aim is to describe an initial Canadian experience in offering the choice of surgery or AS for low risk PTC. This is an ongoing prospective observational study. Consenting eligible adults with low risk PTC smaller than 2 cm in maximal diameter are offered standardized written and verbal information about the options of surgery (which is our current standard of care) or AS. Questionnaires are administered at baseline and after the disease management decision is finalized. Patients' baseline level of confidence in decision-making is measured using the Decision Self-efficacy Scale, in which scores may range from zero (not confident) to 100 (extremely confident). Satisfaction with decision-making is measured using the Satisfaction with Decision Scale (possible range of scores 5 to 30, and a score ≥24 indicates high satisfaction). Descriptive data are presented. To date, 52 individuals with low risk PTC have been offered the choice of surgery or AS, and finalized their disease management decision. As is typical for PTC, 75.0% (39/52) of the participants are women and the mean age is 52.2 years (standard deviation, SD 15.4, range 26 to 82). The percentage of participants who have chosen AS over surgery is 73.1% (37/52). Participants reported a high level of confidence in medical decision-making, with a mean decision self-efficacy score of 95.6 (SD 8.2). Furthermore, 90.4% (47/52) of participants indicated that they were the ones who ultimately made the PTC disease management choice, whereas the rest made the decision with their doctor. The large majority (98.1%, 51/52) of patients reported high satisfaction with the final disease management decision. Our preliminary data suggest that, if given the choice and information, the majority of low risk PTC patients favor AS over immediate surgery. Furthermore, patients who are offered information on the choice of surgery or AS may feel empowered to make their own choice, and perceive a high degree of satisfaction in the final disease management decision.
Thyroid Cancer Saturday Poster Clinical
The link between chronic lymphocytic thyroiditis (CLT) and papillary thyroid carcinoma (PTC) is widely recognized. Considering the strong association between raised TPOAb and CLT, we postulated that preoperative TPOAb can predict the prognosis of PTC, especially the recurrence. A total of 2,158 patients who underwent total thyroidectomy for classical type PTC with tumor size ≥1cm and with available data on preoperative TPOAb and TgAb were enrolled to compare disease-free survival (DFS) according to the presence of preoperative TPOAb, TgAb, and coexistent CLT. Preoperative TPOAb and TgAb were positive in 18.8% (n = 389) and 23.1% (n = 478) of patients respectively. Patients with positive preoperative TPOAb had a significantly better DFS compared to patients without preoperative TPOAb (hazard ratio (HR) 0.53; 95% confidence interval (CI) 0.30–0.94, p = 0.028) while no difference in DFS was found according to preoperative TgAb status. Positive preoperative TPOAb was an independent prognostic factor for structural persistent/recurrent disease after adjustment for major preoperative risk factors such as age, sex, and tumor size (HR 0.52, 95% CI 0.28–0.99, p = 0.048). Although the coexistence of CLT lowered the risk for structural persistence/recurrence in univariate analysis (HR 0.52, 95% CI 0.31–0.86, p = 0.012), it was not an independent favorable prognostic factor by multivariate analysis (HR 0.65, 95% CI 0.38–1.10, p = 0.106). However, when coexistent CLT was combined with positive preoperative TPOAb, it indicated an independent protective role in structural persistent/recurrent disease (HR 0.39, 95% CI 0.16–0.98, p = 0.045). Our study clearly showed that presence of preoperative TPOAb can be a novel prognostic factor in predicting structural persistence/recurrence of PTC for the first time.
Thyroid Cancer Saturday Poster Clinical
Disparities in the diagnosis and treatment of papillary thyroid carcinoma (PTC) based on race and ethnicity have been well documented. Patients with greater access to care have also been found to have a higher rate of diagnosis of PTC, but few studies have examined whether patients with different insurance are treated differently once they have a diagnosis. We hypothesized that patients with different insurance types may receive different treatment for similar-stage PTC. Using the National Cancer Database, we included all patients diagnosed with papillary thyroid cancers >2mm from 2004–2015. We used multivariable regression to determine factors independently associated with more aggressive treatments: total thyroidectomy (vs. hemithyroidectomy), adjuvant radioactive iodine (RAI), and prophylactic lymphadenectomy.
Privately insured patients were 49% more likely to have papillary microcarcinomas (T1a, cN0, cM0 tumors) than uninsured patients (OR 1.49, p < 0.001). Adjusting for race and other demographics, income, hospital type, and TNM staging, private insurance was independently associated with total thyroidectomy (OR 1.17, p < 0.001) and adjuvant RAI (OR 1.48, p < 0.001). Patients with Medicare and Medicaid were also more likely to receive RAI (OR 1.35 and 1.24, both p < 0.001), but not total thyroidectomies (OR 1.06 and 1.04; p = 0.41 and p = 0.62, respectively). Additionally, upon subgroup analysis of patients with microcarcinomas, private insurance was predictive of prophylactic lymphadenectomy (OR 1.37, p < 0.001), again adjusting for demographics, income, hospital type, ETE, and M staging. Patients in this subgroup with Medicare were also more likely to undergo lymphadenectomy (OR 1.19, p < 0.05), however, Medicaid patients were not (OR 1.05, p = 0.52).
After controlling for patient demographics, tumor characteristics, and location of care, insurance status was independently associated with variations in treatment of PTC. While important, racial differences alone may not completely account for disparities in diagnosis and treatment of thyroid cancer. Efforts should be made to standardize treatment among patients with all insurance types.
Thyroid Cancer Saturday Poster Clinical
Most thyroid cancers are low-grade endocrine malignancies, such patients usually receive thyroidectomy with ablative radioactive iodine therapy. Meanwhile, the patients were followed with thyroid ultrasonography with other image modalities and serial serum thyroglobulin evaluation. However, serum thyroglobulin generally cannot be detected in lower levels, and serum thyroglobulin seemed having limitation for early detection of high risk recurrent patients. Costly recombinant human TSH is typically needed to stimulate serum thyroglobulin for detecting local recurrence or distant metastasis. Thus, earlier biological markers for predicting prognosis of thyroid cancer are needed. Exosomes are nanovesicles secreted into extracellular environments. Cancer cell-derived exosomes are found in the plasma, saliva, urine, and other body fluids of patients with cancer. We analyzed urinary exosomal proteins, including thyroglobulin and galectin-3, to identify early prognostic biological markers in urine in this prospective study (
Thyroid Cancer Saturday Poster Clinical
The objective of this nationwide survey is to evaluate whether there has been a change in practice on the release of differentiated thyroid cancer patients (pts) treated with I-131 since the 2011 NRC regulatory issue summary Title 10 addressing pt release.
A survey was emailed to ∼25,000 members of ThyCa: Thyroid Cancer Survivors' Association, Inc. and was available online since March 2018. Responses were included from pts >18yo and who received their most recent I-131 therapy (Tx) in 2011-2018 (post11). Responses in this survey were compared to a previous survey on practices in 1997-2009 (pre09) (Lima 2017 Thyroid). Of the 1550 responses, 1027 met the inclusion criteria. Since 2011, more pts were Tx as outpatients (81%) than pre09 (72%). Compared to pre09, more pts were involved in a discussion on the choice of an inpatient or outpatient Tx (60% vs. 55%), and there was negligible decline in the influence of the insurance company post11 (4%) compared to pre09 (5%). Radiation safety instructions (RSI) are given to pts before I-131 therapy and more are able to discuss and individualize the RSI post11 (56%) than pre09 (35%). The same percentage of pts were given oral and/or written RSI post11 (97%) and pre09 (97%) with a shift away from nuclear medicine physician providing the RSI post11 (43%) than pre09 (53%). However, 1% of pts do not recall ever receiving RSI post11; this is lower than the 3% pre09.
For outpatients, more pts are discharged within 30 min after receiving I-131 Tx post11 (77%) than pre09 (70%; P < 0.001). Approximately 98% of pts traveled by car after being released from the Tx facility, but less pts travelled >2h with ≥2 occupants in the vehicle within 3ft of the pt post11 (3%) than pre09 (8%; P = 0.026). Immediately post-Tx, more pts went to a private residence post11 (89%) than pre09 (85%; P < 0.0001), while slightly fewer pts stayed in a hotel post11 (4% vs. 5%; P = 0.54). The specific RSI received by the pts varied widely.
This survey suggests that since the 2011 NRC publication regarding pt release, there has been a significant improvement in some practices on release of outpatients, pt travel and lodging. These survey results warrant greater implementation of the 2011 NRC regulations.
Thyroid Cancer Saturday Poster Clinical
Columnar cell papillary thyroid carcinoma (CCPTC) is a rare variant of papillary thyroid carcinoma (PTC), accounting for about 0.15–0.4% of all PTC cases and characterized by the presence of pseudo-stratified columnar cells. CCPTC was first described by Evans in 1986 and several case reports have been published since that, most of which were focus on the pathological characteristics and diagnostic criteriawhile the aggressiveness and prognosis of it remain controversial. We investigated the Surveillance, Epidemiology, and End Results (SEER) program records from 2004 to 2013, identified 60739 patients with classic papillary thyroid cancer (CPTC), 5419 patients with follicular thyroid cancer (FTC) and 986 patients CCPTC. Cox proportional hazards regression analysis was used to estimate hazard ratios (HRs) representing the effects of histologic subtype and other risk factors. Patient survival was compared using Kaplan–Meier curves and log-rank tests. Propensity score matching analysis was applied toadjust potential baseline confounders.CCPTC patients have significant shorter survival time than classic PTC and FTC patients, as well as higher rate of thyroid cancer-specific and all-cause mortality per 1000 person-years. The multivariate Cox regression indicated that CCPTC patients had higher cancer-specific and all-cause mortality rates than CPTC patients but the same result was not found between CCPTC and FTC patients. However, propensity score matching analysis of different influential factors demonstrated that, no matter adjusting the general information (age, sex and race), clinical pathological factors (T, N and M stage, multifocality, extension) or treatment variants (radiation therapy, surgical treatment), CCPTC patients all showed significant higher rate of thyroid cancer-specific and all-cause mortality than CPTC and FTC patients. The results indicate that CCPTC patients have greater risk of lymph node metastasis and extrathyroidal extension as well as poorer prognosis compared to CPTC and FTC patients. Given the aggressive behavior and poor prognosis of CCPTC, we advocate that surgeons should consider more radical treatments when dealing with affected patients.
Thyroid Cancer Saturday Poster Clinical
To summarize the clinical experience of reoperation of operative thyroid cancer patients who underwent radiofrequency ablation (RFA) treatment.
Retrospective analysis of 22 cases of reoperation patients during February 2014 to July 2015, who core needle histological biopsy confirmed as papillary thyroid carcinoma before RFA in other hospital. Ipsilateral thyroid lobes with isthmic resection in 16 cases, thyroidectomy in 6 cases. All patients underwent central lymph node dissection (CLN), including 2 case of ipsilateral cervical lymph node dissection. No central lymph node metastasis in 6 cases, while central lymph node metastasis in 16 cases, accounting for 72.73% (16/22). Residual papillary carcinoma lesions were found on the side of thyroid which underwent RFA in 4 cases (4/22,18.18%). All 22 patients were followed up from 3 months to 18 months with an average of 7.8 months. All the patients had no recurrence and metastasis.
Operative thyroid cancer should not be treated by RFA. RFA is not a radical cure for cancer, and need strict rules and regulations. This present study shows reoperation can achieve a better prognosis.
Disorders of Thyroid Function Saturday Poster Case Report
Our objetive is to present a young patient with gestacional subclinical hyperthyroidism, postpartum thyroid storm and subsequent complications with life commitment. A 38 year old patient gravida 6, subclinical hyperthyroidism with negative thyrotrophin receptor antibodies (TRAb) diagnosed during pregnancy without antithyroid drugs treatment. She consulted 3 months after normal delivery and breastfeeding because of sweating and tachycardia, and thyroid function tests revealed a hyperthyroid status. She started methimazol (MMI) 20 mg daily dose. After 12 days, she presented fever and rash accompanied by severe neutropenia. MMI was discontinued. 48 hours later, she was admitted to IUC with thyroid storm. She was treated with intravenous (IV) beta-blockers, lithium, cholestyramine and corticosteroid. A week later thyrotoxicosis was controlled and total thyroidectomy was performed without complications. After surgery she developed hungry bone syndrome. She required IV calcium replacement for many days until she developed sepsis (Pesudomona Aeruginosa) pulmonary septic emboli and thrombophlebitis. She was treated with appropriate antibiotics and required multiple surgical interventions (thrombectomies and phlebectomies). She was an inpatient for two months. She was discharged on anticoagulants, calcium and vitamin D supplementation, levothyroxine, and antidepressants. Postpartum thyroid dysfunction is rather a common problem during the postpartum being found in approximately 5% of mothers in the general population. It occurs from subclinical autoimmune thyroiditis that is aggravated after parturition and causes various types of thyroid dysfunction. Immune activity is physiologically suppressed during pregnancy so that the fetus is not rejected, and rebounds above the normal level after parturition. This patient had negative thyroid antibodies but probably was an autoinmune occult status causing clinical hyperthryoidism in the postpartum and subsequent complications secondary to methimazole prescription and discontinue. Guidelines state that subclinical gestacional hyperthyroidism may not require any treatment, but postpartum can aggravate the natural course of the disease.
Thyroid & Development Saturday Poster Case Report
Our objetive is to present a patient who underwent three surgeries with five parathyroid gland excision for primary hyperparathyroidism (HPT) and persisted.
A fifty six years old woman with primary HPT. Neck ultrasound (US) showed normal thyroid gland and no enlarged parathyroids. Technetium 99m-MIBI −SPECT scintigraphy showed left superior thyroid pole enhanced uptake. With no concordant localization studies patient underwent bilateral and upper mediastinum exploration surgery. Five slightly enlarged parathyroid glands were found (right inferior was beneath thyroid capsule). Subtotal parathyroidectomy (three and a half) was performed. No PTH or calcemia level decline was achieved. Pathologic report informed three hyperplastic glands and one normal. Follow up images (US, RMN, F18-choline PET/CT) and selective internal jugular vein PTH blood samples were taken with no remarkable findings. Due to hypercalcemia which required hospitalization, second cervical exploration was decided and total thyroidectomy, resection of remaining parathyroid glands, thymectomy and bilateral carotid sheet dissection was performed; no achieving PTH or calcium decline. After second surgery, a new 99m-MIBI scitigraphy–SPECT showed mediastinum uptake. Thoracoscopic resection of mediastinal tissue was made and again, PTH and calcium remained elevated. She is taking cinacalcet 90 mg daily dose, and alendronate 70 mg once a week orally and periodic intravenous pamidronate. Calcium level remain stable and controlled.
ThisThis is a patient with recurrent or persistent hyperthyroidism after many surgeries. Differential diagnosis can be thought as occult parathyroid gland adenoma, or a rare an uncommon condition called parathyromatosis, consisting of hyperthyroid tissues scattered throughout the neck. A therapeutic option involves calcimimetic agent and bisphosphonates.
Although extensive pre–operative studies and surgery were performed, hyperparathyroidism remains irresolute. Persistent primary HPT in this setting is a challenging problem and no further surgical treatment will be made until hyperfunctional parathyroid tissue is localized.
Thyroid Cancer Saturday Poster Clinical
Serum Thyroglobulin (Tg) is a biomarker of persistent or recurrent disease. Highly sensitive Tg (hsTg) assays with improved functional sensitivity (FS) allows detection of very low Tg concentrations. Our objetives were: To evaluate the performance of early post-operative serum hsTg measurement as an early predictor of disease recurrence and response to therapy, and to study the association with other clinical implications, including age, sex and risk of recurrence.
An observational retrospective study was performed on 114 patients with DTC who underwent total thyroidectomy (TT) from March 2014 to December 2017. We evaluated serum hsTg at 6–8 weeks after surgery in all DTC patients as well as other clinical variables. Patients were divided in 2 Groups, Low and Intermediate/high Risk of Recurrence. Serum Tg measurement was performed in the absence of anti-Tg antibodies using an electrochemiluminescence highly sensitive assay (FS: 0.1 ng/ml). Statistical analysis was performed to correlate hsTg levels with response to therapy and other clinical parameters, and ROC curve analysis was used to determine sensitivity, specificity, and also to extrapolate the optimum cut-off hsTg value to predict inadequate response to treatment. Results show a statistically significant association between early hsTg levels and response to therapy using both t test and Mann-Whitney test (p < 0.01), strongly suggesting that higher Tg values are associated with inadequate response. ROC curve revealed that using a hsTg of 1.5 ng/ml as a cut-off, specificity and sensibility to predict worse response to therapy were 88% and 54%, respectively (AUC 0.71, CI 95%: 0.54–0.87). There were no statistically significant differences in early serum hsTg distribution between risks of recurrence, patients age and sex.
Early measurement of serum Tg using a highly sensitive immunometric assay could be a helpful and relevant tool at the beginning of DTC patients follow-up, allowing physicians to observe closely for those with suspected worse prognosis. Further investigations may indicate if this approach could contribute on RAI use decision-making process, regardless risk of recurrence.
Thyroid Cancer Saturday Poster Case Report
The incidence of differentiated thyroid carcinoma (DTC) arising from a thyroglossal duct cyst (TGDC) is rare. Among the DTCs, papillary thyroid cancer (PTC) is more commonly seen in TGDC. Management after resection of the TGDC containing the DTC remains controversial. A 37 year old woman is evaluated for a 4 year history of a small submental neck swelling, progressing to a 3 cm mass over the past year. Imaging revealed a TGDC. Once excised, pathology showed a 1.2 cm nodule of classic PTC in the cystic space, with negative margins and absence of lymphovascular invasion; lymph nodes were not sampled.
A pre-operative thyroglobulin (Tg) level is not known, but two months after surgery, her Tg was 25.8 ng/mL. Thyroid ultrasound at 1 month and 1 year after surgery showed a normal thyroid, without thyroid nodules, hypervascularity, or suspicious lymphadenopathy.
The patient currently remains asymptomatic, and continues to decline total thyroidectomy. Hence, annual ultrasound surveillance is planned. TGDC cancer is rare, and generally diagnosed at a younger age. While most TGDC cancers are diagnosed post-operatively on pathology, pre-operative imaging may show a mural mass, microcalcifications, and suspicious cervical lymphadenopathy on ultrasound. After excision of the TGDC and confirmation of DTC intrinsically, further treatment with a total thyroidectomy in the absence of known primary thyroid cancer or thyroid nodules remains debatable. Because of their shared embryologic origin, the presence of a remnant thyroid tissue within the TGDC causing thyroid cancer versus metastases from a thyroid primary is hypothesized to be the etiology of this ectopic thyroid cancer. TGDC cancer may or may not coexist with thyroid cancer; a high index of suspicion is necessary for its detection, with most diagnosed incidentally. Pre-operative radiographic studies are vital in evaluating cancer in a TGDC. Further treatment after TGDC excision may not be indicated and the decision for thyroidectomy should be personalized based on known risk factors, such as age, extent of disease, or prior radiation exposure. Patients with low risk DTC in TGDC do well, with observed cure rates of 95%, and long-term survival of 95-100 %.
Thyroid Cancer Saturday Poster Case Report
The incidence of thyroid cancer increases with age, where the most aggressive forms generally arise in elderly patients. Kinase inhibitors (KIs) have successfully emerged in managing advanced thyroid carcinoma (AdvTC); however, this may come at the cost of side effects. Balancing the adverse events (AEs) with benefits is challenging, hence physicians may be more apprehensive prescribing KIs in the elderly population. With limited studies available exclusively evaluating KIs in geriatrics population, strategies to manage and monitor these patients need to be further explored. An 87 year old Caucasian woman, with history of breast cancer in remission, presents for recurrence of a follicular thyroid carcinoma (FTC) with insular pattern(pT3NxMx). After thyroidectomy, she received 2 doses of radioactive iodine (RAI) ablation over a 2 year period, totaling 345.6 mCi, where second post-ablative scan did not show evidence of known recurrent FTC in the neck and the new metastatic lesions in bones.
As preparations were made for radiation to the spine and new symptoms of hip pain arose, imaging revealed rapid progression of disease in neck, chest, and hip. Biopsy of several metastatic sites confirmed FTC. After receiving radiation to neck and hip, given her minimal cormorbidities, it was decided to initiate lenvatinib, at a reduced dose of 14 mg. To date, she has remained on treatment (lenvatinib and denosumab) for 5 months, with AEs (hypertension, dry mouth, dysguesia, dysphagia, and fatigue) closely monitored and addressed. Her disease has remained stable and her unstimulated Tg has dropped from her peak at 258 (462 stimulated) to 19. While she has returned to most of her daily activities, her greatest limitation is mild fatigue and weight loss due to dysphagia. In the era of personalized medicine, targeted therapies (TTs) need to be more closely studied in the geriatric population, where the incidence of AdvTC is higher. Reduced dose can provide better tolerance and the same efficacy of KI's in elderly. With disciplined monitoring, these drugs are a major step forward in the safe and effective treatment of select geriatric cancer patients.
Thyroid Cancer Saturday Poster Case Report
Metastases to the thyroid gland from a non-thyroid primary is not usual, and rarely from breast. We report a case of Metastases to the thyroid gland and bilateral cervical lymph nodes. We discuss the diagnosis, management and surveillance. A 47-year-old-woman presented ten years ago with a history of Brest Infiltrating Ductal Carcinoma with invasive component (HER2 negative, estrogen and progesterone receptor positive) and axillary lymph nodes positive. Postoperatively, the patient underwent chemotherapy, radiotherapy and hormonotherapy. Two years ago she presented bilateral cervical lymphadenopathy and thyroid nodule; FNA biopsy: Brest Carcinoma Metastases; she was started on chemotherapy and radiotherapy. She presented poor response, so we decided to perform Total Thyroidectomy+Bilateral Neck Dissection. Then, she underwent only chemotherapy. Thyroid is rarely the site for metastatic deposits. In this case, negativity of TTF-1 and thyroglobulin and positivity of CK7 of thyroid and cervical lymph nodes tumour cells was helpful to do the diagnosis. There is still a doubt about the extent in thyroid surgery because of the complications after total thyroidectomy; there is no data that determinate the importance of the lymph node dissection. We performed Total Thyroidectomy and Bilateral Neck Dissection; and as adjuvant treatment, our patient received Chemotherapy with good outcome. In a patient with a previous breast carcinoma history, the appearance of a cervical mass (thyroid and lymph nodes) should be regarded as potentially matastatic. Also, metastatic malignancies therapy is often considered to be palliative, aggressive surgical treatment in some cases may be curative and increase survival.
Thyroid Cancer Saturday Poster Case Report
Multiple endocrine neoplasia is a rare autosomal dominant syndrome, with estimated 1/30,000 people. Patients with MEN2a may have medullary thyroid cancer, unilateral or bilateral pheochromocytoma and hyperparathyroidism. A 27 yo AAM who presented to the ENT due to enlarging neck mass. An ultrasound of the thyroid showed a 3.7 cm solid with cystic component and partially calcified mass. Patient underwent FNA, and later that day developed hypertensive crisis, hypoxic respiratory failure requiring intubation, rhabdomyolysis and associated acute congestive heart failure with EF of 10-15% and renal failure requiring dialysis. His urine normetanephrine were positive, and his initial calcitonin level was 11420. He also had elevated PTH of 166 with normal calcium. With a confirmatory CT abdomen showing bilateral adrenal masses patient underwent bilateral adrenalectomy and later thyroidectomy with partial parathyroidectomy and neck lymph node resection. Genetic testing confirmed the RET pro-oncogene mutation. The patient died from metastatic medullary thyroid cancer to spine, trachea, lungs and spine 11 years later.
Patient mother had a history of pheochromocytoma in her 30's with a total right adrenalectomy and partial left adrenalectomy performed. She was 50 years old at the time of her son's diagnosis and underwent screening for MTC. An US of the neck showed a 1.9 cm left and 1.1 cm right nodules and calcitonin level of 1680. She underwent total thyroidectomy which confirmed MTC with lymph node involvement, after which she had recurrent disease requiring further neck dissection and EBRT to neck and mediastinum, with incomplete response, and further recurrent disease. About 98-100% of patients with MEN2a mutation develop MTC, and about 50% develop pheochromocytoma. Patients with pheochromocytoma could develop severe crisis with a minor procedure. Family history is important to be aware of this potential outcome.
Thyroid Cancer Saturday Poster Case Report
Female patient was diagnosed thyroid cancer (papilar microcarcinoma in left lobe). Thyrodectomy was done ande radioiodine ablation not performed.
After one month, cancer on left breast was diagnosed. Surgery, radioterapy and chemotherapy were done. Tamoxifeno was used for several years.
in 2017, she showed a small alteration on thyroglobulin levels. However the TSH was not suppressed.
Neck ultrasound requested, it showed suspicious lynphonodes.
Biopsy showed suspicion of breast cancer and negative thyroglobulin. A female patient, 63 years old, with thyroid and breast cancer, both in the left side, during a control cervical ultrasound, suspicioua lynphonodes in level 4 was found. Biopsy showed of breast cancer and negative thyroglobulin. In surgery, the lynphonodes were removed and breast cancer was confirmed.
PET-CT showed multiples lesions that suggested secondary implants.
Pacient have gone through evaluation for breast cancer,6 months before, which showed no alteration.
Level 4 of the cervical region is not usual place of breast cancer metastasis.
The thyroglobulin dosage in the aspirate can help in differencial diagnosis and the removal of the lymphonodes was essential for de definitive diagnosisThere is a correlation between thyroid and breast cancer. We need to be attetive to the cancer control exams, especially the ultrasound, which as in this case showed a metastasis of breast cancer an unusual place.
Thyroid Cancer Saturday Poster Case Report
Multiple endocrine neoplasia type 2 syndrome (MEN2) is an autosomal dominant disorder caused by germline mutations of RET proto-oncogene. It is divided according to clinical presentation in MEN2A and MEN2B (5% of cases). MEN2B is the most aggressive form characterized by medullar thyroid carcinoma (MTC), pheochromocytoma, gastrointestinal ganglioneuromatosis and marfanoid body habitus. Achalasia and megaesophagus due to ganglioneuromatosis has been rarely associated with MEN2B. A 32-year-old male with mucosal neuromas, prominent lips, chronic constipation and dysphagia for solids and liquids was referred to the department of endocrinology for a thyroid nodule investigation. Evaluation revealed MTC and pheochromocytoma and he was submitted to adrenalectomy and subsequently total thyroidectomy with bilateral neck dissection. Genetic analysis revealed a M918T RET germline mutation. Evaluation of dysphagia included sorology for Chagas disease which was negative and imaging studies such as barium esophagram, esophageal manometry, and upper/lower endoscopy which revealed a dilated esophagus with delayed emptying, aperistalsis of the entire esophageal body, incomplete lower esophageal sphincter relaxation; findings consistent with megaesophagus and achalasia. In addition, patient had significant megacolon with constipation. Despite repeat esophageal dilations, patient remained with symptoms which were likely responsible for poor tolerance and response to tyrosine kinase inhibitor therapy resulting in early death from metastatic disease. Alimentary-tract ganglioneuromatosis is a major component of MEN2B and up to 65% of patients present with megacolon. Esophageal manifestations due to megaesophagus and achalasia has been rarely reported, however asymptomatic or mildly symptomatic ganglioneuromatosis of the esophagus may be more frequent. Despite less frequent than megacolon, megaesophagus and achalasia can be observed in MEN2B. Awareness of this condition could lead to earlier diagnosis and treatment avoiding significant morbidity.
Thyroid Cancer Saturday Poster Case Report
Anaplastic Thyroid Cancer (ATC) is a rare and aggressive tumor with a median survival of 3 to 9 months. In patients with BRAF-mutated ATC new targeted therapy using a combination of a BRAF inhibitor with a Mitogen-activated Protein Kinase inhibitor has recently shown promise. A 69 year old male presented with two month history of a rapidly enlarging right anterior neck mass with worsening dysphagia and dyspnea. US showed a 3.5 cm anterior amorphous neck mass contiguous with the right lobe of the thyroid. CT scan and FDG-PET confirmed metastases to the lungs, mediastinum and musculoskeletal system. FNA showed a poorly differentiated carcinoma of uncertain origin.
He underwent an extensive local neck dissection with anterior chest flap. Histopathology showed 60% poorly differentiated thyroid carcinoma that stained positive for TTF-1 and thyroglobulin. Next-Generation Sequencing Genetic analysis revealed 5 sequence mutations: BRAF V600E (34%), TERT (37%), RET (55%), CDK4 (48%) and EZH2 (60%).
Given the rapid tumor progression, he was started on oral Dabrafenib (Dab) 150mg bid, Trametinib (Tram) 2 mg daily, and dexamethasone 8mg daily. CT scan 1 month later showed significant interval reduction and/or resolution of several lung nodules, near total resolution of bilateral basal lung consolidations, reduction in size of multiple mediastinal, hepatic & splenic lesions (partial response by RECIST criteria with >30% reduction in target lesions). Two months after initiating therapy, he is pain free, active, off oxygen support, gaining weight. He has no diarrhea but reports short lived drug induced fevers. The combination of Dab/Tram is a novel therapeutic approach to ATC. Subbiah et al (J Clin Oncol 36(1):7-13. 2018) have reported a positive response rate of 69% in 16 anaplastic thyroid cancer patients with this combination. Sequence mutation of TERT reportedly occurs in 47% of ATC and is associated with poorer prognosis, distant metastasis and decreased survival. RET mutation is rare in ATC. CDK4 and EZH2, have not previously been reported in ATC, but have been seen in lymphoma & breast cancer. Further research is required to determine the role of disease progression for each of the mutations found in this patient.
Thyroid Cancer Saturday Poster Case Report
We present the case of a 67-year-old woman who came to the surgical oncology clinic for evaluation of a rapidly growing mass in the neck. The patient was originally diagnosed with a thyroid mass 6 years prior, followed with serial clinical exams. Over two months she experienced rapid growth of the neck mass, shortness of breath, dysphagia to solids, odynophagia and stridor. She could no longer walk across a room without significant limitation and was unable to breathe during a conversation. On assessment, oxygen saturation was 95% on room air. Neck exam revealed a firm, non-mobile but tender thyroid mass without palpable lymphadenopathy. Imaging revealed a multinodular goiter with invasion into the upper trachea and laryngeal cartilages. Laryngoscopy revealed a fungating mass obstructing the trachea in 90% of its circumference. Further treatment included tumor debulking for control of the airway and tracheal stenting. After pathology provided the diagnosis of a primary squamous cell carcinoma (SCC) of the thyroid gland a metastatic workup was completed. Additional imaging revealed no metastatic disease. Definitive surgical therapy with a stent removal, total thyroidectomy, total laryngectomy and bilateral selective neck dissections with flap reconstruction was performed from which patient recovered well. Primary squamous cell carcinoma of the thyroid is a rare thyroid neoplasm. It represents less than 1% of all primary carcinomas of the thyroid gland and it is associated with a very poor prognosis, with a behavior like that of anaplastic carcinoma where the median survival is less than 6 months. Its prompt recognition is crucial, since an R0 resection is critical and a more aggressive surgical resection compared to anaplastic thyroid cancer is reasonable. Optimal management includes surgical excision with adjuvant radiation and chemotherapy, however, studies suggest that this tumor tends to be resistant to radiation and have a poor response to chemotherapy, emphasizing the importance of attempting to achieve an R0 resection.
Thyroid Cancer Saturday Poster Case Report
New Ga68 DOTATATE PET scans are now used in patients with neuroendocrine tumors, but they have also been reported to be effective in patients with other tumors richin somatostatin receptors such as medullary thyroid cancer. These scans can be used to detect evidence of metastatic disease when usual imaging modalities like CT and octreotide scans are either unable to detect or underestimate tumor burden. Here we present a case of metastatic medullary thyroid cancer with rising calcitonin levels where DOTATATE PET was successful in identifying recurrent disease. 60 year male with medullary thyroid cancer presented for evaluation of rising calcitonin levels. He had completion thyroidectomy and central and lateral lymph node dissection but surveillance labs revealed rising calcitonin levels (130>>563) over 3 years. Conventional FDG-PET, chest, abdomen, and pelvic CT, liver MR, and octreotide scan did not reveal evidence of disease. His calcitonin levels rose further (563 > 906), and a DOTATATE PET was performed which accurately localized the disease within the superior mediastinum. He remains asymptomatic and is currently under close surveillance with plans to consider systemic therapy if the disease progresses further. DOTATATE PET has much higher sensitivity than conventional CTor octreotide scans to detect tumor burden and localize metastatic disease. This allows for better planning for surgery. It also lays the foundation to newer targeted therapies like peptide receptor radionuclide therapy (PRRT) for treatment of neuroendocrine tumors. While Lutathera is approved for treating gastrointestinal neuroendocrine tumors, clinical trials are being conducted for evaluation of PRRT for other cancers such as medullary thyroid cancer. DOTATATE PET can be used for staging and localization of tumors expressing somatostatin receptors. It might also be helpful in therapy if somatostatin receptor density and distribution can be used to guide suitability ofsomatostatin therapy or PRRT in the future. It can also be extremely beneficial in restaging after response to therapy and detecting suspected disease recurrence post-surgery as in our case.
Thyroid Cancer Saturday Poster Case Report
Thyroglossal duct remnants might represent a cyst, duct or an ectopic thyroid. They occur along the path of thyroid descent and lie close to the hyoid bone.TDR carcinomas are rare, with 274 reported and a prevalence of less than 1% in surgically removed thyroglossal duct cysts. A 29-year-old female, presented with a nontender neck mass without dysphagia. Neck CT and US findings were confirmed on MRI showing a lobulated, multiloculated lesion involving the sublingual and submandibular space with 2 components:1 midline, below the foramen cecum, extending anteriorly to the hyoid bone. The anterior aspect of this component was cystic and measured 1.6 × 2.2 × 2.2cm with the posterior aspect measuring 1.3 × 1.0 × 1.1cm;The 2nd lesion (2.6 × 3.6 × 2.7 cm), in the right of midline with a lateral extension to the right submandibular gland resulting in obstruction of the adjacent SMG duct. An US-guided FNA was non-diagnostic. The patient underwent surgical resection of the tumor with hyoid myotomy. The pathology report showed a metastatic 1.5 cm PTC, classical type, arising in a thyroglossal duct cyst, with lymphovascular and hyoid bone invasion,1 positive lymph node with a metastatic deposit of 0.2 cm. A total thyroidectomy with limited neck dissection was also completed and no malignancy was found in the thyroid. 27 mCi I-131 were given and 10-day post-therapy scan demonstrated localization of I-131 to the tongue base/preepiglottic fat and along the right aryepiglottic fold. TDC although rare are usually papillary types and <5% are of squamous cell origin. They could arise as primary cancers in small remnants of ectopic thyroid tissue in the duct or as metastases from primary cancers in the thyroid gland. A microscopic focus of papillary carcinoma, without cyst wall invasion, might be managed with a Sistrunk procedure. TGD papillary carcinomas with hyoid bone or lymphovascular invasion should undergo TGD removal and total thyroidectomy followed by RAI treatment. Follow up thereafter has not been standardized. The diagnosis of TDR carcinoma can be missed due to its rarity. In the current case, atypical findings on the MRI suggested the need for surgical intervention. After surgery, individualized management is based on risk stratification.
Thyroid Cancer Saturday Poster Case Report
Distant metastases occur in 10-15 percent of patients with follicular thyroid cancer (FTC), with bone and lung metastases being the most common. It is unusual for FTC to solely present with vertebral metastasis. We are reporting a case of FTC presenting with T8 vertebral metastasis in a patient with remote history of total thyroidectomy for a benign goiter. To our knowledge, this is the first case report of such a presentation in a patient who had total thyroidectomy with reported benign surgical thyroid pathology.73 year old woman has past history of non-toxic multi-nodular goiter diagnosed at age 58. Fine needle aspiration of one of the thyroid nodules was consistent with follicular neoplasm. Thus, total thyroidectomy was performed at that time. However, surgical pathology came back consistent with multi-nodular colloid goiter with no evidence of malignancy. Most recently, the patient has been experiencing progressive back pain for approximately six months. MRI of the thoracic spine showed a solitary left-sided T8 vertebral body lesion highly concerning for malignancy. CT-guided biopsy of the vertebral mass was consistent with metastatic thyroid carcinoma, with morphology consistent with FTC. Neck ultrasound showed no residual thyroid tissue and no lymph node enlargement. PET scan and I-131 whole body scan confirmed T8 vertebral metastasis with no evidence of other metastases. The patient was treated initially with radiation therapy followed by radioactive iodine ablation and months later with anterior trans-thoracic corpectomy of T8 vertebra to protect the spinal cord. Almost a year after her initial diagnosis, she is without clinical progression of her cancer, and there is excellent biochemical response with progressive reduction of her thyroglobulin level from 414 ng/mL to 45 ng/mLDistant metastasis without history of diagnosed thyroid cancer is rare. We present an extremely rare and possibly first case report of metastatic thyroid cancer diagnosed over a decade after total thyroidectomy without any malignant thyroid pathology at time of thyroidectomy. Interventions to treat such rare presentations could be variable and dependent on goal of care and the risk of damage to surrounding organs.
Thyroid Cancer Saturday Poster Case Report
We present a case of unusual pathology of a lung mass in a patient with papillary thyroid cancer. A 77-year-old male smoker had a PET/CT for enlarging left lower lobe (LLL) pulmonary mass on screening CT scans, which showed hypermetabolic activity in the left thyroid lobe, the LLL of lung, the left hilum and a subcarinal lymph node (LN). Biopsy of the thyroid nodule revealed papillary thyroid cancer and biopsy of the subcarinal LN demonstrated carcinoma that stained positive for thyroglobulin (Tg). Total thyroidectomy showed a 2 cm encapsulated, multifocal, papillary thyroid cancer, follicular variant, with uninvolved margins. No tumor was detected by the endocrine surgeon in the cervical LN's or soft tissue.
One-month post-thyroidectomy, thyroid cancer monitoring labs demonstrated Tg level of less than 0.4 ng/mL (ref <0.4) with low titer Tg antibody. Because of the undetectable Tg level, a biopsy of the LLL lung lesion was obtained and revealed malignant cells with cytoplasmic mucin and signet ring features, which stained positive for Tg and PAX-8. Morphologic features were similar to the subcarinal LN malignant cells and dissimilar to the papillary thyroid cancer tissue. Radioactive iodine was pursued and post-treatment scan demonstrated uptake in the thyroid bed with lack of uptake in the subcarinal region, left hilum, or LLL lung lesion. The clinical possibilities of this case fall into one of two rare possibilities: 1) an aggressive thyroid cancer metastatic to the lung with morphological features of adenocarcinoma or 2) two primary cancers (thyroid and lung) with a lung adenocarcinoma that stains with Tg and PAX-8, immuno-histological stains normally specific for thyroid. The latter possibility is favored for several reasons: it would be unusual for a papillary thyroid cancer to involve the mediastinum and lung without cervical soft tissue and lymph node involvement, to have undetectable Tg despite bulky disease, and to have a negative post-radioiodine treatment scan. Furthermore, the smoking history and the pathology findings consistent with adenocarcinoma favor the diagnosis of a primary lung cancer. The etiology of the lung mass remains perplexing and is probably a case of two primary malignancies.
Thyroid Cancer Saturday Poster Case Report
Papillary thyroid cancer (PTC) with nodular fasciitis or fibromatosis-like stroma is a rare morphologic variant of papillary carcinoma, with fewer than 30 cases reported in the literature. Here we report a case of PTC with nodular fasciitis presenting as a benign-appearing thyroid nodule in an asymptomatic, clinically euthyroid 20-year-old male. A 20-year-old male was found to have a left-sided thyroid nodule on physical examination. He was clinically euthyroid and denied any local compressive symptoms. Physical examination revealed a firm, non-tender left-sided thyroid nodule without palpable lymphadenopathy. Neck ultrasound demonstrated a solid 3.2x1.9x2.7cm hypoechoic, heterogeneous nodule in the left upper pole without microcalcifications or increased internal vascularity. Fine needle aspiration (FNA) was consistent with benign granulomatous inflammation. Surveillance imaging was recommended, and follow-up ultrasound at six months revealed that the nodule had grown to 3.9cm in largest dimension. Therefore, the patient was referred to endocrine surgery for surgical consideration. Repeat FNA showed atypia and a spindle cell neoplasm could not be excluded. Given the possibility of malignancy, a left hemithyroidectomy was performed. Pathology demonstrated a papillary thyroid carcinoma (PTC) with fibromatosis-like stroma, also known as nodular fasciitis-like stroma of the thyroid gland. The PTC comprised less than 10% of the tumor without extra-thyroidal extension, while the fibromatosis-like stroma made up the bulk of the tumor and extended outside the thyroid gland into adjacent muscle. The stromal component showed rare mitotic figures (<1 per 10hpf), aberrant ß-catenin nuclear staining, and negative immunostain for BRAF V600E. The patient subsequently underwent a completion thyroidectomy and had an uneventful postoperative recovery. Papillary thyroid carcinoma with nodular fasciitis is a rare histologic finding and may present in the setting of clinical euthyroidism with a benign-appearing fibrous thyroid nodule. The mechanism for this post-inflammatory fibrous reaction is unknown, as are demographic risk factors and long-term prognosis for this histologic subtype.
Thyroid Cancer Saturday Poster Case Report
While the association between pheochromocytoma and medullary thyroid cancer is well documented in multiple endocrine neoplasia type 2, concomitant metastatic papillary thyroid carcinoma and pheochromocytoma is rare. We present a case of a 58 year old male who was found to have an incidental pulmonary nodule on CT angiogram with follow up CT chest further revealing nodules in the right adrenal and left thyroid glands. PET-CT were notable for FDG avidity in all three nodules. Biopsies of adrenal and thyroid nodules revealed pheochromocytoma and tall cell variant papillary thyroid carcinoma respectively. The patient subsequently underwent resection of the pheochromocytoma followed by total thyroidectomy with molecular testing showing BRAF and TERT promoter mutations. Resection of lung lesion was positive for metastatic papillary thyroid carcinoma. A definite genetic cause had not yet been elucidated between pheochromocytoma and papillary thyroid carcinoma. There are some case reports of patients with succinate dehydrogenase subunit D (SDHD) or succinate dehydrogenase subunit B (SDHB) mutations that develop both pheochromocytoma and papillary thyroid cancer1. However, additional case reports hypothesize a sporadic association, including a report of a 42 year-old woman with bilateral pheochromocytoma, paraganglioma, and papillary thyroid carcinoma who was negative for RET proto-oncogene mutation, von Hippel Lindau mutation, SDHB and SDHD mutations3. This case highlights the rare association between pheochromocytoma and metastatic papillary thyroid carcinoma as well as underscores the need for further classification a possible genetic association between the diseases.
Thyroid Cancer Saturday Poster Case Report
Papillary Thyroid cancer has been associated with lymphoma and leukemia. Polycythemia Vera is a Myeloproliferative Neoplasm characterized by proliferation of myeloid cells and involving the JAK 2 mutation and increasing awareness of familial inheritance patterns. We present an interesting case that brings to light a possible association between Polycythemia Vera and Papillary Thyroid Cancer. 36 year-old female with no significant past medical history who was found to have right thyroid nodule measuring 1.4 × 1.2 × 1.3 cm, hypoechoic, with calcifications, regular borders, doppler flow II. Fine needle biopsy reported Bethesda IV. She was referred for thyroidectomy. During pre-operative workup, patient was found to have erythrocytosis, leukocytosis and severe thrombocytosis. Patient had no history of malignancies, no risk factors for secondary erythrocytosis Bone marrow biopsy revealed panmyelosis of all cell lines, megakaryocytic atypia, and low erythropoietin levels, as well a confirmed JAK 2 mutation, all supporting the diagnosis of Polycythemia Vera. Patient underwent total thyroidectomy pathology revealed papillary thyroid carcinoma, follicular type. The idea of Papillary Thyroid Cancer being linked to specific mutations in RET/PTC, NTRK1, RAS, BRAF and MEN, encourages the idea of PTC being associated with other oncologic diseases. BRAFV600E mutation, implicated in Papillary Thyroid Cancer, might be playing a role in Myeloproliferative Neoplasms. In addition the locus of the RET protoncogene rearranged in papillary thyroid cancer, has been shown to be located near the predisposition site of MEN- 2. Research suggests some of the inheritable genetic mutations involved in Pheochromocytoma-Paraganglioma syndrome, are part of a common pathway shared by hypoxia-inducible factors. The possibility of hypoxia being a potential factor in the development of this MEN 2 related Neoplasia directs attention towards the implication of hypoxia in Papillary Thyroid Cancer and Polycythemia Vera. This case draws attention to two seemingly unrelated malignancies and warrants further investigation into the genetic link connecting these two diseases.
Thyroid Cancer Saturday Poster Case Report
Poorly differentiated thyroid carcinoma (PDTC) has unique histologic architecture between well differentiated thyroid carcinoma (WDTC) and anaplastic thyroid carcinoma (ATD). It was previously classified as a WDTC variant until recognized as distinct entity in 2004. It is rare with an incidence of 0.23% to 2.6% that varies with geography; extra thyroidal extension in 30% to 59%; distant metastasis in 13% to 33% and 5-year mortality rate of 60-83%. 64-year-old female with past medical history of Left thyroid lobectomy in 2009 with pathology showing WDT of uncertain malignant potential, gastric bypass, protein C deficiency presented after being found on the floor by neighbor. Patient was not able to use her lower extremities with difficulty walking for the past several weeks. On exam patient had a 0/5 strength and positive Babinski sign in bilateral lower extremities. CT cervical spine showed a 2.1 cm R thyroid nodule and neck ultrasound confirmed the finding. CT thoracic/lumbar spine showed mass at T10 with pathologic fracture extending into the posterior spine with chord compression. STAT MRI demonstrated a compression at T10 and scattered metastatic disease. Patient underwent emergent surgery and surgical pathology showed a metastatic malignancy consistent with metastatic poorly differentiated carcinoma of the thyroid. The immunohistochemistry staining supported the diagnoses of poorly differentiated carcinoma of the thyroid. Surgery and radiation oncology were consulted with the plan for completion thyroidectomy and subsequent radiation. However, patient refused procedure and was discharged to acute care rehab with plan to follow up and have the thyroidectomy outpatient. A few weeks later patient was readmitted to hospital for acute GI bleed and later expired from severe sepsis and organ failure. A missed opportunity in this case was back in 2009 at the time of the left lobectomy. The pathology at the time was descriptive of PDTC and if completion thyroidectomy were done the outcome may have been different. Because of its rarity and aggressiveness, knowledge regarding the optimal management of PDTC remains limited. That is why it is important to continue to learn to better address this in the future.
Thyroid Hormone Action Saturday Poster Basic
The incidence of breast cancer (BC) has increased alarmingly in recent years. Several studies have been lead to the discovery of amphiregulin (AREG) as an oncogene, with its expression related to various cancer types. Our group showed the action of T3 on different genes in BC cells using microarray, but the mechanism which T3 regulates the expression of these genes and the involvement of ER have not been evaluated yet. The relationship between the expression of AREG and the presence of TH remains unknown, therefore, the aim of this study was to verify the nuclear and extra-nuclear action of T3 on AREG gene expression in breast adenocarcinoma cell lines, MCF-7 and MDA-MB-231. The cell lines were subjected to treatment with 10-8M T3 at the times 10', 30', 1h and 4h in the presence or the absence of Fulvestrant (ICI 182,780) - ER inhibitor, Actinomycin D (ACTD) - inhibitor of gene expression and cycloheximide (CHX) - inhibitor of protein synthesis. The AREG mRNA levels were analyzed by RT-PCR. For data analysis we used ANOVA followed by the post hoc Tukey's test with a significance level of 5%.T3 increased AREG gene expression levels, compared to the control group in both cell lines, regardless of the incubation times. Our study confirms that AREG gene expression is increased in the presence of T3 in both cell lines and at all the times studied. The data from this study indicate that T3 might act through ER, decreasing AREG expression after 30' treatment in MCF-7 cells and did not alter the expression of this gene in MDA-MB-231 cells, which lack ER. Furthermore, we suggest that T3actionon AREG gene expression occurs indirectly. The T3 maintains AREG expression even after the inhibition of transcription. Considering the above, this study demonstrates the potential effect of oncogene by means of T3 actions. Knowledge of the molecular bases of hormonal action will allow the development of more specific and targeted drugs in the control of neoplasias and several other diseases related to extranuclear actions that may be associated with thyroid dysfunctions.
Thyroid Hormone Action Saturday Poster Basic
Fatigue decreases quality of life in many diseases and disorders, yet there is a lack of FDA-approved drugs to treat fatigue. We have previously shown that a thyrotropin-releasing hormone (TRH) analog, taltirelin (TAL), alleviates fatigue-like behavior in preclinical models of cancer-related fatigue via TRH receptor activation. However, it is unknown whether TRH receptor activation alleviates other undertreated forms of fatigue, such as immunologically-induced fatigue. This study aimed to determine if TAL could alleviate fatigue in a mouse model of immunologically-induced fatigue. The immunostimulant, polyinosinic-polycytidylic acid (poly I:C), was injected (12 mg/kg, i.p.) to induce fatigue in mice. Two behavioral assays were used to measure fatigue—voluntary wheel running activity (VWRA) and the treadmill fatigue test (TFT). VWRA allows for a longitudinal measurement to determine the duration and intensity of fatigue-like behavior. In contrast, the TFT is a superior assay for assessing the efficacy of fatigue interventions, but can only do so at a select time point. Thus, mice received PBS or poly I:C and VWRA was used to verify that fatigue was induced and select an appropriate time point for a separate TFT experiment, in which mice received poly I:C as well as PBS or TAL (1 mg/kg, i.p.). Poly I:C significantly decreased VWRA during the first dark phase after administration (mean±SEM counts, PBS: 32768 ± 4006; poly I:C: 16111 ± 1431; p < .01), indicating fatigue. Further analysis showed fatigue was primarily present during the first 4 h bin of the dark phase (PBS: 11907 ± 1409; poly I:C: 1677 ± 869, p < .001), but not the second (PBS: 10923 ± 1801; poly I:C: 7152 ± 935; p = .09) or final (PBS: 7021 ± 1686; poly I:C: 5448 ± 1022; p = .44) 4 h bin. Thus, the TFT was conducted 3 h after poly I:C to ensure fatigue was present and PBS or TAL injected 30 min prior to TFT. TAL significantly increased the distance run by poly I:C-treated mice (distance [m]: poly I:C+PBS: 34.5 ± 14.8; poly I:C+TAL: 366.8 ± 109, p < .05), indicating a reversal of fatigue-like behavior. This study expands upon our prior findings in cancer-related fatigue models and provides evidence that TAL may be of therapeutic value in immunologically-induced fatigue.
Thyroid Hormone Action Saturday Poster Case Report
Thyroid storm is a rare metabolic crisis that is associated with significant mortality. Standard therapy consists of thionamides, glucocorticoids, and nonselective beta blockers. Second line agents includes lithium, cholestyramine, and potassium iodide. Therapeutic plasma exchange is suggested when there is a failure of conventional treatments for thyroid storm of any etiology. The efficacy of therapeutic plasma exchange is not clearly studied and currently there is no consensus available on the exact percent reduction of Free Thyroxine (FT4) that can be anticipated with each session of plasma exchange. This case illustrates the extraction kinetics of FT4 with each session and over time.
We report a case of a 66 year old Caucasian female with past medical history of Graves' disease in remission, recurrent hospital admissions for atrial fibrillation, and recent initiation of amiodarone, who presented with heart failure exacerbation and thyroid storm. She was started on methimazole but experienced acute pancytopenia and so the medication was discontinued. Therapies including glucocorticoids, lithium and cholestyramine were initiated but without clinical or biochemical improvement. Therapeutic plasma exchange was chosen as bridging therapy to thyroidectomy for definitive treatment.
Patient underwent 4 sessions of plasma exchange. FT4 measurement before and 2 hours post plasma exchange showed approximately 15–33% reduction with each session. However, FT4 rose again prior to the next day of therapy but not to pre plasma exchange levels. In spite of the rise between therapies, each treatment resulted in progressive decline in the overall FT4. Cumulatively, after 4 sessions, there was a 54% reduction in FT4 levels. When primary synthesis of thyroid hormone is not interrupted because of intolerance to antithyroid medication, FT4 rises following each session of plasma exchange. This trend describes the extraction efficacy of FT4. This will need to be evaluated in patients who are on antithyroid medications to see if the trend is similar.
Thyroid Hormone Metabolism & Regulation Saturday Poster Basic
We previously showed that TSH receptor (TSHR)/IGF-1 receptor (IGF-1R) cross-talk is involved in TSHR-stimulating antibody (TSAb) induction of hyaluronan secretion by Graves' orbital fibroblasts and upregulation of thyroid-specific genes in human thyrocytes in vitro. In this study, we sought to determine whether TSHR/IGF-1R cross-talk occurs in U2OS-TSHR cells, human osteoblast-like cells made to overexpress TSHRs, and whether β-arrestin-1 may be involved in cross-talk since we previously demonstrated that β-arrestin-1 was important for TSH-induced upregulation of osteoblast markers.
Stimulation of osteopontin (OPN) production in response to TSH alone or in combination with IGF1 or linsitinib was measured in U2OS-TSHR cell culture media after 7 days. siRNA-mediated gene silencing was used to knockdown IGF-1R and β-arrestin-1. U2OS cells expressing HA-tagged TSHRs were utilized in co-immunoprecipitation experiments in membrane lysates.
IGF-1 robustly potentiated TSH-mediated OPN upregulation (5-fold) and linsitinib, an inhibitor of IGF-1R signaling, inhibited the effect of TSH alone by 44%. The suppression of IGF-1R or β-arrestin-1 levels by siRNAs increased TSH-stimulated cAMP production whereas the decreases in IGF-1R or β-arrestin-1 levels inhibited TSH-stimulated OPN production. These findings are consistent with the idea that both IGF-1R and β-arrestin-1 are involved in TSHR/IGF-1R cross-talk. Both IGF-1R and β-arrestin-1 co-immunoprecipitated with TSHR in U2OS-HA-TSHR cells, demonstrating that TSHR, IGF-1R, and β-arrestin-1 are proximal to each other in these cells, that is, may be part of the same signaling complex.
In conclusion, we demonstrated that cross-talk between TSHR and IGF-1R occurs in U2OS-TSHR cells and we found that this phenomenon may occur within a signaling complex in which TSHR, IGF-1R, and β-arrestin-1 are present.
Thyroid Hormone Metabolism & Regulation Saturday Poster Basic
De novo T3 hormonogenesis requires iodination of Tyr residues and coupling of monoiodo- and diiodo-Tyr within Thyroglobulin (TG) - a 330kDa secretory glycoprotein comprising 4 structural regions including the C-terminal Cholinesterase-Like Domain (ChEL D).
Hyperactivation of thyroidal TSH receptors (TSHRs) favor increased de novo T3 formation in TG which is believed secondary to other TG post-translational modifications such as its phosphorylation. Upon TSHR hyperactivation, Fam20C (a secretory serine kinase) is upregulated, accompanied by increased T3 formation. Conversely, suppression of Fam20C decreases de novo T3 synthesis. Interestingly, a phospho-Ser present in hTG occurs at a canonical Fam20C phosphorylation site (equivalent to position S2718 in mTG). We hypothesize that Fam20C-mediated S2718 phosphorylation triggers increased T3 formation in mTG. To analyze the presence of phosphate in the ChEL D, we utilized calf intestinal phosphatase followed by immunoblotting with anti-TG Ab. To study the effects on T3 formation upon disruption of mTG-S2718 and the restitution of the mTG 2718 phospho-environment we bioengineered mTG-S2718A and mTG-S2718E, respectively. We co-expressed the TGs +/- Fam20C, +/- Fam20C inhibitor FL-1607, performed enzymatic iodinations of the secreted TGs, and monitored de novo T3 formation by immunoblotting with mAb anti-T3 and anti-TG Ab. Dephosphorylation of the isolated ChEL D shifts its SDS-PAGE migration and, as we reported, dephosphorylation decreases de novo T3 formation in TG. Co-expression of WT mTG and Fam 20C promoted T3 formation in TG and this effect was blocked by Fam 20C inhibitor FL-1607. Further, disruption of the established phosphorylation site mTG-S2718A blocked Fam 20C-stimulated T3 formation, and this effect was reverted in the phosphomimetic mutant mTG-S2718E. Our data supports the hypothesis that de novo T3 formation in TG is stimulated by Fam 20C-mediated phosphorylation of mTG-S2718.
Since Fam 20C levels are increased in states of TSHR hyperactivation, Fam 20C-induced de novo T3 formation may be a contributor to the increased T3 found in hyperstimulated thyroid glands such as occurs in autoimmune hyperthyroidism of Graves' disease.
Thyroid Hormone Metabolism & Regulation Saturday Poster Clinical
Patients often report weight gain after thyroid surgery, and many express significant concern about this possibility pre-operatively. Patients with thyroid nodular disease frequently have a choice between a thyroid lobectomy (TL) and a total thyroidectomy (TT). The purpose of this study was to determine if there is a difference in postoperative weight changes among patients undergoing either a TL or TT for benign disease, and to investigate if postoperative thyroid stimulating hormone (TSH) changes correlated with weight changes. We conducted a retrospective review of 205 patients who underwent TL (116) or TT (89) for benign disease from January 2015 to December 2016. Six week postoperative TSH changes and 1-year postoperative weight changes were recorded. Patients were classified as either euthyroid (TSH in the normal range) or non-euthyroid (TSH above or below normal) at 6-weeks postoperatively. Group mean weight changes were compared using the unpaired student's t-test, and Pearson's correlation coefficient tested the association between TSH and weight changes. Overall, patients gained an average of 4.2 ± 0.83 lbs in the first year after either type of thyroid surgery, while 37.6% of patients gained >5 lbs. Weight gain was higher in patients undergoing a TT vs. TL (5.6 ± 1.52 vs. 3.2 ± 0.89, p = 0.167), but this was not statistically significant. Patients that achieved or maintained a euthyroid status at 6 weeks had less weight gain than those non-euthyroid at 1 year after a TL (2.3 ± 0.93 lbs vs. 7.0 ± 2.32 lbs, p = 0.069), but that difference was not seen after a TT (4.8 ± 2.33 vs. 6.3 ± 2.03 lbs, p = 0.634). There was no correlation between change in TSH shortly postoperatively and 1-year postoperative weight changes for either TL (r = -0.05) or TT (r = 0.13).
Weight changes are common after thyroidectomy. Weight gain was lowest in patients undergoing a thyroid lobectomy who are able to maintain a euthyroid status at 6 weeks. Unfortunately for patients undergoing a total thyroidectomy, achieving a euthyroid state shortly after surgery post-operatively did not impact total weight gain at one year.
Thyroid Cancer Saturday Poster Clinical
The internet is a key source of health information and aids patients' treatment decisions. We examined the quality, readability, and content of websites about thyroid cancer treatment options and references to the 2015 American Thyroid Association (ATA) Guidelines. We identified the top 60 websites by searching Google, Bing, and Yahoo for “thyroid cancer.” We examined website quality using three well-validated measures: DISCERN; Journal of the American Medical Association (JAMA) benchmark criteria; and Health-on-Net Foundation Certification (HONcode). We evaluated readability with the Suitability Assessment of Materials (SAM) method. To assess website content, a board of 16 thyroid cancer patients, surgeons, and endocrinologists developed 29 content criteria (CC) important for making treatment decisions. Of the 60 websites, 22 were unique and analyzed. Websites included hospital-affiliated (36.4%), commercial (31.8%), non-profit (22.7%), and governmental (9.1%). The DISCERN scores showed the quality of the written information for all was “fair” (mean score 3.2), and 22.7% met the criteria for “good” quality. Websites scored only 30.0% of the JAMA benchmarks, which evaluated authorship, ownership, currency of content, and conflicts of interest. Only 40.1% were HONcode certified, indicating the website was recognized to contain ethical medical information. The SAM method found 77.3% of sites had adequate readability and comprehension. Analysis of website CC revealed that only 28.2% met all 29 criteria. All sites discussed total thyroidectomy, but only 81.8% discussed lobectomy. Lobectomy was mentioned as standard for microcarcinomas (≤1cm) in 22.7%. Websites discussed permanent complications infrequently (31.8% for recurrent nerve injury and 27.3% for hypoparathyroidism). Lifelong thyroid hormone was discussed in 63.6% after total thyroidectomy, and in 36.4% as a possibility after lobectomy. The overall quality, readability, and content of websites about thyroid cancer treatment is fair and needs improvement. Most sites lack updates from the 2015 ATA guidelines and information about treatment options and complications that is necessary for patients to make informed decisions.
Thyroid Hormone Metabolism & Regulation Saturday Poster Clinical
Thyroid dysfunction during pregnancy is common in child-bearing age women. To diagnose thyroid dysfunction during pregnancy, ATA guidelines recommend to establish specific reference ranges for thyroid-related indicators in different region. However, most of the established thyroid specific reference ranges for pregnancy were only for singleton populations, while twin pregnancy studies were relatively few. Besides, serum β-HCG levels may be higher in twin pregnancies, which may lead to different TSH levels between the two groups. The aim of this study was to establish the reference ranges for thyroid-related indicators in twin pregnancies in early pregnancy. A total of 321 twin pregnant women with complete clinical information and thyroid test results during the early pregnancy were retrospectively collected in Peking University First Hospital from October 2013 to December 2016. 164 pregnant women, who conformed to the National Academy of Clinical Biochemistry criteria, without adverse pregnancy outcomes and obstetric complications were enrolled in the study. Meanwhile, applying the same enrolled criteria and matching 3 to 1 with twin pregnancy, we screened 492 single pregnant women as controls. TSH and FT4 were compared between singleton and twin pregnant women. The reference ranges for thyroid-related indicators of twin pregnancies were FT4:16.11 (12.46–23.77) pmol/L and TSH:0.82 (0.01–3.68) uIU/mL. The median level of TSH during 7–12 weeks was significantly lower than that of 4–6 weeks (0.68 vs 1.79 uIU/mL, P < 0.05) while the median of FT4 (16.12 vs 15.39 pmol/L, P < 0.05) was significantly higher than that of 4–6 weeks. Compared to singleton pregnancy, the median TSH levels were significantly lower in twin pregnancies (0.82 vs 1.67 uIU/mL, P < 0.05) and FT4 levels were significantly higher (16.11 vs 15.53 pmol/L, P < 0.05) in twin pregnancies. The reference ranges of specific thyroid-related indicators in early pregnancy was different between singleton and twin pregnancies. It is reasonable to establish specific reference ranges of thyroid-related indicators for twin pregnancies to avoid misdiagnosis of thyroid dysfunction in the early pregnancy.
Thyroid Hormone Metabolism & Regulation Saturday Poster Clinical
To investigate the correlation between body mass index (BMI) and the risk stratification of thyroid nodules in a multi-center healthy population. A total of 6070 subjects were enrolled from five medical physical examination center from January 2015 to December 2017 in China. All the participants'general information and parameters were recorded. Thyroid nodules were detected by color Doppler ultrasonography. All ultrasound doctors are trained and passed through certification.(1) the total prevalence rate of thyroid nodules was 49.3%, single nodues accounted for 49.4% and multiple nodules accounted for 50.6%; in all the largest nodules, larger than 1cm accounted for 13.3% and smaller than 1cm accounted for 86.7%. Compared with the non thyroid nodule group, thyroid nodule group tended to be more women, older age, with higher fasting blood glucose, and lower FT3 and FT4 (P < 0.01). (2) among all the nodules, there were 166 high-risk nodules (3.7%) according to the ATA guidelines. Compared with the other nodules, patients with high risk nodules were low in weight and low in fasting blood glucose (p < 0.01). Low weight (OR = 2.9, 95% CI: 1.461 to 5.783, P = 0.002) was independent risk factors for high- risk nodules. (3) compared with those with normal weight, the detection rate of high risk nodules increased significantly in the low weight population (p < 0.01). There was no significant difference between overweight and obesity group. (4) thyroid nodule risk stratification was not statistically different among groups of low weight, normal weight and overweight and obesity group in the <55 age group (p > 0.05), in ≥55 years old group, more high risk nodules were detected in low weight group (p < 0.01). Low weight is a risk factor for high risk thyroid nodules among people ≥55 years old.
Thyroid Imaging Saturday Poster Clinical
The Thyroid Imaging Reporting and Data System (TI-RADS) was introduced to standardize the management of thyroid nodules based on ultrasound appearance. We seek to evaluate the utility of the TI-RADS system for malignancy risk stratification in indeterminate nodules. This is a retrospective study of all patients with nodules presenting to the endocrine surgery clinic, October 2017 through March 2018. Inclusion criteria were fine-needle aspiration (FNA) results consistent with indeterminate nodules (Bethesda classification III, IV, V) who were assigned TI-RADS ultrasound scores. Demographics and available information on final surgical pathology results was analyzed. One-hundred fifty-six patients presented with nodules during the study period; of these, 46 met inclusion criteria with indeterminate FNA results (Bethesda III, IV, V) and had TI-RADS scores assigned. Mean patient age was 56.6 ± 12.9 years, and the majority were female (n = 42, 91.3%) with a mean BMI of 35.0 ± 25.5 kg/m2 and mean nodule size of 3.3 ± 3.0 cm. One patient (2.2%) was assigned a TI-RADS score of TR3 (mildly suspicious), 22 patients (47.8%) were scored TR4 (moderately suspicious), and 23 patients (50.0%) were scored TR5 (highly suspicious). Only one patient (2.2%) in the TR4 category did not meet size criteria for follow up or FNA per TI-RADS. Twenty nine of the 45 patients (64.4%) meeting criteria for follow up or FNA per TI-RADS underwent surgery; of those patients, final pathology was benign in 19 patients (65.5% of surgeries, or 42.2% meeting criteria for FNA or follow-up per TI-RADS). Final pathology was malignant in 8 patients (27.6% of surgeries, or 17.8% meeting criteria for FNA or follow-up per TI-RADS). Suspicious classification in the TI-RADS system (TR3, TR4, TR5) did not prove helpful in malignancy risk stratification of indeterminate thyroid nodules. Additional multi-institutional studies are needed to evaluate the utility of this system.
Thyroid Imaging Saturday Poster Clinical
The majority of Primary thyroid lymphoma (PTL) arises from Hashimoto's thyroiditis (HT), which could show diffuse thyroid F-18 fluorodeoxyglucose (FDG) uptake. The aim of the study was to compare findings of FDG PET/CT with those of ultrasound (US) in PTL. Total of 93 patients, who were clinically suspected PTL due to enlarging goiter with Hashimoto's thyroiditis, were enrolled. All patients underwent neck US, US-guided core needle biopsy, and FDG PET/CT. Either or both of Tg Ab and TPOAb were positive in all. Specimen of core needle biopsy was subjected to immunohistochemical staining (CD20, CD3, CD79a, Ki- 67, etc.) along with H-E staining. In addition, IgH re-arrangement was analyzed by PCR. On PET/CT images, FDG uptake in the thyroid was categorized as nodular or diffuse by visual interpretation. Intensity of FDG uptake was assessed according to 5- point scale (5PS) from The Lugano Classification. Additionally, FDG uptake was semi-quantitatively evaluated in form of SUVmax. US was performed using a 12MHz linear probe. US findings was categorized as hypoechoic nodular (nodular) or diffuse non-homogenous low echo without dscrete nodular formation (diffuse).
Of 93 patients, 45 were confirmed as PTL. Pathological diagnosis was MALT lymphoma in 34 and DLBCL in 11. The remaining 48 were diagnosed as Hashimoto's thyroiditis Clinical stage for PTL was IE in 29, IIE in 12, IIIE in 2 and IV E in 2. FDG uptake was postive in all. 5PS score was 5 in 33, 4 in 9, and 3 in 3. Nodular uptake was seen in 14 and diffuse uptake was seen in 31. On US, 21 showed nodular pattern while 24 showed diffuse pattern. All patients with nodular FDG uptake showed nodular pattern on US. In contrast, 8 (26%) out of 31 patients with diffuse FDG uptake had nodular pattern on US. There was no significant difference in the average value of SUVmax for FDG between nodular uptake and diffuse uptake (6.7 vs. 8.3). In addition. there was no significant difference in SUVmax between nodular pattern and diffuse pattern on US (7.6 vs. 6.6). Our study shows a poossible dissociation between findings of FDG PET/CT and those of US in assessment of PTL.
Aout one-fourth of patients having diffuse FDG uptake are assocated with nodular pattern on US.
Thyroid Nodules & Goiter Saturday Poster Basic
To treat thyroid nodules with minimally invasive approach became very popular and a efficient, cost-effective device is needed. The objective of this experimental study was to evaluate the efficacy and safety of newly developed low-cost coaxial device «Thyrablator» for bipolar radiofrequency ablation (BRFA) of small thyroid lesions. Surgically removed thyroid nodules (n = 30) were treated with «Thyrablator» (a sterile disposable 20-gauge needle) with an Electrosurgical Generator (Integral, Belarus). «Thyrablator» was inserted in the thyroid nodule and four power regimens were used: 3, 5, 10, 15 Watts (W). For each of power mode ten applications were performed. All sessions were digitalized and dynamic temperature control with a thermal imager «IRTIS – 2000M» was performed. All treated nodules were cut along the «Thyrablator» axis after the sessions for gross examination, and histological sections stained with hematoxylin and eosin. The longitudinal and transverse diameters of ablated lesions were measured for six time increments (5, 10, 15, 20, 25, 30 sec) and the area of the ellipsoid was calculated for further comparisons. Temperature on the surface of the nodule varied from 25C° to 89C° during the BRFA procedure. It started to grow after the fifth second of application, increased until 20-25 seconds, and then began to decrease. All ablation lesions were ellipsoidal and sized up to 55.65 ± 6.44 mm2 and 53.17 ± 2.92 mm2 that were achieved for 30 seconds with applying 3.5 and 5W respectively. Besides, 10W power applied for 20 seconds resulted in a maximum size lesion 46 mm2 (P < 0.05), whereas 15W power leaded to 29 mm2 maximum sized lesion during 15 seconds (P < 0.05). In histological sections, chief cells in the ablated area characterized by elongation and increased nuclear basophilia.“Thyrablator” effectively eliminated small-sized thyroid nodules with applied power of 3.5-5W during 25-30 seconds. Future investigations should evaluate if the moving-shot technique and/or pre-treatment application will improve efficacy of the RFA.
Thyroid Nodules & Goiter Saturday Poster Clinical
Non-operative surveillance is often employed for thyroid nodules with indeterminate cytology and a benign Afirma gene expression classier result (GEC-B), but clinical follow up data are limited. This study evaluates the long-term outcomes of Afirma GEC-B nodules. A multicenter, investigator-initiated, retrospective analysis of all thyroid nodules ≥1cm with atypical (AUS/FLUS) or follicular neoplasm (SFN/FN) cytology and GEC-B through 5/1/16 to allow time for US monitoring. Follow up data included growth on US, surgery, repeat FNA, and histopathologic diagnoses. Only cancers within the GEC-B nodule were considered. Nodule growth for US evaluation >6 months after GEC-B was defined as: change in volume >50%, 2 dimensions >20%, or single dimension >2mm. Linear regression analysis was performed to identify predictors of nodule growth. There were 546 GEC-B nodules in 518 patients. Median patient age was 57 years (20-88 years), 82.1% were female, median nodule size was 20mm (10-80mm) and 401 nodules (73.4%) were AUS/FLUS. Overall, 97/546 (17.8%) nodules were resected. Of these, 7 (7.2%) malignancies were found, representing 1.3% of all GEC-B nodules. These were 2 follicular carcinoma, 2 papillary carcinoma, 2 papillary microcarcinomas, and 1 NIFTP. US follow up was available for 310 (56.8%) nodules at median of 27 months (interquartile range 17–88 months). Repeat cytology was done for 43 (13.1%) nodules: 21 (48.8%) were benign and the remainder were AUS/FLUS or SFN/FN. Growth occurred in 154 (49.7%) nodules. In multivariable analysis, predictors of growth were female sex (OR 2.36, 95%CI: 1.24–4.49) and nodule size 20–29mm (OR: 2.56, 1.30–5.02) and 30–39mm (OR: 5.39, 2.20–13.19) compared to 10-19mm nodules. However, malignancy rate was the same between nodules that grew during surveillence compared to those that remainded stable (1.3% vs. 1.3%, p = ns). No thyroid cancer deaths were observed. In the largest follow up assessment of GEC-B nodules thus far reported, almost 20% underwent surgical resection with very low rate of malignancy. Repeat FNA during follow up did not impact the recommendation for observation. Larger nodule size was associated with nodule growth during surveillance and may warrant closer monitoring.
Thyroid Nodules & Goiter Saturday Poster Clinical
Afirma Gene Expression Classifier and the newer Genomic Sequencing Classifier have been used to stratify malignancy risk in thyroid nodules with Bethesda III and IV cytology (indeterminate nodules). Ultrasound characteristics using Thyroid Imaging Reporting and Data System (TIRADS) are also predictive of malignancy in thyroid nodules. We aim to evaluate how the Afirma assay has been incorporated into clinical practice and impacted the management of patients with indeterminate, TIRADS-scored thyroid nodules. All patients from our institution with indeterminate thyroid nodules who underwent Afirma analysis over 6 years were included. Most samples sent for Afirma were collected as an aliquot of two passes sent for FNA cytology, not as separate passes. Patient and nodule characteristics were retrospectively collected, including cytology details, the ultrasound TIRADS score and histology of index nodules. There were 180 patients with 184 FNA-indeterminate nodules that underwent Afirma analysis. Six samples (3%) had insufficient RNA, which corresponded with pauci-cellular samples on cytology. Forty-seven patients (26%) had Afirma analysis done with the first indeterminate FNA, sparing them additional needle sticks. Afirma analysis classified 82 nodules (44.6%) as benign, 100 (54.4%) suspicious for thyroid cancer, 1 (0.5%) suspicious for medullary thyroid cancer, and 1 (0.5%) suspicious for parathyroid tissue. Seventy-five of 99 patients (75.8%) with Afirma “suspicious for malignancy” nodules underwent surgery, with the final histology showing 43.7% benign, 18.3% neoplastic and 38% malignant nodules. Seventy-three out of 79 patients (92.4%) with a benign Afirma classifier were observed, with a mean follow-up duration of 10.4 months. In this cohort, TIRADS score was not predictive of a suspicious Afirma classification or malignant histology on univariate analysis. The Afirma assays enabled 40% of patients with indeterminate thyroid nodules to avoid surgery. Collecting RNA on the first FNA aspirate saved a quarter of our patients additional needle sticks and resources with a low rate of insufficient RNA specimens and greater consistency between cytology and Afirma result. TIRADS did not add predictive value.
Thyroid Nodules & Goiter Saturday Poster Clinical
Thyroid Nodules & Goiter Saturday Poster Clinical
The prevalence of thyroid nodules in different age groups and sexes is thought to vary, with low incidence in pediatric patients (up to 2%) but high malignancy rates (up to 70%). While incidence of nodules as well as aggressiveness of cancers may increase with age, surgical management of thyroid nodules in elderly is controversial due to medial comorbidities and possible mortality from non-thyroid disease. The aim of this study is to evaluate rates of malignancy (ROM) of surgically-resected nodules by age and sex. All nodules subject to FNA, reviewed by in-house cytopathologists, and surgically resected at our institution were identified. FNA diagnosis was correlated to final histologic diagnosis. ROM (overall and by sex; M = male, F = female) were calculated for pediatric (≤21), adult (22–74), and elderly (≥75) patients. Clinical outcome data were collected from the electronic medical record. Thyroidectomies of 1394 biopsied nodules were identified: 46 pediatric (11 M, 35 F), 1279 adult (284 M, 995 F), and 69 elderly (17 M, 52 F). Overall ROM decreased with age: 60.9%, 37.9%, and 18.8%, respectively (p < 0.01). ROM in M (n = 312) were 72.7%, 44.7%, and 41.2%, respectively (p > 0.05; differences were not significant by age). ROM in F (n = 1082) were 57.1%, 36.0%, and 11.5%, respectively (p ≤ 0.01). In pediatric patients, ROM in M was similar to F (p = 0.4); in adult and elderly, ROM in M was higher than F (p ≤ 0.01). PTC was most common in all groups. 18.5% of pediatric and 15.4% of elderly cancers recurred (1 year average follow-up), mostly locoregionally. ROM in surgically-resected nodules were highest in the pediatric age group and lowest in the elderly. Despite higher incidence of nodules in females, children of both sexes demonstrated similar ROM and males of adult and elderly age had higher ROM. These data support age- and sex-related differences in ROM. Recurrence rates in pediatric and elderly patients were similar to reported 5-year averages.
Thyroid Nodules & Goiter Saturday Poster Clinical
Thyroid nodules are common and approximately 90% are benign. It is recommended that a thyroid ultrasound be performed for known or suspected thyroid nodules. However, we have observed in our practice that thyroid ultrasounds are commonly performed without knowledge or suspicion of a thyroid nodule (i.e. screening). We hypothesized that thyroid nodules found via screening will have a lower rate of fine needle aspiration (FNA) and malignancy than those found clinically or incidentally upon imaging. We retrospectively reviewed the charts of patients who were evaluated by the division of endocrinology for thyroid nodules. Demographic, radiologic and laboratory data were recorded. Records were queried to determine how the nodules were discovered. Patients were divided into 3 groups: those who had nodules found clinically, those who had nodules found incidentally on imaging, and those who had nodules found via screening. We compared the rates of FNA and malignancy for each category. A total of 607 patients were evaluated, and 146 patients were excluded as the indication for thyroid ultrasound was unknown. Four hundred and sixty one patients were included in the final analysis. The average age was 51.6 years; 78.52% of patients were female; and the average number of nodules per patient was 2.8. Overall the rate of malignancy was 8.9%. One hundred and eighty four patients (39.91%) had nodules found clinically, 122 (26.46%) had nodules found incidentally on imaging, and 155 (33.62%) had nodules found via screening. The rate of FNA and malignancy was 75% and 14.7 % for nodules found clinically, 69.7% and 9.8% for nodules found incidentally, and 27.7% and 1.3% for screening nodules (Fisher's exact P value <.0001 for both FNA and malignancy). Thyroid nodules found through screening are less likely to be clinically significant, as they require less FNA and have a lower rate of malignancy compared to nodules discovered clinically and incidentally on imaging studies.
Thyroid Nodules & Goiter Saturday Poster Clinical
In 2015 the ATA relesed guidelines to evaluate and manage thyroid nodules & DTC in children. These guidelines defined certain sonographic features of thyroid nodules which are more likely to be associated with malignant histology. These guidelines recommended fine needle aspiration biopsy (FNAB) for all nodules that are solid or partially cystic with suspicious US features even if they measure <1cm.
In this study we aim to detect the significance of aplying the 2015 guidelines on US readings of patients who attended endocrine clinic At the Children hospital Of Montefiore betwen 2004 - 2017. Our goal is to determain the expected benefits of limiting unnecessary further work up of thyroid nodules such as FNAB or excitional surgical biosy without missing any of the potentially malignant cases. We conducted a review of thyroid nodule US images obtained before publishing the 2015 pediatrics guidelines or obtained after that but read without describing all nodular features mentioned in the 2015 guidelines.
Patients included in this study:
18 years old or less, males and females. All patients attended pediatric endocrinology clinic at the Children Hospital At Montefiore.
US images read by board certified pediatric radiologist at the Children hospital At Montefiore. Eeach of them read all included nodules. Nodular features described based on 2015 guidelines for evaluating & managing thyroid nodules in children. Based on these guidelines recomendations we determained weathr FNAB is indicted or not for each nodule. Priliminary results
57 Patients & 68 nodules included
44 females, 13 males
Mean age = 12.5 years
Total malignant nodules = 16
Total benign nodules (Beth II or benign histology) = 52
Based on guidelines
1- FNA biopsy was recommended for All nodules which fond to be malignant later
2- FNA biopsy or tisue biopsy were not recommended for 12 nodules ( about 23% ) of all nodules which found to be benign later.
Still working on statistical anlysis of the dataApplying the thyroid nodule sonographic features recommended by the 2015 ATA guidelines in reporting nodules, effectively reduce the number of unnecessory FNAB or tisue bipsy without missing any potential malignant cases.
Thyroid Nodules & Goiter Saturday Poster Clinical
The objective of our study was to report our initial experience with the novel Afirma Genomic Sequencing Classifier (GSC) in the evaluation of cytologically indeterminate thyroid nodules, and to compare its performance against the previously utilized Afirma Gene Expression Classifier (GEC). Retrospective chart review of all patients with cytologically indeterminate thyroid nodules (Bethesda III/IV) who underwent testing with either Afirma GEC or GSC from December 2011 through December 2017 at the Cleveland Clinic (Cleveland, OH). Differences between the two tests were assessed using a 2-sample test for equality of proportions. Histopathological data were collected on patients who underwent thyroid surgery after GEC or GSC testing to calculate measures of test performance. Afirma GEC was performed on 191 cytologically indeterminate thyroid nodule samples (December 2011 - July 2017). Considering adequate samples (182, 95.3%), GEC was benign in 76 (41.8%) cases, and suspicious in 106 (58.2%) cases. Afirma GSC was performed on 48 cytologically indeterminate thyroid nodule samples (July 2017 - December 2017). Considering adequate samples (46, 95.8%), GSC was benign in 31 (67.4%) cases, and suspicious in 15 (32.6%) cases. The benign call rate for GSC was 25.6% higher than for GEC (p = 0.003). The overall thyroid surgery rate for nodules tested with GEC was 47.3% versus 32.6% for nodules tested with GSC (p = 0.105). The calculated sensitivity of GEC was 97.1%, with a specificity of 63%, a positive predictive value (PPV) of 43.6%, and a negative predictive value (NPV) of 98.7%*. The calculated sensitivity of GSC was 92.3%, with a specificity of 93.8%, a PPV of 85.7%, and a NPV of 96.8%*. [*calculations assumed that unoperated GEC/GSC benign nodules were true negatives]. The benign call rate among cytologically indeterminate thyroid nodules was significantly higher with Afirma GSC. GSC maintained a high sensitivity and NPV (consistent with previously reported validation results), while providing a significantly higher specificity and PPV. In the long run, GSC testing may help prevent more unnecessary diagnostic thyroid surgeries, along with reducing potential associated costs and life-long consequences.
Thyroid Nodules & Goiter Saturday Poster Clinical
Thyroid lobectomy is appropriate treatment for unilateral symptomatic benign nodules, indeterminate nodules, or well differentiated thyroid cancer less than four centimeters without high risk features. Those with excellent response to therapy should be maintained with thyroid stimulating hormone (TSH) of 0.5–2 mIU/L. We aimed to determine factors associated with need for thyroid hormone following lobectomy in compliance with these guidelines. We performed a retrospective single institution study of patients undergoing thyroid lobectomy from January 2016 to December 2017. Exclusion criteria were prior thyroid surgery, preoperative thyroid hormone supplementation, Graves' disease, and lack of postoperative TSH. Clinicopathologic variables were collected including sex, age, nodule cytology, preoperative thyroid sonographic characteristics, TSH, histopathology of thyroid nodule and thyroid parenchyma, completion thyroidectomy, and thyroid hormone supplementation status. Univariate statistical analysis was performed with Fisher's exact and Kruskal-Wallis testing for categorical variables and Wilcoxon rank sum for continuous variables with a significance of p < 0.05. One hundred and thirty-nine patients underwent thyroid lobectomy, 100 patients met inclusion criteria. Mean follow up was 10.5months (SD 7.7 months) and 53% did not require thyroid hormone. When comparing those that did and did not require thyroid hormone, there were no differences between the groups with regard to sex, age, race or ethnicity, sonographic heterogeneity of the thyroid gland, cytology Bethesda category, size of specimen, or length of follow up. Patients who required thyroid hormone were more likely to have malignant final pathology: 40% versus 13% of those not requiring (p = 0.002); more likely to have thyroiditis on final pathology 26% versus 3.8% (p = 0.002); and had higher preoperative TSH: mean 1.88mIU/L (SD 1.17) versus 1.16mIU/L (SD 0.77) (p = 0.0002). Seventy three percent of those with cancer required thyroid hormone to reach goal TSH, versus 38% with benign pathology. In patients who undergo thyroid lobectomy, the need for exogenous thyroid hormone is associated with preoperative TSH level, thyroiditis, and malignancy.
Thyroid Nodules & Goiter Saturday Poster Case Report
A 90-year-old woman with longstanding multinodular goiter and subclinical hyperthyroidism was admitted with acute respiratory failure. She had a history of a large asymptomatic multinodular goiter for >15 years. However, there had been a rapid goiter growth over the past 5 years with an estimated size of ∼800 grams and radiological evidence of severe airway compression. The patient had refused surgery due to her age and fear of complications. She is a Jehovah's Witness and refusal of blood products was a consideration in her decision. She had been clinically and biochemically euthyroid on methimazole 5mg daily for the past 6 years. The patient presented to the ED with acute development of stridor. Laryngoscopy demonstrated a small but visible airway with significant post cricoid swelling. Fiberoptic intubation was attempted twice before successful intubation by direct laryngoscopy. CT neck demonstrated a right thyroid lobe of 6.8 × 9.4 × 11cm and left lobe of 6.9 × 7.4 × 13.8 cm extending from the inferior margin of the parotid glands to the superior mediastinum at the level of the aortic arch with severe upper airway compression. She underwent urgent left hemithyroidectomy.
She was extubated on postoperative day 2. On exam she was noted to have marked right thyromegaly with multiple palpable nodules. She was continued on low dose methimazole on discharge. Her hemoglobin remained stable without need for transfusion. The surgical specimen (left thyroid lobe) weighed 330 grams and pathology was consistent with benign nodular goiter. The etiology of her acute decompensation remains unclear, however it may have been exacerbated by an upper respiratory infection. Bacterial and viral respiratory cultures were negative. We describe a case of a 90-year-old woman with a massive goiter and acute respiratory failure who require urgent surgery. She underwent successful hemithyroidectomy without post-operative complications. Benign multinodular goiters can occasionally grow rapidly to become massive causing upper airway compromise. Markedly enlarged goiters should be considered for early surgical intervention when critical airway compression is seen on imaging.