Abstract
Thursday, September 22, 2016
Thyroid Cancer Thursday Translational
T1a papillary thyroid carcinomas (PTC) can vary from indolent to aggressive, with some tumors presenting with N1b disease which warrants more aggressive therapy. BRAFV600E, TERT, and TP53 are some of the more well-known oncogenic mutations associated with aggressive behavior. Our aim is to identify additional mutations that are predictive of biologic behavior in T1a tumors. We performed whole exome sequencing and IBM Watson analysis on blood and tissue samples from 6 T1aN0, and 6 T1aN1 PTC from the Thyroid Nodule and Thyroid Cancer Collaborative Registry at the University of Nebraska Medical Center. There were 2/12 with inadequate tissue. Ten samples were analyzed (5/10 T1aN0, 4/10 T1aN1b, 1/10 T1aN1a). The majority were female (9/10), 8/10 had classic variant of papillary, and 2/10 had follicular variant of PTC. No actionable mutation were found in 2/5 T1aN0 tumors. BRAFV600E activating mutations were present in 4/4 T1aN1b and 2/5 T1aN0 tumors. Both the T1aN0 BRAFV600E tumors were multifocal. All of the tumors with BRAFV600E mutations had concurrent actionable mutations (PDGFRA, STAT3, ALK, PDGFD, PHLPP2, EPHA2, PIK3CB, INPPL1, EGFR, STAT3), but there was no consistent pattern between tumors. STAT3 and BRAFV600E were both present in 2 tumors, but the type of mutations were different (N1b activating, N0 inactivating). ALK and BRAFV600E were both present in 2 tumors and type of mutations were also different (N1b inactivating, N0 activating).
Additional nonactionable mutations were also found. Activating SLC25A5 mutation was shown in 3/4 N1b tumors that also all had BRAFV600E mutations. CDC27 mutations were seen in 2/5 T1aN0 tumors, both were germline mutations. MUC4 mutation was positive in 2/4 T1aN1b and 2/5 T1aN0 tumors and present in both follicular variant of PTC. Consistent with previous studies, BRAFV600E mutations were present in the majority of T1aN1b tumors, and fewer T1aN0 tumors in this study, suggesting a more aggressive biological behavior. Two novel mutations were identified: SLC25A5 in 3/4 N1b BRAFV600E positive tumors and CDC27, a potential germline mutation, in 2/5 N0 tumors. More research is needed to determine the clinical significance of these mutations.
Thyroid & Development Thursday Basic
Adult organ-specific stem cells are essential for tissue homeostasis and repair. Since the intestinal epithelium is constantly renewed every 2–6 days throughout adulthood and uncontrolled proliferation of ISC can lead to intestinal cancer, the intestinal epithelial stem cells (ISC) are often used as a stem cell model system. Indeed, elucidating the molecular mechanisms regulating the formation of adult stem cells during development is important to determine how stem cell activity leads from normal renewal to cancer development. During mouse development, formation of adult ISC takes place around birth when plasma thyroid hormone (TH) levels peak. TH is essential for postembryonic development and functions by binding to nuclear TH receptors (TRs), which in turn recruit coactivators and promotes gene transcription. One of these coactivators is the protein arginine N-methyltransferase 1 (PRMT1) that is upregulated around birth in the developing stem cells. Thus, we hypothesize that PRMT1 is involved in TH-dependent ISC formation. To investigate the role of PRMT1 in ISC development, we generated a mouse line with conditional KO of PRMT1 only in the intestinal epithelium and analyzed the phenotype via Immunohistochemistry. Our analyses indicate that the conditional PRMT1 KO affected the formation of the adult intestine. The crypts, where the adult intestinal stem cells reside, are more elongated and thinner compared to WT animals. Further, both cell proliferation and apoptosis in the epithelium are reduced, indicating a reduction in stem cell activity. By using a chemically induced intestine-regeneration model, we showed that PRMT1 is required for proper intestinal regeneration. However, during intestinal formation, the first 3 weeks after birth, the intestinal morphology is similar to the WT. In contrast, administration of TH during stem cell formation reveals the specific PRMT1 KO morphology we have discovered in adults. These findings indicate that PRMT1 is important for the TH dependent mouse intestinal maturation, likely in part by affecting the formation and/or function of the adult stem cells. They further provide new insights on intestinal diseases since dysregulation of PRMT1 has been linked to cancer.
Thyroid Imaging Thursday Clinical
To validate the American Thyroid Association's (ATA) risk of malignancy assessment based upon sonographic pattern of thyroid nodules undergoing ultrasound (US) guided fine needle aspiration (FNA). Prospective application of ATA sonographic pattern risk assessment (High, Intermediate, Low, Very Low) of 211 thyroid nodules selected for US FNA, with evaluation of the results based on the Bethesda System for Reporting Thyroid Cytopathology, and with surgical pathology results for the subset undergoing surgical excision. There were 199 patients (157 females, 42 males) and 211 thyroid nodules averaging 2.4 cm (Range 1–7cm, SEM 0.07). Using the ATA US pattern risk assessment, nodules were classified as High (4%), Intermediate (31%), Low (38%), and Very Low (26%) risk of malignancy. The size of the nodules selected for US FNA was inversely correlated with sonographic risk assessment; lower risk nodules were larger on average (p < 0.0001). Malignancy rates determined from cytology or permanent pathology varied significantly by ATA sonographic risk (High-100%, Intermediate-17%, Low-12%, and Very Low-1%; p < 0.0001). The distribution of Bethesda cytology classification also varied significantly by ATA US pattern risk assessment (p < 0.0001) [High - 77% malignant or suspicious for malignancy (M/SFM) and 22% atypical (AUS); Intermediate - 6% M/SFM, 30% AUS, 8% Follicular or Hurthle neoplasm (FN/HN), 47% Benign, and 9% non-diagnostic (NDx); Low - 1% M/SFM, 25% AUS/FLUS, 5% FN/HN, 61% Benign, and 8% NDx; and Very Low - 30% AUS/FLUS and 70% Benign]. Malignancy rates of cytological indeterminate nodules surgically excised also varied significantly by ATA sonographic risk (High-100%, Intermediate-21%, Low-17%, and Very Low-12%; p = 0.003). This prospective study validates the new ATA sonographic pattern risk assessment for selection of thyroid nodules for US FNA based upon Bethesda cytology and surgical pathology results. Further, it validates that cytological indeterminate nodules with an ATA High risk sonographic pattern have a high likelihood of being malignant.
Thyroid Hormone Action Thursday Basic
A bimodal switch model is widely used to describe transcriptional regulation by the thyroid hormone receptor (TR). In this model, unliganded TR forms stable, chromatin-bound complexes with transcriptional co-repressors (e.g., NCOR1) and associated histone deacetylase, HDAC3, to hypoacetylate histones and repress transcription. Binding of hormone dissociates co-repressors and facilitates recruitment of co-activators, such as histone acetyltransferase, CBP/p300, to hyperacetylate histones and activates transcription. The aim is to explore alternative mechanisms for TR interaction with chromatin, that are relevant for understanding the molecular basis for TR mutations associated with human disease with focus on TR signaling in mouse liver tissue.
Thyroid Hormone Metabolism & Regulation Thursday Translational
Selenocysteine is incorporated into selenoproteins via recoding of a UGA stop codon in a process that depends on the selenocysteine insertion sequence binding protein 2, SBP2. Partial SBP2 deficiency in humans causes a complex syndrome with multiorgan involvement of various severities. However, the characteristic pattern of thyroid function tests (TFTs), with high serum T4 and rT3, low T3 and elevated TSH, is present in all reported patients and has not been identified in other inherited or acquired defects. The etiology of this pattern is hypothesized to be due to putative deficiencies in the three iodothyronine deiodinases selenoenzymes (Ds) that metabolize thyroid hormone (TH), yet direct evidence is lacking and their individual contribution to the phenotype is unknown. Therefore, a study of the whole organism using a mouse model of global Sbp2 deficiency is required to assess the various components of this thyroid hormone metabolism abnormality. To bypass the embryonic lethality of lacking Sbp2, a cre-estrogen receptor/loxP approach was employed to generate induced knockout mice, iCKO. Tamoxifen was injected ∼P30 and serum TFTs and tissue Ds activities and expression were analyzed 4 weeks later. Sbp2 iCKO mice had 3.5-fold increase in TSH, 2.3-fold increase in rT3 and 48% increase in T4 compared to wild type (Wt) littermates, thus replicating for the first time the TFTs of human SBP2 deficiency. Liver D1 enzymatic activity (EA) was significantly decreased to 32% in iCKO compared to Wt mice, and cerebrum D2 EA and D3 mRNA expression were also significantly decreased to 53% and 66%, respectively. The pathognomonic thyroid phenotype of patients with SBP2 defects is replicated in iCKO Sbp2 deficient mice. Investigations on these mice demonstrate that the decrease in both 5′ and 5 deiodination, as well as the effect of elevated serum TSH contribute to the elevated serum T4. The reduced liver D1 EA also results in decreased degradation of rT3 and subsequent high serum rT3 levels. Experiments using exogenous L-T4 and L-T3 are ongoing to further interrogate the regulation of the hypothalamic-pituitary-thyroid axis in Sbp2 deficiency.
Thyroid Hormone Action Thursday Basic
Thyroid Hormone Action Thursday Basic
Monocarboxylate transporter 8 (Mct8)-deficient brains of mice and humans do not show classical signs of hypothyroidism. However, neurological symptoms in Allan-Herndon-Dudley patients including changes in myelination and severe psychomotor retardation, as well as transcriptional regulation and behavioral alterations in global Mct8-deficient mice necessitate further research on the physiological role of Mct8 in the brain. To reduce the complexity of analysis in the brain and filter out BBB effects, we created neuron-specific Mct8-deficient mice (CamK-Cre;Mct8fl/fl ). Characterization of these animals revealed sex-specific changes in thyroid hormone serum concentrations that are not reflected by obvious compensations in the expression of major components of the HPT axis. In vivo analysis of cerebral glucose metabolism detecting products of (1-13C) labeled glucose by NMR measurements revealed less incorporation of labeled 13C into lactate in neuron-specific Mct8-deficient cortex and striatum in comparison to control littermates. Glucose transporter 3, important for neuronal uptake of glucose has a reduced expression in CamK-Cre;Mct8fl/fl brains. Phosphofructokinase 1, a rate-limiting enzyme of glycolysis is also reduced. Interestingly, incorporation of 13C in neurotransmitters as glutamate was not different between neuron-specific Mct8-deficient mice and littermate controls, possibly resolved by an increase in lactate dehydrogenase 1 subsequently yielding enough pyruvate for normal TCA activity. These differences between neuron-specific Mct8-deficient mice and littermate controls are most likely not due to changes in thyroid hormone serum concentrations since we could not detect significant alterations of thyroid hormone regulated genes in the brain. We think that these data provide important novel aspects clarifying Mct8 function in the brain, specifically in neurons. Further research needs to delineate the role of Mct8 in altering cerebral glucose utilization by either being directly involved itself or providing thyroid hormones and their metabolites for the direct or indirect regulation of glucose metabolizing enzymes specifically in neurons.
Thyroid Hormone Metabolism & Regulation Thursday Basic
MCT8 is important for the cellular uptake and efflux of thyroid hormone (TH). Mutations in MCT8 result in the Allan-Herndon-Dudley Syndrome (AHDS). Previous studies have provided valuable insights into the putative mechanism of substrate binding in the inward-open conformation of MCT8, required for TH efflux. Here, we aim to further delineate the mechanism of substrate binding in the outward-open (Ce) conformation, required for TH uptake. To identify residues in MCT8 accessible from the extracellular milieu, MCT8-transfected COS-1 cells were pre-incubated with different residue-specific chemical modifiers, in the absence or presence of substrate, prior to TH uptake assays. Target residues were identified by site-directed mutagenesis. Guided by available in vitro data, an MCT8 homology model in Ce conformation was built using YASARA Structure and a T4 molecule was docked in the putative substrate binding center (SBC). The impact of Ala substitution of several residues in the putative SBC on TH uptake was evaluated. The Arg-specific reagent phenylglyoxal (PG) reduced MCT8-mediated TH uptake, which was partially prevented in presence of substrate. Arg445 and Arg271 were identified as targets for PG modification. An MCT8 homology model in Ce conformation was generated based on the Fucose transporter FucP (3O7P). In line with the current and previous studies, substrate docking in the putative SBC suggested an important role for His192 and Arg445 in substrate binding. Of six other residues predicted at the SBC, Ala substitution of Phe189, Phe279 and Phe287 significantly reduced T3 uptake by 25 ± 8, 28 ± 7 and 72 ± 3% and T4 uptake by 8 ± 3, 38 ± 2 and 87 ± 3%, respectively. Other Ala substitutions did not affect (Gly282, Phe501) or even slightly enhanced (Met227) cellular TH accumulation. Here, we report the first MCT8 homology model in Ce conformation, which supports the important role of His192 and Arg445 in TH uptake. The importance of other residues (Phe189, Phe279, Phe287) at the putative SBC depends on their position relative to the substrate. Our findings provide novel insights in MCT8 function and can be used to predict the pathogenic mechanism of mutations found in AHDS patients.
Thyroid Hormone Metabolism & Regulation Thursday Basic
Thyroid hormone receptor (TR) activation has long been associated with the regulation of metabolism and thermogenesis, although the basis for these effects is not yet clear. In order to identify the mechanism(s) by which TR activation leads to the induction of thermogenesis, we comprehensively characterized the effects of diverse TR agonists in various mouse models of metabolic disease. These studies revealed that the pharmacologic activation of TR signaling by select TR agonists is sufficient to induce the entire program of adaptive thermogenesis in white adopcytes both in vitro and in vivo, a process often referred to as ‘beiging’. Further, TR mediated beiging exhibits characteristics that distinguishes TR agonism from other methods being explored to so: 1) The magnitude of TR agonist induced beiging is noteworthy. Ucp1 protein levels approach those of bona fide brown fat and beiging is accompanied with rapid fat loss and pronounced anti-diabetic effects. 2) TR agonists activate beige fat without increasing the activity of classical brown fat, making them the only agents that we are aware of to dissociate beige fat activation from that of canonical brown fat. 3) TR mediated beiging is cell autonomous and perhaps the only method capable of strongly inducing beiging in white adipocyte cell culture. 4) Indications thus far suggest that TR agonism can activate beige fat and adaptive thermognesis independent of β-AR stimulation, classically thought to be the key regulator of adaptive thermognesis. These findings demonstrate that TR activation is a crucially important, heretofore overlooked, regulator of beige fat activity.
Thyroid Cancer Thursday Translational
Recently the application of targeted next generation sequencing (tNGS) testing for more than 300 mutations has been proposed to improve the pre-surgical molecular diagnosis of cytologically indeterminate thyroid nodules. While the results of this approach are very promising, mutations were only detected in few hot spots. These results question the application of time and cost intensive tNGS in the pre-surgical diagnosis of thyroid cancer. Therefore, the aim of this project was to set up a highly accurate, cost efficient MALDI-TOF mass spectrometry mutation detection (MassARRAY) and to tests its performance in a set of molecular well-defined fine needle aspiration (FNA) samples. A MassARRAY panel analyzing the 53 most prevalent thyroid cancer specific point mutations was applied to RNA and DNA from 48 routine air-dried FNAs (27 indeterminate, 13 suspicious, and 8 malignant). All these samples were previously characterized for the presence of BRAF, NRAS, HRAS, and KRAS mutations by pyrosequencing. All the mutations previously identified by pyrosequencing (15 BRAF, 6 NRAS, 1 HRAS) were also detected by MassARRAY. A high correlation of the BRAF mutation percentage detected by MassARRAY and pyrosequencing was observed (r2 = 0.89, p < 0.0001). In addition to the 3 BRAF, 6 NRAS, and 1 HRAS mutations detected in 10 indeterminate FNAs by pyrosequencing, MassARRAY detected 13 additional mutations (1 BRAF, 1 NRAS, 1 HRAS, 6 TERT, 3 IDH1, 1PIK3CA) in further 10 out of 27 indeterminate FNAs increasing the number of mutation positive indeterminate FNAs from 37% to 74%. Our data show that mutation detection by MassARRAY can be successfully applied to minute amounts of degraded DNA from routine air-dried FNA smears. The application of a 53-mutation-panel resulted in a promising detection rate of 74% of cancers in the indeterminate category. These data strongly suggest the extension of the panel by the most prevalent gene fusions and its application in a prospective study.
Thyroid Cancer Thursday Clinical
Lenvatinib is approved for use in patients (pts) with radioactive iodine resistant (RAIR) DTC. Few data exist regarding early adverse events, impact on quality of life (QOL) and post-approval “real world” lenvatinib outcomes; we report our initial lenvatinib experience Outcomes among consecutively-treated patients between 02/2015 and 05/2016 were analyzed retrospectively Twenty five pts with progressive, metastatic RAIR DTC were treated with lenvatinib (14 papillary, 7 poorly differentiated, 3 Hürthle cell, 1 follicular). Median age = 55 yrs (range 27–81); 52% were female. All had received RAI, 11 (44%) radiotherapy; 8 (31%) >1 prior kinase inhibitor [3 (12%) had received 2 prior kinase inhibitors]. Fourteen (56%) were on antihypertensives at baseline. Mutation status was available in 13 (52%); of these 2 each (15%) had BRAF or TERT, and 5 (39%) had both mutations.
Starting lenvatinib dose was reduced in 4 pts due to: older age (2), renal impairment (1) or prior colitis (1). Most pts (21, 84%) developed adverse events in the first month of therapy. Hypertension arose in 16 (64%). Antihypertensive dose adjustment/addition was required in 6 (24%)/12 (48%) pts respectively in the first 6 wks of therapy. Dose reduction was required in 11 (44%) due to adverse events; median time to first dose reduction = 33 days (range 11–84); 8 pts (32%) required >1 dose reduction. Therapy interruption of >3 weeks occurred in 4 (16%: 2 cholecystitis, 1 diverticulitis, and 1 skin lesions). Median overall QOL change at 2 months was 0 (stable, range +2 to −9, P = 0.23), and fatigue score change was +2 (worsening; range −2 to +10, P = 0.007), 10 point scales.
Mean duration of lenvatinib therapy was 6.5 mos (range 1–12). Lenvatinib was discontinued in 7 pts (28%), due to: disease progression (1, 4%) or adverse events [6, 24%: general decline (1), GI bleeding (2), diverticulitis (1), fatigue (1), and hemoptysis (1)]. RECIST PR was achieved in 10 pts (40%); 20 pts (80%) were alive at the time of this report. Lenvatinib is a promising therapeutic in patients with RAIR DTC, but toxicities are great and occur early, and dose reductions frequent; QOL can be maintained on lenvatinib therapy.
Thyroid Cancer Thursday Translational
There is a critical unmet therapeutic need for ATC. Various strategies including immune based therapies are underway. In this study, we sought to characterize the immune infiltrate associated with ATC tumors. We analyzed ATC tissue sections for tumor infiltrating lymphocytes (TILs: CD4, CD8, Foxp3, CD45Ro, Granzyme B [GrB]), macrophages (CD68) and immune suppression markers (PD-1, PD-L1) using Aperio Image Toolbox. PD-L1 expression was evaluated in tumor cells as % positive cells and H-score (% positive cells combined with intensity). Other markers were evaluated as density (# positive cells/mm2). 5 random 1 mm2 intratumoral areas were analyzed. The results were presented as the median (range across samples) of the average of the 5 areas. Correlation between markers was assessed using Spearman correlation. 21 ATC tumors (15 primary, 5 nodal, 1 distant metastasis) resected prior to treatment were analyzed. Median age was 67 yrs (32–82); 57% women, median tumor size was 5.5 cm (2–10); stage 4A (14%), B (48%), C (38%); BRAF V600E+ (52%). Median % PD-L1+ tumor cells = 40% (0.4-99.9) and PD-L1 H-score = 41 (0.4-233). Median cell density: PD1 = 63 (7-102); CD4 = 702 (47-4028), CD8 = 430 (54-3196), CD45Ro = 538 (113-2682), FoxP3 = 217 (43-873), GrB = 156 (23-1265), CD68 = 196 (23-1568). There was strong positive correlation between PD-L1 and CD4, CD8, CD45Ro, and GrB (rho ≥0.6; p < 0.05) and moderate positive correlation (0.6 ≥ rho ≥0.4, p < 0.05) with PD-1 and Foxp3, and no correlation with CD68. The difference of PD-L1 between BRAF+ and BRAF- was weakly significant (82 vs 13, p = 0.085). Median overall survival (OS) was 20 months (95%CI, 9.5–30.5). There is no evidence that PD-L1 is associated with OS, although these patients received various treatments (surgery (90%), chemoradiation (71%), cytotoxic (24%), targeted therapy (24%)). Immunoprofiling of a large ATC cohort shows that PD-L1+ tumor cells and TILs are present in high frequency. Additionally, strong positive correlations between tumor cells expressing PD-L1 and TILs exist. Higher PD-L1 expression was observed in BRAF+ tumors. These data point to the presence of a hot immunogenic environment that can be targeted with immune based therapies alone or with targeted agents.
Thyroid Cancer Thursday Clinical
The non-invasive encapsulated follicular variant of papillary thyroid carcinoma is a lesion with low malignant potential for which a reclassification has been proposed into “Non-invasive follicular thyroid neoplasms with papillary-like nuclear features” (NIFTP). Removing the diagnosis of cancer could impact significantly the treatment and follow-up of these patients. We aim to evaluate the outcomes of NIFTP in our institution and compare it to the invasive-follicular variant of papillary thyroid carcinoma (I-FVPTC). Two pathologists (LK and MEL) reviewed all FVPTC with available histology diagnosed and managed at our cancer center from January 1998 to December 2015. Tumors were reclassified according to current criteria (nuclear features diagnostic of PTC with <1% of papillary formations). A third pathologist (BAC) independently reviewed the slides in all discordant cases. A total of 215 tumors in 203 patients met these criteria (mean age at presentation 52 years; 70% female; mean size 2.3 cm). We excluded 74 cases from the analysis due to concurrent (incidental or not) thyroid cancer to avoid interference with outcomes. Of 141 FVPTC, 93 met criteria for NIFTP (66%). At presentation, lymph node metastases were less frequent in NIFTPs (2.2% vs. 12.5%, p = 0.02), but distant metastases were not (2.2% vs. 6.3%, p = 0.34). Follow-up data >6 months after surgery was available in 76 patients with NIFTP and 35 with I-FVPTC. Initial treatment was less aggressive for lesions now identified as NIFTP: lobectomy alone in 26% vs. 11%, p = 0.09; and use of radioactive iodine in 35.5% vs. 57.1%, p = 0.04. Length of follow-up was identical in NIFTPs and I-FVPTCs (mean 42.4 vs. 46.7 months, p = 0.97). There were no differences in status of disease at last visit (p = 0.12) and no recurrences have been identified during follow-up in either group. All patients with persistent structural disease (n = 3, 2 NIFTP and 1 I-FVPTC) or death from disease (n = 2, both I-FVPTC) presented with distant metastases. A small proportion of NIFTP have nodal and distant metastatic spread. Although lobectomy alone may be sufficient initial treatment, follow up may be justified and these tumors should not be classified as benign.
Thyroid Cancer Thursday Clinical
Everolimus is an inhibitor of mTOR. We have previously reported on the initial activity in aggressive thyroid cancer (TC) and here we present the long term outcome data with tumor sequencing results. Patients (pts) with metastatic, RAIRTC who had shown radiographic progression by RECIST within 6 months prior to enrollment received Everolimus 10 mg orally daily. Exploratory cohorts included pts with medullary TC (MTC) with progression within 6 mo prior to enrollment and anaplastic TC (ATC). The primary endpoint was progression free survival (PFS). NexGen sequencing of 505 relevant genes was performed on tumor tissue. The study was open at 4 centersEnrollment finished in 2013. 33 patients with RAIRTC including 12 Hurthle cell TC (HCTC), 10 patients with MTC and 7 with ATC were enrolled. For the RAIRTC cohort, median PFS was 12.9 months (95% CI 7.3–18.5). Median follow up for those alive was 27.9 months and median OS was not reached. Three patients continue treatment 45.1, 47.1, and 57.6 mo. PFS for the HCTC cohort was 11.7 mo (95% CI 2.03–20.6) and PFS at 24 mo was 18.3% (95% CI 2.8%–44.4%). Among MTC patients PFS was 13.1 months. Among 7 ATC patients, 2 had a PFS of 17.9 and 26 months, respectively. Sequencing was available in 35 cases. Among 13 RAIRTC's (excluding HCTC) BRAF V600E was present in 5 (38.5%). Mutations along the PI3K pathway occurred in 5 (38.5%). Mutations in 9 HCTCs were rare with no mutations of the PI3K/mTOR pathway. In 6/7 MTC, RET was mutated. Both cases of ATC with long survival had mutations affecting PI3K/mTOR pathway (2/6): TSC2 Q1178* (reported previously), and PIK3CA I391M, mTOR A329T, NF1 R1534*. Side effects were as expected and manageable. Everolimus has significant anti-tumor activity in patients with aggressive thyroid cancer. A high rate of mutations of the PI3KmTOR pathway compared with TCGA data was observed in our RAIRTC cohort, possibly contributing to aggressive biology and treatment response. Full genetic results will be presented at the meeting.
Autoimmunity Thursday Poster Clinical
An association exists between autoimmune thyroid diseases (AITD) and other organ specific/systemic autoimmune disorders. However, data obtained from several studies might have been hampered due to the small sample sizes and the use of control populations not matched for age, or gender, or geographic location.
We evaluated 3069 oupatients, with diagnosed chronic autoimmune thyroiditis (AT), to investigate the prevalence of other autoimmune disorders, compared to 2 age- and sex-matched control groups. The first control group consisted of 1023 subjects, collected from a random sample of the general population without thyroid disorders, and the second control group of 1023 patients with non-toxic multinodular goiter, collected from the same random sample of the general population, who had similar iodine intake.
AT patients (with respect to both controls) showed a significant increase of the prevalence of autoimmune disorders, such as chronic autoimmune gastritis (CAG), vitiligo (Vit), rheumatoid arthritis, polymialgia rheumatica (Polym), celiac disease, diabetes, sjogren disease, multiple sclerosis, systemic lupus erythematosus, sarcoidosis, alopecia, psoriathic arthritis, systemic sclerosis, HCV-related cryoglobulinemia. The association of 3 autoimmune disorders was observed in AT patients: the most frequent associations were AT+ CAG+Vit and AT+CAG+Polym.
In conclusion, our study demonstrates a significant increased risk of other autoimmune diseases in patients with AT. We suggest that patients with AT, (still unwell, or developing new not specific symptoms though adequate treatment) should be screened for other autoimmune disorders, avoiding the delay in the diagnosis.
Thyroid Cancer Thursday Poster Translational
Testing the sensitivity of primary anaplastic thyroid cancer (ATC) cell cultures (pATC) established from each subject to different drugs could lead to an increase in the effectiveness of the treatment, and not to administer inactive therapeutics.
In this study we evaluate the antineoplastic effect of vandetanib, and lenvatinib [tyrosine kinase inhibitors (TKIs) agents], in primary cells from anaplastic thyroid cancer (ATC) obtained both from biopsy (biop-pATC), or from fine needle aspiration (FNA-pATC).
The antiproliferative effect was evaluated (by WST-1 assay and apoptosis test) in ATC cell cultures (both biop-pATC, such as FNA-pATC), in 5 patients. The concentrations of vandetanib, and lenvatinib, used in the in vitro experiments were 1 nM, 30 nM, 100 nM, 300 nM, 1000 nM.
Data obtained from WST-1 assay in FNA-pATC, or biop-pATC, cells showed a significant reduction of proliferation compared to control with lenvatinib, and slightly with vandetanib. Both compounds increased dose-dependently the percentage of apoptotic cells in FNA-pATCs, or biop-pATC. No significant differences in sensitivity to vandetanib, and lenvatinib, between the tested ATC cells (from FNA, or biopsy) was shown.
In conclusion: - primary cells from FNA have a quite similar sensitivity to TKIs agents with respect to primary cells from biopsy; - vandetanib, and lenvatinib, are able to reduce cell growth, increasing apoptosis in ATC; - testing sensitivity to different TKIs in each patient could lead to increase the efficacy of treatments, avoiding the administration of inactive drugs.
Autoimmunity Thursday Poster Basic
The condition of gastrointestinal tract (GIT) at autoimmune thyroiditis (AIT) has been studied insufficiently. However, in connection with the development of systemic inflammation and also because of the change of thyroid function, AIT can negatively influence morphofunctional condition of GIT and the course of GIT diseases. GIT structural changes, in turn, can modify thyroid function and the possibilities of pharmacological correction of its function at AIT. We have observed 36 ambulant patients (26 females and 9 males) aged 44–72 who consulted a gastroenterologist about possible GIT disturbances. Earlier all the patients were diagnosed with AIT at SH stage. Average AIT duration was 4.6 ± 0.4 years. All the patients underwent complex investigation of GIT upper parts, including laboratory tests (hematological, biochemical, hormonal), ultrasound tests of abdominal and dynamic cholecystography, as well as esophagogastroduodenoscopy. All observed patients showed different combinations of functional and organic GIT pathology. Chronic nonatrophic gastritis has been found in 21 patients, of them 19 showed helicobacter-associated gastritis. Sphincter of Oddy dysfunction of biliary type was diagnosed in 17 patients, non-alcoholic fatty liver disease – in 22 persons, gallbladder dysfunction of hypomotoric type – in 15 persons, and cholelithiasis – in 11 cases. There have been rare cases of GORD, chronic acalculous cholecystitis, chronic pancreatitis, chronic calculous cholecystitis, chronic atrophic gastritis, gastric and duodenal ulcer. Pathogenic connection of prevailing pathology, namely, chronic nonatrophic gastritis with AIT can be mediated by combined influence of the thyroid hormone deficit and the products of systemic immune inflammation on stomach secretory activity and its motor function. Different combinations of functional and organic GIT pathology has been found in all observed patients with AIT at SH stage. Chronic nonatrophic gastritis, functional disorders of the biliary tract and non-alcoholic fatty liver disease dominate in patients with AIT at SH stage. Obtained data should be considered both at administration of pathogenetic therapy of GIT upper parts diseases, and thyroid pathology.
Autoimmunity Thursday Poster Clinical
Thymus is a primary lymphoid organ, whose main function is the development of central T-lymphocyte tolerance by process called negative selection. Dysfunction in this process could lead to many autoimmune disease (AD) including Autoimmune Polyglandular Syndrome. Neoplasia of thymus gland has also been responsible as an etiology for many AD like mysthania gravis, pure red cell aplasia, Morvan syndrome etc. Although pathophysiology is not very clear, antibody against specific target, are considered to be responsible for this condition. Hence, here we describe a case of Morvan syndrome, which presented with generalized sweating and myokymia triggered by recurrent thymoma resection. 32-year-old Caucasian female with history of stage II thymoma status post resection in 2009, presents for the evaluation of sweating to the office. Her recent history includes detection of new lesions in right thorax region on a routine PET scan; right thoracotomy performed on January of 2016, and surgical pathology consistent with recurrent metastatic thymoma. During her postoperative recovery period as an outpatient, she developed progressive generalized sweating, shakiness, insomnia, and weight lose requiring multiple hospital admissions. Patient was being treated with Trazadone, Alprazolam and Seroquel all this time with the working diagnosis of panic attack. No other etiology was being eluded over next 3 months, despite extensive work up including endocrine test's like thyroid function test, FSH, LH, estradiol, serum metanephrines, calcitonin and 24-urine collection for 5-HIAA. Latter, autoimmune process was suspected as a cause of her symptoms. Hence, serum voltage gated potassium channel antibody and electromyography was performed. The results of this test were consistent with Morvan syndrome, which is characterized by Central, Autonomic, and Peripheral hyperactivity. Treatment with high dose steroids, Immunoglobulin and tegratol was initiated. This resulted in complete resolution of symptoms with favorable outcome over next two week's. This case highlights, the uncommon cause of sweating and tremors whose pathophysiology involves autoimmunity with good response to immunosuppresent treatment.
Autoimmunity Thursday Poster Case Report
Type 1 DM and autoimmune thyroid disease occur within the same individual, a condition known as polyglandular syndrome type 3, one of the variants of the autoimmune polyendocrine syndrome. The prevalence of thyroid antibody positivity in patients with type 1 DM may reach 50%, with a further risk of progression to overt hypothyroidism or hyperthyroidism of about 50%.
A 22-year-old female with type 1 diabetes mellitus for 10 years, failure to thrive, palpitations, and recurrent diabetic ketoacidosis in the last few month. Last DKA 2 month ago associated with fetal demise at 30 weeks gestations. Complains of abdominal pain, nausea and vomiting for 2 days. On initial physical examinations, BP 124/92, HR 156, RR 18, a temperature 98.3, PO2 99%. The patient looks sick, cachectic with acidotic breathing, tachycardia on cardiac exam, and no thyromegally or eye symptoms. EKG showed sinus tachycardia. The laboratory finding showed HB 12g/dl, glucose 461mg/dl, anion gab 32, Co2 9mmol/l, PH is 7.10. Patient was treated with fluids and insulin drip. The next day the anion gab closed. The tachycardia remained despite improvement in the DKA. Investigation for thyroid function was initiated. TSH 0.010 micro Units/mL, FT4 2.24 ng/dL, T3 214 ng/dL, TPO 598 IU/mL, TSI 332%. Thyroid U/S The thyroid gland demonstrates increased Doppler flow. Thyroid iodine uptake elevated thyroid uptake consistent with the clinical diagnosis of Graves' disease. The treatment for Graves' disease started with bet blocker and anti-thyroid medications. The patient was discharged in a good condition to follow up as out-patient. Diabetic patients have a higher prevalence of thyroid disorders compared with the normal population. Because patients with one organ-specific autoimmune disease are at risk of developing other autoimmune disorders, and thyroid disorders are more common in females, it is not surprising that up to 30% of female type 1 diabetic patients have thyroid disease. Patient with type 1 DM at a higher risk to develop other autoimmune diseases. Of which the thyroid disease is the most common. There is overlap between the hyperthyroidism and diabetes symptoms and physician should be vigilant to recognize the presence of both conditions.
Autoimmunity Thursday Poster Case Report
Methimazole (MMI) is the preferred thionamide for the treatment of hyperthyroidism due to its favorable side effect profile. Rarely, it is associated with minor side effects such as arthralgia. Arthralgia can be the first symptom of antithyroid arthritis syndrome, for which prompt discontinuation of MMI is indicated. Symptoms generally resolve rapidly after cessation of MMI. To our knowledge, there are only 2 cases reported with recurrence of transient arthralgia and 1 case with progression to migratory polyarthritis after cessation of MMI. An 18-year-old female with type 1 diabetes and hyperthyroidism presented with migratory polyarthralgia three months after initiating MMI. On physical exam, she was afebrile and tachycardic. The thyroid was non-tender and diffusely enlarged with bruit present. She was tender to palpation of the neck, chest, shoulder, arm, and hip; however, no synovitis or rash were noted. Laboratory evaluation revealed TSH <0.01 mcIU/mL, free T4 2.42 ng/dL [0.8–1.8], free T3 10 pg/mL [2–4.4], TPO antibody 52.8 IU/mL [< 9], and positive antinuclear antibody (1:80 titer). Inflammatory markers were elevated; however, an extensive infectious and rheumatologic evaluation was negative. MMI was discontinued due to concern for MMI-associated arthralgia. The patient had complete symptom resolution three days later. However, her arthralgia recurred on the fourth day with synovitis on exam. She was treated with naproxen for pain and cholestyramine and atenolol for hyperthyroidism with plan for radioactive iodine ablation. The pathogenesis of MMI-associated arthritis is unclear. Onset of arthralgia is usually within 8 weeks, but can be as long as 3 years after initiation of MMI. Prompt cessation of MMI is paramount given potential progression to antithyroid arthritis syndrome or ANCA-associated vasculitis. Symptoms usually resolve within days, but can persist for months after discontinuation of MMI. Definitive therapy should be pursued due to the high cross reactivity between MMI and propylthiouracil. It is important to recognize MMI-associated arthralgia and its potential progression to polyarthritis and vasculitis. Prompt cessation of MMI and definitive therapy of hyperthyroidism should be pursued.
Disorders of Thyroid Function Thursday Poster Basic
To evaluate all-cause and disease-related healthcare costs in hypothyroid patients who initiate their therapy with Synthroid and later switch to other levothyroxine agents.
A retrospective cohort study was conducted using claims database on a study sample of adult males, with ≥1 Hypothyroidism diagnosis code between 01/01/2007–12/31/2014 and who have initiated their therapy with branded levothyroxine (Synthroid) and who were at least 80% adherent to their Synthroid therapy in the first 6 months. Patients were required to have a continuous enrollment in 6 months prior and one year post-index period. Patients who remained on Synthroid during the one year follow-up period were categorized as “continuous users”, while those who switched to other levothyroxine agents (i.e. other branded or generic levothyroxine) during the follow-up period were categorized as “switchers”. Patients in the two groups were matched 1:1 based on age, gender, plan type, index year, and number of baseline co-morbidities. Of the 10,159 patients identified in the analysis, 2,168 (21.3%) were categorized as switchers. In the matched analysis, 2,052 patients were included in each cohort, who had a mean age of 48.9 years and 81.3% were female. Switchers reported higher mean medical ($6,949 vs $6001) and total all-cause costs ($9,388 vs $8,440) compared to continuous users. However, disease-related costs in the switchers group were found to be statistically significant. Disease-related medical costs in the switchers group were ($1,023 vs $596, p < 0.0032), while the total disease-related costs were ($1,132 vs $757, p < 0.0097).
Patients who continued to use Synthroid during the study period were associated with lower all-cause and disease related costs as compared to patients who switched to another levothyroxine agent. This study suggests that patients who switch tend to utilize more healthcare resources and therefore may be responsible for driving higher costs.
Disorders of Thyroid Function Thursday Poster Clinical
To investigate if biochemical differences exist between those clinically euthyroid on levothyroxine (T4) only versus those requiring combination treatment with T4 and T3 we compared thyroid function tests between two groups while on T4 treatment; 1. clinically euthyroid on T4 replacement, 2. T4 treated with persistent symptoms of thyroid hormone deficiency Patients undergoing medical management of hypothyroidism were identified by chart review consecutively and were assigned to one of two groups; 1. Hypothyroid being treated with T4, generic or brand, who were free of symptoms attributable to thyroid hormone deficiency 2. Hypothyroid previously treated with T4, brand or generic, with persistent symptoms switched for this reason to Armour Thyroid (AT) replacment. Subsequently, within the group converted to AT we selected those who rated the benefit of transition as 5 out of a possible 5 indicative of AT being much better for symptomatic relief than T4. HIPAA compliance was maintained throughout the study. There were 64 subjects in group 1, 57 in group 2 and 49 in a control group (3). T4/T3 ratio in group (1) 10.30 ± 1.91 was not different than group (2), 9.60 ± 3.1. Mean T3 level in group (2), 0.96 ± 0.20 was greater than group (1), 0.88 ± 0.15, p = 0.03. However T4 levels were comparable between these two groups (9.2 ± 1.74 versus 8.89 ± 1.31 respectively). TSH levels were also comparable between groups 1 and 2. TSH levels in group (1) were lower than controls, 1.24 ± 0.74, versus 1.58 ± 0.73, p = 0.017 but were comparable to control in group (2) Biochemical parameters while on levothyroxine treatment were essentially comparable between the group treated with T4 exhibiting persistent symptoms versus those with a satisfactory response to levothyroxine. Unexpectedly, T3 levels were slightly higher in the group with persistent symptoms. If a biochemical abnormality exists in those with persistent symptoms on T4-only therapy, it might be characterized by lower peripheral T3 levels than T4 responders, due to reduced D2 deiodinase in the peripheral tissue in this group (Bianco et al). Our results suggest that sampling of peripheral blood for this signal may not be sufficient to distinguish these two groups.
Disorders of Thyroid Function Thursday Poster Clinical
Lipid metabolism is affected by thyroid dysfunction. However, those alterations observed in lipid metabolism could be related to other factors as autoimmunity and inflammation that are frequently present in thyroid dysfunction. The aim of this study was to examine the effects of clinical hypothyroidism on lipid metabolism in women after thyroidectomy for thyroid cancer when thyroid tissue is absent or nearly absent. Ten women with thyroid cancer in euthyroid state were studied before thyroidectomy, and after total thyroidectomy, before radioiodine scan, when they were in clinical hypothyroidism. Patients age was 46 ± 12 years and BMI 27,3 ± 5,8 kg/m2. Thyroglobulin in clinical hypothyroidism state was 2.1 ± 1.7 ng/mL. Methastases were not detected on WBS and iodine uptake after 48 hours in 9 of 10 patients was very low (1.78 ± 2.54%). Lipids and apolipoproteins, PON 1 activity, CETP and LCAT concentration, HDL particle size, in vitro transfer of lipids to HDL were determined in their plasma samples. LDL (128 ± 37 vs 178 ± 41, p = 0,0005) and non-HDL cholesterol (153 ± 38 vs 211 ± 50, p = 0,0003), free cholesterol (52 ± 7 vs 74 ± 19, p = 0,0012), triglycerides (129 ± 50 vs 166 ± 77, p = 0,0633) and apo B (1.00 ± 0.26 vs 1.34 ± 0.27, p = 0,0009) plasma concentrations were higher in the clinical hypothyroid compared to the euthyroid state, but HDL-cholesterol and apo A-I were equal. PON1 activity was increased in hypothyroidism (114 ± 57 vs 148 ± 82, p = 0,0295). There were no changes in HDL particle size, CETP and LCAT concentrations.
Regarding the lipid transfers, the free cholesterol (4,6 ± 1,9 vs 3,2 ± 1,0, p = 0,0722) and triglyceride (3,9 ± 1,2 vs 2,9 ± 0,7, p = 0,0453) transfers were diminished in hypothyroidism, but the phospholipid and cholesterol ester transfer were unchanged. In conclusion, in post-thyroidectomy clinical hypothyroidism, the classical deleterious LDL changes were observed. Although HDL-cholesterol was unchanged, as well as CETP and LCAT, the reduction of free cholesterol and triglyceride transfers to HDL may suggest that the HDL functional aspects are also affected, thus also contributing to atherogenesis. On the other hand, higher PON 1 activity could improve the anti-oxidative HDL capacity in hypothyroidism.
Disorders of Thyroid Function Thursday Poster Clinical
Thyroid disease and breast cancer both have a life-time prevalence rate of 12.5% in female, 1 in 8 will develop the disease over the course of her life. Many studies have found some relationships between thyroid dysfunction and breast cancer, however, still controversial since several studies had conflict results. The relationship has not been well-studied in Asian population. In this case-control study, we utilize the Taiwanese National Health Insurance Research Database (NHIRD), one of the largest administrative health care databases around the world, to analyze the epidemiological evidence of association between thyroid disease and breast cancer risk in Asian population.
Female patients with the diagnosis of primary breast cancer and with no previous cancer history were identified from the NHIRD (1999–2010). Age and gender matched patients without breast cancer diagnosis were selected as the control group.
We then identified patients with and without thyroid disorders prior to the diagnosis of breast cancer in the case group or the same index date in the control group. Noted that we did not include thyroid malignancy. Conditional logistic regression model was applied in the analysis. A total of 103,466 patients were enrolled in our study, 51,733 in each group. No statistical difference between the two groups in age (p = 0.137). There were 4,926 patients (9.5%) with the diagnosis of thyroid disorder in the case group, while 4,866 patients (9.4%) in the control group. When combining both hyper- and hypo-thyroidism, there was no statistical difference between the two groups (p = 0.538). The odds ratio of breast cancer associated with thyroid disorders was 1.01 (95% CI 0.97–1.06, p = 0.564) using conditional logistic regression model. Our case-control study utilizing the nationwide database suggests that there may not be a significant association between thyroid disorder and breast cancer. The relationship may change when we further break down to hyperthyroidism and hypothyroidism or investigate the breast cancer survival, which are our next steps in process.
Disorders of Thyroid Function Thursday Poster Clinical
The aim of the study was to detect the effect of percutaneous coronary intervention (PCI) on thyroid functions and ultrasonographic features.
Disorders of Thyroid Function Thursday Poster Clinical
The incidence of thyroid disease has increased in recent years and it is important to have updated epidemiological data. Our study aims epidemiological statistical analysis of a large sample of patients, even in developing countries where the available data are lacking, in order to plan and actualize appropriate health strategiesIn the Butterfly Onlus prevention projects, we analyzed 1949 patients, of which we report data from a sample of 414 patients studied in Bamenda, Cameroon, mean age 38 years (min 3, max 91), of which 77.3% female (320) and 22.7% (94) men. 97.8% (405) had both parents of Cameroonian origin,1.7% (7) came from other Africans countries and 0.5% (2) by non-African countries. 99% (410) had resided in the previous 10 years in a mountainous area or iodine deficient area, 1% (4) near the sea; 93.7% (388) in the urban environment, 6.3% (26) in rural area. We have distributed a questionnaire in order to create a score of the different symptoms and evaluate them statistically. Then, by physical examination and by ultrasound scan (U.S.) with Color Doppler, we have detected eventual morphological alterations and by blood tests we have detected metabolic alterations 79.3% of patients had a negative symptom questionnaire, 20.4% borderline and 2% positive. In the 86% of patients physical examination was negative, in 14% positive. 64.5%of patients showed an U.S. negative for solid nodules and/or abnormalities predisposing to disease, 2% U.S. with predisposing alterations and 33.5% positive U.S. for the presence of solid nodules. 48.1% of 133 patients who carried the hormone assay (TSH, FT3, FT4) is found to be in euthyroidism, 15% in hypothyroidism, 4.5% in hyperthyroidism, 30% in subclinical hyperthyroidism (FT3 and FT4 normal, TSH levels below the normal range), while 2.3% in subclinical hypothyroidism (FT3 and FT4 normal, TSH above the normal range).
The incidence of thyroid disease in our sample of patient demonstrated via ultrasound, hormone assay, physical examination and questionnaire of symptoms is not insignificant and additional epidemiological studies are needed to enlarge the sample in order to develop appropriate measures for the prevention, diagnosis and treatment of thyroid disease
Disorders of Thyroid Function Thursday Poster Clinical
Studies have suggested an association between hyperthyroidism and clinical outcomes in patients with atrial fibrillation (AF) including patients undergoing radioablative therapy. The impact of hyperthyroidism in patients with AF after left atrial appendage occlusion (LAAO) has not been studied. The objectives of this study is to evaluate whether hyperthyroidism affects important outcomes in patients with AF undergoing LAAO. This is a retrospective cohort study using the 2013 National Inpatient Sample (NIS). Patients were included if they were adults and had a principal or secondary diagnosis of AF undergoing LAAO and were further classified according to the presence or absence of hyperthyroidism. Our main outcome measurements were In-hospital mortality, length of stay and total hospitalization charges. Multivariate logistic regression was used to adjust for potential confounders including age, gender and the Charlson Comorbidity index for administrative data. This study included a total of 16,019 patients with AF undergoing LAAO, the mean age of the population was 70 SD 0.2 years and the proportion of females was 37.14%. Patients with AF undergoing LAAO with hyperthyroidism had an increased adjusted inpatient mortality rate (odds ratio [OR] 4.34; 95% confidence interval [CI], 1.01 – 18.72, P = 0.049) compared to the same population without hyperthyroidism. There was no difference in length of stay (P = 0.24) nor in total hospital charges (P = 0.87). Patients with hyperthyroidism and AF undergoing LAAO had a statistically significant increased rate of inpatient mortality compared to patient with AF undegoing LAAO without hyperthyroidism. There was no difference in length of stay nor total hospitalization charges. This study continues to reinforce the important role of hyperthyroidism in clinical outcomes of patients with AF.
Disorders of Thyroid Function Thursday Poster Clinical
Subclinical hypothyroidism (SCH) has been inconsistently associated with adverse pregnancy outcomes. Due to the lack of randomized trials the 2011 American Thyroid Association guidelines found insufficient evidence to recommend for or against universal levothyroxine (LT4) therapy in negative TPO antibody (TPO-) pregnant women with SCH. We aimed to describe the potential benefits of LT4 in TPO- pregnant women with SCH. We reviewed the medical records of pregnant women evaluated at Mayo Clinic, Rochester, from January 2011 to December 2013, who met the criteria for SCH (TSH >2.5 mIU/L for 1st trimester or >3 mIU/L for 2nd and 3rd trimester but ≤10 mIU/L). We performed a descriptive subgroup analysis of the TPO- cohort (TPO checked in 24% of initial cohort, 62% were TPO-). Women were divided into 2 groups: group A had been started on LT4, whereas group B had not. We excluded women with twin pregnancy or use of medications affecting thyroid function. We compared the rate of pregnancy loss (primary outcome) and other pre-specified adverse outcomes between groups. There were 22 women in group A and 34 in group B. The groups were not different regarding age, body mass index, smoking status, history of pregnancy loss or preterm delivery. Group A had higher TSH level (median 4.9 mIU/L, interquartile range 4.3–5.8) compared to group B (median 3.5 mIU/L, interquartile range 2.9–4.3), p < 0.001. Group A had fewer pregnancies lost (9.1% vs 17.7%), fewer preterm deliveries (4.6% vs. 23.5%) and no offspring with low birth weight (LBW) (0% vs 14.3%) or 5-min Apgar score ≤7 (0% vs 7.1%) compared to group B. However, group A had higher incidence of gestational diabetes (9.1% vs 2.9%) and premature rupture of membranes (PROM) (18.2% vs 8.8%) compared to group B. There was similar incidence of gestational hypertension (4.6 vs 5.9%) and preeclampsia (4.6 vs 5.9%) for group A and B, respectively. In a small cohort of TPO- pregnant women with SCH, those who received LT4 had lower incidence of pregnancy loss, preterm delivery, and offspring with LBW or low Apgar score, but higher incidence of gestational diabetes and PROM. Larger studies are required to assess the effects of LT4 on this population.
Disorders of Thyroid Function Thursday Poster Clinical
Radioactive iodine (RAI) therapy is one of the effective treatment options for Graves' disease. However, there still remains controversy about prediction of treatment failure after RAI. The objective of this study is to investigate the factors associated with the success rate of RAI for treatment of Graves' hyperthyroidism. We reviewed patients received radioiodine therapy between January 2010 and December 2013 in Severance hospital, Seoul, Korea. Thyroid outcome, pre-RAI ultrasonographic results and clinical parameters were evaluated retrospectively in the 103 patients followed for at least 6 months after RAI (mean radioiodine dose 11.6 ± 1.8 mCi). Hypothyroidism was resulted in 59 patients (57.3%), euthyroidism was achieved in 16 patients (15.5%) and 28 patients (27.2%) remained hyperthyroid status. Age, gender, BMI, selenium status, pre-RAI thyroid function, or thyroid stimulating immunoglobulin (TSI) levels were not associated with treatment outcome. Length of thyroid isthmus (P < 0.001), 2/24-hour iodine uptake ratios (P < 0.001) were significantly associated with treatment failure defined as a persistent hyperthyroid status after RAI therapy. Patients with longer isthmus had higher risk to remain hyperthyroid, and isthmus length threshold was resulted in 5.2 mm, with sensitivity of 71.4%, and specificity of 70.3% for treatment success. High failure rates were observed in patients with long isthmus of thyroid or high iodine turnover. Measurement of length of thyroid isthmus can be a simple and useful way to predict RAI outcome.
Disorders of Thyroid Function Thursday Poster Clinical
Obesity may modify the pharmacokinetics of several drugs, including thyroxine. Oral thyroxine has a narrow therapeutic index and the dose must be tailored on the patient to avoid the over- or under- treatment and the related side effects. Studies on thyroxine (T4) requirement in obese subjects are scarce and were mostly carried out in thyroidectomized patients and/or in non standardized treatment schedule. We compared thyroxine requirement in normal, overweight and obese patients taking T4 in a tightly controlled fashion. Following the exclusion of patients non-compliant and/or using drugs and/or with diagnosed gastrointestinal disorders, 95 patients aged between 18 and 60 years were enrolled. The study group consisted in 60 overweight/obese hypothyroid patients with Hashimoto's thyroiditis (55F/5M; median age = 44years). This group was further subdivided in: 26 overweight (O), 17 class I obese (C-I), 10 class II obese (C-II), 7 class III obese (C-III). Thirty-five age-matched patients (34F, 1M; median age = 40ys) with normal BMI (<25 kg/m2) and similarly treated, represented the reference group (RG). All the patients enrolled were treated with oral T4 under fasting conditions and abstaining from eating or drinking for at least one hour after treatment. Once stably attained the desired serum TSH (0.8–2.5 mU/l), daily T4 requirement was compared in each subgroup. Normal patients showed higher median T4 requirement than the whole study group (1.27 vs. 1.15 μg/Kg/day; p < 0.0001). However, when subdivided by BMI value, normal and overweight patients exhibited an identical LT4 requirement (both 1.27 μg/Kg/day) to attain similar serum TSH values. In contrast, a significantly reduced need for T4 (-17%; p < 0.0001) was observed in obese as compared to both normal- and overweight patients. T4 requirement inversely correlated with BMI ranging from 1.12 μg/Kg/day (C-I; n = 17) to 1.00 μg/Kg/day; (C-II/III; n = 17) (-12%; p = 0.023). Daily T4 requirement is similar in normal and overweight patients while all classes of obese patients showed a progressively reduced need for T4 requirement. Weight-specific reference doses should be used to properly treat obese patients in an individually tailored fashion.
Disorders of Thyroid Function Thursday Poster Clinical
Although neurological symptoms have been associated with thyroid dysfunction, few studies have explored the impact of thyroxin levels on brain structure and cognition. We investigated the presence of depression, memory dysfunction and brain atrophy in patients with Graves'disease in hyper and euthyroidism. We evaluated 43 patients with Graves'disease, 20 patients with active hyperthyroidism (HYPERT,18 women, median 34 years; compared to 19 controls balanced for age and sex) and 23 euthyroid patients (under metimazol, controlled for at least six months) (EUTHYR, 20 women, median 49 years, compared to 22 controls balanced for age and sex). Subjects underwent 3T MRI, depression inventory (Beck Depression Inventory) and memory tests [Rey Auditory Learning Test –RAVLT (codification-COD, recall–RECA and recognition-RECOG). Images were processed with FREESURFER 5.3, wich yields automatic parcellation of brain structures. For imaging analysis, we compared EUTHYR (19 patients) with 36 paired controls; HYPERT group (14 subjects) was compared with 25 paired controls. Compared to controls, HYPERT group presented poorer performance on RAVLT-COD (p = 0.004) and RECA (p = 0.035); there was also a trend for higher BDI scores (p = 0.05). We identified significant inverse correlation between serum free thyroxine (FT4) and hippocampi volumes for right (r = -0.66, p = 0.015) and left side (r = -0.644, p = 0.018). Compared to controls, there were bilateral hippocampi volumetric reduction, although significant only at right side (p = 0.02).
EUTHYR patients presented only a trend for poor performance on RAVLT-RECA (p = 0.056); however, they presented significant reduction of left hippocampus (p = 0.02). No significant correlations were observed between hippocampi volumes and FT4, neither differences of BDI scores. Our preliminary analysis show a negative impact of higher FT4 levels on hippocampal volumes and memory performance, which only partially resolves when the patients reach euthyroidism. Although hormone levels normalize, our data suggest that changes in hippocampal volume may be permanent. Larger groups of subjects, with longitudinal analyses may further the interaction between FT4 and brain strucutures/function.
Thyroid Cancer Thursday Poster Clinical
Persistent post-treatment fatigue has been reported among thyroid cancer (TC) survivors. Our objective was to describe the severity of fatigue among TC survivors. We performed a cross-sectional survey of recent TC patients from a tertiary care Endocrinology clinic in Toronto, Canada. A paper-based, mail-out, survey containing demographic questions and the Brief Fatigue Inventory (BFI) was self-administered by patients. TC disease and treatment characteristics were ascertained by medical record review. The primary outcome was the global fatigue score (values <4 defined as mild, >7 severe, and others, moderate). DTC initial clinic-pathologic disease stage was defined by the American Thyroid Association (ATA) 2009 Risk of Recurrence Classification system. Data were reported descriptively. One-way ANOVA analysis was used to compare mean BFI global fatigue scores among ATA risk groups in DTC patients.
More than half of respondents (52.5%, 106/202) reported feeling unusually tired in the week before completing the survey. The mean global fatigue severity score was 3.5 (SD 2.4, range 0 to 9.6, N = 204). The distribution of fatigue severity score was categorized as follows: mild – 58.8% (120/204), moderate – 30.9% (63/204) and severe – 10.3% (21/204), respectively. Among DTC respondents, the mean global fatigue score according to ATA risk level was as follows: Low Risk – 3.4 (SD 2.5), Intermediate Risk – 3.7 (SD 2.1), High Risk – 2.6 (SD 2.7) (p = 0.582 for difference among groups).
Disorders of Thyroid Function Thursday Poster Clinical
In most clinical scenarios, biochemical assessment of thyroid function can be achieved with TSH alone. Additional free thyroid hormone (FTH) tests such as free thyroxine (fT4) and free triiodothyronine (fT3) are often requested in the absence of an appropriate clinical indication. As part of a quality improvement (QI) initiative, we examined the frequency and indications of FTH testing. All tests for TSH, fT4 and fT3 performed at University Health Network
Disorders of Thyroid Function Thursday Poster Case Report
Thyrotoxic periodic paralysis (TPP) is a rare complication of hyperthyroidism, most commonly Graves' disease.
We present a case of TPP in a 41 year old African American female with past medical history of Graves' disease and 2 prior episodes of TPP. Unique to this case was that her recovery was longer and symptoms worse on subsequent admissions for TPP. The patient presented to our hospital in January 2016 with severe proximal muscle weakness worse on the right side. Her potassium level was found to be 1.5 meq/L. Prior to her hospitalization she was taking methimazole 30 mg in divided doses and metoprolol 25 mg daily with good compliance. On admission her TSH was suppressed and Free T4 4.21 ng/dL and Free T3 9.4 pg/ml.
Subsequently, her methimazole was increased to 20 mg four times a day, metoprolol was continued and potassium iodine was added for acute treatment. Thyroid function tests improved to the normal range; however, potassium remained at 3.0 meq/L and muscle weakness persisted. On day 4, she was converted from metoprolol to propranolol. As a result of the change, potassium and muscle function improved significantly.
Our patient had two similar episodes of TPP in June and October 2015 and in both instances it took her only 1 day to recover muscle function and normalize her potassium. On both prior presentations her potassium was never below 2.0 meq/L. TPP is thought to be caused by elevated triiodothyronine (T3) and thyroxine (T4) acting on the Na-K-ATPase driving potassium intracellularly leading to a hypokalemic state and flaccid proximal muscle paralysis. Most of the literature discusses TPP in young Asian males occurring symmetrically and in the early morning of the summer months. Additionally, case reports show improvement of TPP with the use of propranolol but not selective beta 1 blockers like metoprolol. Our case is unique in that this occurred in an African American female in her 40s, with asymmetric presentation in the afternoon and in the winter. Interestingly, her episodes got subsequently worse over subsequent admissions and it took longer for the potassium and muscle symptoms to improve. Switching from metoprolol to propranolol led to quicker improvement.
Disorders of Thyroid Function Thursday Poster Case Report
Choriocarcinoma, a form of gestational trophoblastic disease, is a rare complication of pregnancy. It occurs in approximately 1: 70,000 pregnancies per year, and may occur after a normal pregnancy. There is established molecular mimicry between human chorionic gonadotrophin (hCG) and thyroid-stimulating hormone (TSH), and hence cross-reactivity with the TSH receptor. Our case demonstrates a rare form of hyperthyroidism secondary to choriocarcinoma.
Our patient is a 33-year-old female with no past medical history who initially presented with vaginal bleeding. Biopsy from her dilation and curettage was consistent with choriocarcinoma, and she was subsequently found to have pulmonary and brain metastases. She was started on methimazole 30 mg twice a day to prevent the development of thyroid storm in the context of hCG elevated to 432,110 mIU/ml. On admission for chemotherapy her thyroid function tests were found to be within normal limits, and methimazole was discontinued. Chemotherapy was delayed, and given new onset tachycardia, thyroid function tests were repeated showing TSH of <0.15 mIU/ml Free T4 4.71 ng/dL and Free T3 11.5 pg/mL. hCG had increased to 724,280 mIU/ml, and her Methimazole was resumed at 30 mg daily. Repeat hCG four days later was found to be 1.3 million mIU/ml and TSH was <0.15 mIU/ml with Free T4 3.29 ng/dL and Free T3 9.1 pg/mL. Methimazole was increased to 30 mg twice a day. Four days later thyroid function tests worsened with a suppressed TSH and Free T4 of 3.73 ng/dL and Free T3 of 11.9 pg/mL. Methimazole was increased to 40 mg twice a day. hCG subsequently decreased to 28, 311 mIU/ml after her first round of chemotherapy, and her methimazole was tapered over several days to 30 mg daily. Her chemotherapy included high dose dexamethasone which also helped to improve thyroid function.
hCG's potency for the TSH receptor is approximately 4000 times less than TSH, and therefore extremely high levels of hCG are usually required for a clinically significant effect on thyroid function. This case demonstrates the parallel rise and decline of Free T4 and hCG with chemotherapy. Early recognition and monitoring of thyroid function tests is important in the management of choriocarcinoma.
Disorders of Thyroid Function Thursday Poster Case Report
The objective of this presentation is to discuss a unique case of alternating thyroid autoimmunity and potential mechanism. A 39-year-old female with hypothyroidism on levothyroxine (LT4) for >3 years presented with one month of fatigue, tremors, heat intolerance, tachycardia, and Graves' ophthalmopathy. Her symptoms worsened despite decreasing LT4. Laboratory results showed TSH <0.01 m[IU]/L, free T4 3.19 ng/dL, free T3 15.9 pg/mL, thyroperoxidase antibody (TPO Ab) 533.3 IU/mL, and thyrotropin receptor antibody 15.00 IU/L. Thyroid ultrasound showed a normal sized, heterogeneous thyroid without discrete nodules. Her symptoms, free T4, and free T3 improved on dexamethasone, methimazole, and propranolol. After total thyroidectomy, pathology showed Hashimoto thyroiditis with areas of hyperplastic changes, adenomatous nodules, and a 1 mm incidental focus of Papillary Carcinoma. She resumed LT4 replacement and remains biochemically and clinically euthyroid. Conversion from primary hypothyroidism to hyperthyroidism is rare. This phenomenon has been reported in patients who develop a relative predominance of thyroid-stimulating autoantibodies (TSAb) compared to TSH blocking autoantibodies (TBAb). Expression of both antibody types have been reported in patients with environmental stimuli such as radiation therapy exposure, immune reconstitution after HIV suppression, post-partum Graves', and transient neonatal thyroid dysfunction. Reported cases are even fewer for patients who spontaneously switch from hypothyroid Hashimoto's thyroiditis to Graves' Disease as our patient did. The literature suggests LT4 therapy may adversely alter dendritic and regulatory T cell function leading to the emergence of TSAb. On the contrary, de novo development of TSAb in TPO Ab positive patients may simply be a coincidence. More studies are needed to understand the pathophysiology of hypo- and hyperthyroidism conversion. Providers should be aware that spontaneous conversion to Graves' Disease is possible in a patient with longstanding, treated hypothyroidism. Further studies are warranted to elucidate thyroid autoimmune physiology that mediates this switch from hypo- to hyperthyroidism and vice versa.
Disorders of Thyroid Function Thursday Poster Case Report
Oral LT4 remains the mainstay of treatment of Hypothyroidism. Few cases in literature have been reported in which Refractory Hypothyroidism responded only to oral LT3. We aim to provide a possible explanation of LT4 malabsoption in a female patient with Liver Disease and Intestinal Resection due to Carcinoid Tumor which received escalating dosage of LT4 without resolution of Hypothyroidism. Case of a 45 y/o woman with T2DM, Hypothyroidism, NASH which underwent a pancreatoduodenectomy due to a duodenal neuroendocrine non-hormone producing tumor. Developed high TSH, fatige and constipation after the procedure. On examination, she had dry skin, peripheral edema, hepatomegaly, B/P of 110/60 mm Hg, BMI of 39.45 kg/m2. Labs showed anemia, low 25-hydroxyvitamin D, and high levels of TSH, transaminases and ammonia. Gastrin levels were 76 pg/mL (0–115 pg/mL). She was started on IM LT4 injections but discontinued due to negative receptivity. She was subsequently provided with oral LT4 but maintained persistent high TSH level despite compliance with oral LT4. Thyroid profile on 200 mcg of oral LT4 showed TSH of 59.46 μIU/ml and low FT3, FT4. She was then initiated on oral LT4 plus oral LT3 achieving euthyroid state. Doses provided were 200mcg and 75mcg respectively. FT4 and FT3 values with combination therapy were 0.46 ng/dL (0.8–2.8 ng/dL) and 3.68 pg/mL (1.4–4.2 pg/mL) accordingly. Low absorption continued despite administration of high doses of oral LT4. We contemplate that high TSH levels come forth due to selective LT4 malabsorption, suggested by normal FT3, TSH and low FT4. Reduced gastric acid production after intestinal resection may impair LT4 absorption, however in our case gastrin levels were normal. This is a unique case of clinical and biochemical hypothyroidism on a patient with liver disease that underwent intestinal resection. Summative hepatic disease could worsen LT4 hepatoenteric absorption since the liver is one of the major sites of T4 conversion to T3. We know that T3 is not firmly bound to serum protein, making it readily available to body tissues. This proves that oral LT3 could be of benefit in specific cases. To our knowledge, there is no report describing improvement of hypothyroidism by T3 ingestion.
Disorders of Thyroid Function Thursday Poster Case Report
Euthyroid hypothyroxinemia is characterized by low total T4 and T3 but normal free T4 and TSH. This occurs in thyroxine-binding globulin (TBG) deficiency and relying on total T4, rather than free T4, can lead to a false diagnosis of hypothyroidism. We present a patient with likely hereditary TBG deficiency who was misdiagnosed with hypothyroidism and developed iatrogenic atrial fibrillation (AF). A 70-year-old man with AF was referred to Johns Hopkins Endocrinology clinic for evaluation of hypothyroidism. Hypothyroidism had been diagnosed two years earlier when evaluation for fatigue revealed TSH 2.7 mU/L and total T4 2.1 ug/dL. Despite increasing levothyroxine (LT4) dose, the total T4 was persistently low with suppressed to normal range TSH and there was no symptom improvement.
Two months earlier, he had been hospitalized for new onset AF. While inconsistently taking LT4 200 mcg daily, TSH was 0.06 mU/L (0.36–3.74) and total T4 was 2.2 ug/dL (4.5–12.1). Three days later, TSH was 0.87 mU/L, total T4 2.0 ug/dL and free T4 1.13 ng/dL (0.76–1.46). Evaluation for central hypothyroidism included normal pituitary MRI and adrenal insufficiency was ruled out.
He presented to our clinic with ongoing weakness. He weighed 92 kg and the general physical and thyroid exams were normal. The history was suspicious for euthyroid hypothyroxinemia. TBG measured by ICMA was <4 ug/mL confirming TBG deficiency. TSH was 0.006 mU/L, free T4 2.83 ng/dL, T4 4.3 ug/dL, and T3 70 ng/dL. LT4 was discontinued and 3 months later, his weakness and fatigue had drastically improved with TSH 5.12 mU/L and total T4 2.1 ug/dL – free T4 measurement was omitted by his referring provider. Reduction in TBG occurs in X-linked recessive TBG deficiency, protein-losing conditions, major systemic illnesses, and use of drugs that decrease TBG concentration (ie. androgenic steroids, danazol). This leads to low total T4 but normal free T4 in euthyroid individuals. Misdiagnosis of hypothyroidism can lead to unnecessary treatment. Relying on total T4 and ignoring TSH can lead to a false diagnosis of central hypothyroidism in euthyroid hypothyroxinemia and thus, free T4 or assessment of TBG or TBG binding capacity is crucial to making the correct diagnosis.
Disorders of Thyroid Function Thursday Poster Case Report
Nivolumab is one of the human immunoglobulin G4 (IgG4) monoclonal antibody agents (anti-PD-1-mAb). It selectively inhibits programmed cell death-1 (PD-1) of T cells leading to unrestrained T cell activation and anti-tumor activity. It can also cause an activation of T cells against host cells and immune-mediated endocrine adverse events. Nivolumab associated auto-immune diabetes mellitus, hypophysitis, thyroid and adrenal dysfunction have been reported. Nivolumab is currently approved for the treatment of melanoma, metastatic non-small cell lung cancer, and advanced renal cell cancer. We report a case of Nivolumab-induced thyroid dysfunction in a 58-year-old man with metastatic clear cell renal cell carcinoma. The patient had normal thyroid function tests (TFTs) prior to treatment with Nivolumab. He presented with symptoms of hyperthyroidism 28 days after receiving the first dose of Nivolumab. TFTs showed low TSH and high free T4 of 3.89 ng/dl (ref: 0.60 – 1.60 ng/dL). Hyperthyroidism symptoms quickly resolved with symptomatic treatment. Thyroid scan showed an uptake of 1.1%, suggestive of thyroiditis. He quickly became hypothyroid with a TSH of 94 mIU/ml (ref: 0.34 – 5.6 uIU/mL) and low FT4, 4 weeks after initial manifestations of thyroid dysfunction. Normalization of TFTs was achieved with Levothyroxine. The reported incidence and onset of thyroid dysfunction (hyperthyroidism and hypothyroidism, or autoimmune thyroiditis) after initiation of anti-PD-1-mAbs is 1.8 - 9% and 2.8 months (range: 15 days - 13.8 months), respectively. Hypothyroidism occurred more frequently in patients receiving combination therapy with the cytotoxic T-lymphocyte antigen 4 monoclonal antibody, Ipilimumab. The occurrence rate of hypothyroidism varied with underlying cancers (22% in melanoma patients vs 8% in renal cell cancer patients). Spontaneous resolution of thyroid dysfunction in mild cases has been reported but some developed permanent hypothyroidism. Discontinuation of Nivolumab therapy is rarely necessary.
In summary, our case highlights the need to obtain baseline and interval TFTs in patients receiving Nivolumab to have an early diagnosis of immune-related thyroid dysfunction.
Disorders of Thyroid Function Thursday Poster Case Report
Hashimoto's thyroiditis subjects individuals to lifelong therapy with levothyroxine. Ensuring correct medication administration and compliance provides a challenge to providers. 70 yo woman who presented for management of treatment-refractory hypothyroidism. Symptoms included sleepiness. HR and BP were normal. Thyroid was normal in size without nodules, skin dry without edema, reflexes normal. TSH was 62.5 on levothyroxine 350 mcg daily (1.5 mcg/kg dose 150 mcg). Pt reported good compliance with the levothyroxine and review of her med list did not reveal increased metabolizers of levothyroxine. UA neg for proteinuria, tissue transglutaminase panel negative, and reverse T3 was 6 (low). Directly observed therapy in our endocrine clinic of her full weekly 1.5 mcg/kg/day dose of levothyroxine resulted in a quadrupling of the free T4 two hours after administration, thus malabsorption was unlikely, and the likely diagnosis was medication non-compliance. The pt was instructed to take once-weekly levothyroxine at home, but this did not normalize TSH, which was still 31.1. Home visiting nurse services were not covered by insurance and the pt was unable to come to our endocrine office every week, so the pt was arranged for weekly directly observed therapy at her primary care office with subsequent TSH improvement to less than 10. While the differential for treatment-refractory hypothyroidism includes underlying pathology such as nephrotic syndrome, malabsorptive diseases, or consumptive hypothyroidism, it is important to take a thorough medication history, as the most common etiology will involve medication indiscretions. One strategy to address this issue is weekly dosing of levothyroxine, which simplifies the regimen for the pt and has been shown to normalize TFTs and reduce the overall dose (Grebe et al. 1997 JCEM). While caution must be shown with underlying cardiac disease, endogenous autoregulatory mechanisms will prevent marked fluctuations in active thyroid hormone to approximate euthyroidism. This case exemplifies the benefits of once weekly levothyroxine dosing, which allows for more convenient directly observed therapy.
Disorders of Thyroid Function Thursday Poster Case Report
TSH-secreting pituitary adenomas (TSH-omas) are uncommon cause of hyperthyroidism due to inappropriate secretion of TSH characterized by elevated levels of FT4, FT3 with unrepressed TSH. Ectopic TSH-omas are even rarer. To date, there are only six cases reported. What's more, none of them has thyroid neoplasm simultaneously. A 27-year-old female was referred to the hospital in 2002, complaining of neck enlargement and palpitation. Thyroid function assay showed increased thyroid hormone with unrepressed TSH. Thyroid ultrasound examination revealed diffuse goiter. The patient was presumptively diagnosed as primary hyperthyroidism and treated with anti-thyroid drugs. Her condition was then improved but the serum TSH was persistently elevated. Therefore, central hyperthyroidism due to TSH-oma or pituitary resistance to thyroid hormone (PRTH) was alternatively suspected. Pituitary MRI was deservedly performed to rule out TSH-oma and it turned out to be normal. Hence, PRTH, as another uncommon cause of inappropriate TSH secretion, was regarded as the working diagnosis. Triiodothyroacetic acid was then administrated but it didn't work well. To control the symptoms completely and normalize the serum thyroid hormone as well as TSH, radioiodine therapy was carried out in 2007, followed by levothyroxine replacement therapy. Unfortunately, though the symptoms were relieved, serum TSH remained high levels even with adequate levothyroxine in the following five years. Unexpected, thyroid papillary carcinoma and a neoplasm in her nasopharynx were successively detected in 2012. Then, they were resected concurrently. Somewhat interestingly, the serum TSH gradually declined to normal right after the operation. With reverse transcription PCR and immunohistochemistry, the neoplasm in her nasopharynx was confirmed to be an ectopic TSH-oma. Though extremely rare, ectopic TSH-oma, as an uncommon cause of thyrotoxicosis, should be taken into consideration especially among those who have a longstanding central hyperthyroidism but do not meet the criterions of eutopic TSH-oma or PRTH. This may be the first case of an ectopic TSH-oma concomitant with papillary thyroid carcinoma occurring after radioiodine therapy.
Iodine Uptake & Metabolism Thursday Poster Basic
In thyroid cancer, a reduction in sodium iodide symporter (NIS) expression at the basolateral plasma membrane (PM) of thyrocytes decreases the efficacy of radioiodine imaging, ablative therapy and treatment of metastases. NIS overexpression in breast cancer has resulted in radioiodine being widely proposed as a novel therapeutic strategy. However, uptake is insufficient for tumor destruction. Augmenting NIS PM localization represents an important therapeutic strategy for increasing radioiodine delivery in both tumor types. We previously described a mechanism by which NIS is internalized by pituitary tumor-transforming gene-binding factor (PBF) in thyroid cells, significantly reducing radioiodine uptake. PBF phosphorylation at Y174 by Src kinase mediates NIS repression, which can be rescued by the Src family kinase (SFK) inhibitor PP1. We have now replicated these findings in breast cancer cells, further elucidated the mechanism of repression and identified a more potent inhibitor of PBF-pY174. In MCF-7 and MDA-MB-231 breast cancer cells PBF significantly repressed radioiodine uptake and this was reversible with PP1 treatment. Mutation of a predicted Src consensus sequence (EEN170-172AAA) abrogated pY174 and radioiodine uptake repression. PBF-pY174 was most potently inhibited by the SFK inhibitor dasatinib, which restored PBF-mediated radioiodine uptake. In the presence of dasatinib-resistant Src (T341I), dasatinib no longer rescued PBF repression of NIS, indicating that Src specifically mediates PBF phosphorylation. A post-translational modification of Src, myristoylation, inhibits Src plasma membrane localization. Utilizing a new high affinity inhibitor of myristoylation, N-myristoyltransferase inhibitor 3 (NMTi3), radioiodine uptake in MDA-MB-231 cells lentivirally expressing NIS was significantly increased. Interestingly, combined dasatinib and NMTi3 treatment synergistically induced endogenous radioiodine uptake in MCF-7 cells (p < 0.01; N = 3). Taken together, these data suggest that Src inhibition can effectively enhance radioiodine uptake in multiple tumor types, with implications for improving outcomes in thyroid cancer and making radioiodine a potentially viable new strategy for breast cancer treatment.
Thyroid & Development Thursday Poster Basic
Thyroid nodules are common and often benign, although prove to be malignant upon surgical pathology in 5–15% of cases. When assessed with ultrasound-guided fine-needle aspiration (USFNA), 15–30% of the nodules yield an indeterminate result. The Afirma® gene expression classifier (AGEC) was developed to improve management of indeterminate thyroid nodules (ITNs) by classifying them as “benign” or “suspicious.” Objectives were (1) to assess the performance of the AGEC in two Canadian academic medical centres, (2) to search for inter-institutional variation and (3) to compare AGEC performance in Canadian versus American institutions. We undertook a retrospective cohort study of patients with indeterminate cytopathology (Bethesda Class III or IV) as per USFNA who underwent AGEC testing. We reviewed patient demographics, cytopathological results, AGEC data and, if the patient underwent surgery, results from their final pathology. In total, 202 patients with Bethesda Class III or IV thyroid nodules underwent AGEC testing, 114 in Montreal, Quebec and 88 in St. John's, Newfoundland. Among the nodules sent for testing, 53% (60/114) in Montreal and 32% (28/88) in St. John's returned as “benign.” None of these patients underwent surgery. On the other hand, 47% (54/114) nodules in Montreal and 54% (48/88) in St. John's were found to be “suspicious,” for a total of 102 specimens. To date, 73 of these patients have undergone surgery. Both in Montreal and St. John's, the final pathology yielded malignant thyroid disease in approximately 50% of the specimens categorized as “suspicious.” Since 2013, no patients diagnosed with a benign nodule as per AGEC testing was found to harbor a malignant thyroid nodule on follow-up. Molecular analysis is increasingly used in the management of indeterminate thyroid nodules. This study highlights the experience of two Canadian centres with AGEC testing. We found inter-institutional variability in the rate of nodules returning as “benign,” however we found similar rates of confirmed malignancy in nodules returning as “suspicious.” According the literature, results for AGEC testing in two Canadian institutions align with results reported in American centres.
Thyroid & Development Thursday Poster Clinical
Minimally invasive thyroid surgery has experienced an evolution from small incision transcervical approaches to remote access endoscopic and robotic approaches. Various extracervical approaches have been devised including the transaxillary and retroauricular robotic approaches which have been limited by unilateral access, increased tissue dissection and an unfamiliar approach with steep learning curve. The transoral approach has been introduced to overcome these limitations and has recently entered the clinical realm. To describe our centers' experience with transoral robotic thyroidectomy with particular attention to the technical details and modifications to facilitate this approach. Transoral robotic thyroidectomy was performed in live human patients at Korea University Hospital. Significant technical modifications to avoid mental nerve injury and facilitate the approach were employed. Patient demographic and operative data were recorded. All patients successfully underwent transoral robotic thyroid lobectomy without need for open conversion. Four right lobectomies and three left lobectomies with a central neck dissection for papillary thyroid microcarcinoma, one left lobectomy with a central neck dissection for follicular adenoma, one right lobectomy with a central neck dissection for nodular hyperplasia, one right lobectomy for nodular hyperplasia were performed in the human subjects using a robotic transoral approach. There was no adverse event. Sensory testing for mental nerve function demonstrated minimal transient hypesthesia. Cosmetic outcomes and patient satisfaction were favorable. The continued evolution thyroid surgery seeks to find a minimally-invasive, midline approach with avoidance of a visible scar. Differently from the previously introduced extracervical approached, the transoral approach is particularly attractive in that it affords a direct approach to the central neck through the lower lip with limited tissue dissection and the ability to perform a total thyroidectomy with bilateral central neck dissections. We demonstrate that this approach is feasible and holds great promise in the search for the ideal extracervical approach to the thyroid.
Thyroid & Development Thursday Poster Case Report
Acute suppurative thyroiditis (AST) is uncommon given the relative resistance of the thyroid gland to infection. It typically presents with neck swelling, pain and fever, and is most commonly associated with a piriform sinus fistula (PSF). Hyperthyroidism at presentation is rare with few cases in the adult literature and no published reports in pediatrics. An 8 year old previously healthy African American female presented initially for evaluation of left sided neck swelling and was diagnosed with cervical lymphadenopathy. Failing to improve on oral antibiotics, she returned to the ER a week later. CT scan of the neck showed “a moderate sized mass not distinguishable from the thyroid”. Laboratory workup revealed elevated FT4 2.07 ng/dl (0.8–1.8), suppressed TSH 0.05 uIU/ml (0.35–5.5), and normal Thyroid Stimulating Ig 23% (0–139). Fine needle aspiration showed gram positive cocci, gram positive & gram negative rods. She was admitted for incision and drainage of abscess and IV antibiotics. Cytology of abscess fluid showed inflammatory cells and macrophages, culture grew Streptococcus and Eikenella. She improved rapidly and was discharged home on oral Cefdinir. At follow-up, she was clinically euthyroid. Thyroid function tests were monitored, normalizing about 2 weeks later. A neck US 4 weeks later showed features of pyriform sinus fistula and fourth branchial apparatus anomaly. She was then referred to ENT for surgical management. AST is rare, the most common underlying abnormality being congenital PSF. Although most patients are euthyroid, transient hyperthyroidism may be seen due to destruction of thyroid follicles. Imaging to clarify an anatomic defect is best done after resolution of the acute infection. Further imaging for direct inspection of sinus tract followed by fistulectomy to prevent recurrence may be required. In a child with left sided neck pain and swelling, underlying PSF may be overlooked leading to recurrence of infection. Rarely, transient hyperthyroidism may be seen. Duration between presentation and diagnosis can be decreased by maintaining a high degree of suspicion based on history and location of abscess. Prompt referral to a surgeon is essential for definitive management.
Thyroid Cancer Thursday Poster Basic
The crucial role of cancer stem-like cells (CSCs) in relapse and metastatization has recently emerged. In thyroid cancer (TC), CSCs are involved in the resistance to treatment observed in fatal cases of poorly differentiated and anaplastic TC. CSCs are able to form three-dimensional thyrospheres in vitro, and allows to test the response to novel therapeutic compounds. We tested the effects of a multikinase inhibitor that we recently characterized, SP600125 (SP), on the spheres derived from differentiated and undifferentiated thyroid tumors (TS) and from paired normal tissue (NS) obtained after surgery. Both TS and NS were treated for 96 hours with SP and effects on growth, morphology and main signaling pathways were analyzed by different methods. Cells with stem-like properties were documented in benign and malignant diseases and were propagated in culture as non-adherent spheres.
Our results showed that SP has significant growth inhibitory effects only on TS. After SP treatment, TS are smaller and tend to disaggregate, indicating the loss of CSCs characteristics. Moreover, TS showed significant alterations in two main regulators of cell proliferation and stem-like phenotype, b-catenin and p53. SP treatment was able to significantly reduce the levels of b-catenin.
In addition, our findings revealed for the first time that there is a significant increase in ROCK activity in TS with respect to either NS or tumor or normal tissues. The treatment with SP is able to restore normal levels of ROCK activity. These data are in agreement with our previous findings in undifferentiated thyroid cancer tissues. Moreover, the enrichment in CSCs, revealed that SP is effective also against differentiated thyroid cancers, especially on that subset of cells responsible for metastatization and therapy resistance. In conclusion, we widely characterized stem-like cells in thyroid tissues and in the corresponding thyrospheres. This in vitro model is expected to become a valuable platform to test the effects of novel compounds on stem-like cells. Consistently, our data show that SP has the potential to revert the alterations present in stem-like cells that are responsible for thyroid cancer aggressiveness.
Thyroid Cancer Thursday Poster Basic
Encapsulated follicular variant of papillary thyroid cancer (EFVPTC) represents an indolent entity in the absence of invasion and has been therefore recently renamed “non-invasive follicular thyroid neoplasm with papillary like nuclear features” (NIFTP). We aimed to analyze a cohort of thyroid carcinoma with distant metastasis and identify whether there are cases of NIFTP. We conducted a retrospective study of patients diagnosed as thyroid cancer with distant metastasis at Gustave Roussy Institute. Histological slides were reviewed by two pathologists. The following features were reported: type and subtype of the tumor, presence of tumor capsule, capsular invasion, extrathyroid extension, vascular invasion, presence of necrosis and mitotic index. We analysed 183 cases of thyroid carcinoma with distant metastasis from our department. The primitive tumor was available for 96 patients. Fifty-four cases (56%) were classified as papillary carcinoma, 18 cases (19%) as well differentiated and pleomorphic follicular carcinoma, and 24 cases (25%) as poorly differentiated carcinoma. We found 10 cases of follicular variant of papillary carcinoma (19%) and, within this subset, 3 cases were encapsulated carcinoma with capsular and vascular invasion. There was no case of non-invasive encapsulated follicular variant of papillary thyroid cancer (NIFTP). Papillary carcinoma represents the most common type of metastatic thyroid carcinoma in our cohort of thyroid carcinoma with distant metastasis. Almost 6% of them were encapsulated follicular variant of papillary carcinoma. All of them were invasive. Thus, it is essential to perform a careful and complete histological examination of the tumor capsule in order to determine the presence of invasion of the encapsulated lesion. This work correlates with the recent findings showing the indolent behavior of non-invasive encapsulated follicular variant of papillary thyroid cancer (now termed NIFTP).
Thyroid Cancer Thursday Poster Basic
Fine Needle Aspiration Biopsy (FNAB), a gold standard method in histopathological diagnosis of thyroid nodules, can be insufficient in the characterization and diagnosis of the follicular variant of papillary thyroid carcinoma (FVPTC). In some cases, when no certain diagnosis is made for FVPTC there is a need for a second surgical operation to remove the other thyroid lobe. In this work, we analyzed peptides in Follicular and Classic Variants (CV) of Papillary Thyroid Carcinoma (PTC), using Matrix-assisted laser desorption/ionization-Imaging Mass Spectrometry (MALDI)-Imaging Mass Spectrometry (IMS) as it requires no homogenization prior to analysis and enables the localization of molecular species along with histology. 10 Formalin fixed paraffin embedded (FPPE) PTC tissues (n = 5 for FVPTC and n = 5 for CVPTC) were used. Tissues underwent antigen retrieval procedure. On tissue digestion was performed using proteolytic enzymes to cleave proteins into peptides. Mass spectra have been acquired using Autoflex III Smartbeam MALDI-TOF/TOF mass spectrometry (Bruker Daltonics GmbH, Bremen, Germany). All acquired spectra range from m/z 600 to 2000, with a raster of 200 micrometers. Samples were stained with hematoxylin and eosin (H&E) for investigating MS data with corresponding histological features. Evaluation of the results was based on single peptide localizations and hierarchical clustering analyses in correlation with histological features. In this preliminary work, up to 250 monoisotopic peaks were detected in the mass spectra of both CVPTC and FVPTC. Numerous peptides correlated with histological structures, which were emphasized by tissue-specific results of hierarchical cluster analyses. This study provided a solid basis for the accurate and reliable identification of more than 50 other peptides. The work presented here demonstrates the capability of MALDI-IMS to accurately classify peptides from CVPTC and FVPTC. It provides a broad knowledge about IMS studies in thyroid pathology and can be further extended to an increased size of sample set with high spatial resolution for biomarker discovery.
Thyroid Cancer Thursday Poster Basic
Src is a promising therapeutic target in thyroid cancer. In addition, our lab recently demonstrated that combined Src and MEK1/2 inhibition results in enhanced anti-tumor responses in vitro and in vivo and improved survival in preclinical in vivo models. In this current study we hypothesized that by defining biomarkers of response, the efficacy of the combination therapy would be enhanced. Dasatinib IC50 values were determined by Cell Titer-Glo assay. Signaling responses were defined using western blot analysis and IHC. Herein, we determined 11 thyroid cancer cell lines were sensitive to single agent dasatinib (<90 nm), and 25 were resistant. Interestingly, 3/3 dasatinib-sensitive and 3/6 dasatinib-resistant BRAF- and RAS-mutant cell lines tested demonstrated elevated apoptosis in response to combined Src/MEK therapy. However, no response was observed in response to the combination in the 3 PIK3CA-mutant cell lines tested. Differential sensitivity was not due to lack of drug efficacy, as both the downstream target of Src (pFAK-Y861) and MEK1/2 (ppERK1/2) were effectively inhibited by the combination treatment in all cell lines. We next analyzed signaling responses to the combination therapy on the PI3K pathway. Surprisingly, BRAF- and RAS-mutant cell lines that were intrinsically resistant to dasatinib exhibited 5–6 fold higher baseline AKT-S473 phosphorylation levels in comparison to the sensitive cell lines, and the levels were similar to those observed in the PIK3CA-mutant cell lines (4- and 8-fold). Interestingly, combined Src and MEK1/2 inhibition in the dasatinib-resistant BRAF- and RAS-mutant cell lines effectively inhibited the PI3K pathway resulting in a synergistic (> 10-fold) reduction in pS6-S235 phosphorylation. Finally, RAS-mutant (Cal62) tumors treated with combined Src and MEK1/2 inhibitors exhibited a significant 1.5-fold reduction in S6-S235 phosphorylation in the combination treated group in comparison to the vehicle control (p = 0.041). Taken together, The PI3K pathway may play an important role in mediating dasatinib-intrinsic resistance and effective inhibition of S6 phosphorylation is a predictive biomarker for increased apoptosis and response to combined inhibition of Src and MEK1/2.
Thyroid Cancer Thursday Poster Basic
Thyroid tumorigenesis is a multistep process involving the alteration of oncogenes and tumor suppressor genes. We have previously reported that the expression of the POZ and Zinc finger transcription factor PATZ1 is down-regulated in human thyroid carcinomas, particularly in poorly differentiated and anaplastic carcinomas. We have also reported that the restoration of PATZ1 expression partially reverted the malignant phenotype of thyroid carcinoma cell lines and that PATZ1 directly regulates p53-target genes involved in EMT and cell migration, an ability that likely accounts for the role of PATZ1 in thyroid cancer progression. To further understand the role of PATZ1 impairment in thyroid carcinogenesis, we investigated the consequences of the loss of PATZ1 expression in the context of a mouse modeling of papillary thyroid cancer. To this aim we crossed transgenic mice carrying the Ret/PTC1 oncogene under the thyroid specific control of the thyroglobulin promoter with heterozygous Patz1 knockout mice, and analyzed onset and histo-pathological features of thyroid tumors in Ret/PTC1 mice carrying one or two Patz1-null alleles in comparison with Patz1 wild-type (Ret/PTC1;Patz1+/+) compound mice. We found that double mutant mice homozygous for a Patz1-null allele (Ret/PTC1;Patz1-/-) display a higher incidence of thyroid carcinomas, with a shorter latency period of onset, compared with Patz1 wild-type and heterozygous (Ret/PTC1;Patz1+/-) compound mice. By 15 months of age, significant histo-pathological and molecular differences were also observed between Ret/PTC1;Patz1+/- and Ret/PTC1;Patz1+/+ mice, including development of anaplastic carcinomas and increased expression of both ERK and AKT pathway in Patz1+/- compound mice. Therefore, our results suggest that PATZ1 loss enhances thyroid carcinogenesis driven by the Ret/PTC1 oncogene and support a role for PATZ1 in thyroid cancer progression, likely acting in a dose-dependent manner.
Thyroid Cancer Thursday Poster Basic
Our aim was to investigate the association between YAP protein expression an clinicopathological features in papillary thyroid cancer (PTC). All available clinical and pathological data were reviewed in 88 patients with PTC. Tissue microarray immunohistochemical (IHC) method to analyze the correlation of YAP protein expression and clinicopathological characteristics of cases with PTC. Excluded some cases that off-chip or other reasons which we could not obtain the information, 88 patients were included for our analysis. Male accounted for 32 (36.4%) and <45 year old accounted for 41 (46.6%) in all these cases, maximum tumor size = <2 cm were 45 cases, accounting for 51.1%; TNM stage I, II, III, IV were 36 cases (40.9%), 13 cases (14.8%), 33 cases (37.5%), 6 cases (6.8%), respectively. Tumors located in unilateral occupied 87.5% (77/88) of patients, and 11 cases (12.5%) were found bilateral. Lymph node metastasis was found in 46.6% (41/88) of patients. YAP protein expression correlated with TNM stage and lymph node metastasis significantly in papillary thyroid cancer (all P value <0.05); however, there was no significant different between YAP expression and age, six, maximum tumor size, tumor location in PTCs. YAP protein were significantly associated with aggressive behavior of PTCs. YAP may as a new potential therapeutic target in PTC.
Thyroid Cancer Thursday Poster Basic
There are limited therapies for patients with advanced thyroid cancer. We have shown that Src is a clinically relevant target in thyroid cancer however, resistance to single-agent therapies inevitably arise. To more effectively target Src and combat mechanisms of resistance, thyroid cancer cell lines resistant to the FDA-approved Src inhibitor, dasatinib were generated. Previously we have shown that dasatinib-resistant (DR) cells are sensitive to the Src inhibitor bosutinib. A compound centric chemical proteomic screen identified FAK as a unique target of bosutinib. Src and FAK signal as a complex to mediate cellular proliferation and invasion. We have previously shown that FAK is overexpressed and activated in thyroid cancer. We hypothesize that thyroid cancer cells may adapt to chronic Src inhibition by promoting FAK signaling. Signaling and cell growth was assessed via Western blot and sulforhodamine B assays, respectively. Invasion was evaluated using matrigel-coated Boyden chambers. An increase in activated FAK (pY397FAK) is observed in both BRAF- and RAS-mutant DR cells compared to control cells. Interestingly, inhibition of FAK kinase activity with two FAK inhibitors, PF-573,228 and PF-562,271, overcomes resistance to dasatinib only in the BRAF-mutant DR cells (2–10-fold increase in sensitivity), but not in the RAS-mutant cells. We previously showed the MAPK pathway mediates dasatinib resistance. PF-562,271 treatment does not affect ERK phosphorylation, indicating that FAK and ERK are parallel drivers of dasatinib resistance in BRAF-mutant cells. Additionally, co-treatment with dasatinib and PF-562,271 in thyroid cancer cell lines has synergistic effects on growth inhibition. As FAK mediates invasion, we observe an increase in invasion in the BRAF-mutant DR cells (1.3-2-fold), while the RAS-mutant DR cells are less invasive (2-3-fold) than their control counterparts. Inhibition of FAK with PF-562,271 attenuates invasion of only the BRAF-mutant DR cells. Taken together, our data suggests that BRAF-mutant DR cells are more dependent on FAK signaling and that FAK may mediate an inhibitor-induced invasive phenotype. Thus, co-targeting FAK and Src may prove to be efficacious in thyroid and other cancers.
Thyroid Cancer Thursday Poster Basic
The telomerase reverse transcriptase (TERT) promoter mutations, in association with BRAF V600E and RAS mutations, have been reported to be associated with poor outcomes of papillary thyroid cancer (PTC). These findings require confirmation, which we pursued in the present study using The Cancer Genome Atlas (TCGA) PTC data. A total of 388 patients with available information on TERT promoter mutation, BRAF V600E mutation, RAS mutation, and clinical outcomes were extracted and analyzed from the TCGA database. Of the 388 patients, 226 (58.2%), 49 (12.6%), and 39 (10.1%) patients harbored BRAF, RAS (including NRAS, HRAS or KRAS), and TERT promoter mutations, respectively. Mutual exclusion between BRAF and RAS mutations and their significant association with TERT promoter mutations were observed (P = 0.015). When patients with RAS mutations were excluded, coexisting BRAF and TERT promoter mutations were synergistically associated with high-risk chinicopathologic characteristics, including older patient age, extrathyroidal invasion, advanced stages, higher recurrence and mortality rates. Similarly, after excluding the patients with BRAF mutation, coexisting RAS and TERT promoter mutations were synergistically associated with high-risk characteristics, including distant metastasis and recurrence. As a specific illustration, recurrence rate was 100% (6 of 6) vs 6.9% (6 of 87) in patients harboring both RAS and TERT promoter mutation versus patients harboring neither mutation (HR, 2.1; 95% CI, 1.6–2.7), which remained significant after adjustment for clinicopathologic factors. Of the TERT promoter mutation-positive patients, 34 (87.2%) harbored BRAF/RAS mutations. These patients showed worst chinicopathologic outcomes. Disease-free patient survival curves displayed a moderate decline with BRAF/RAS mutation alone but a sharp decline with coexisting BRAF/RAS and TERT promoter mutations. This study on the valuable TCGA data confirmed the role of TERT promoter mutations, particularly when associated with the BRAF/RAS mutation, in the aggressiveness of PTC, establishing their robust prognostic values for PTC.
Thyroid Cancer Thursday Poster Basic
Anaplastic thyroid cancer (ATC) is a very aggressive cancer, leading to death in 100% of patients in a few months. Insights into mechanisms that sustain ATC growth and metastatization, and the identification of novel therapeutic targets, are extremely needed. We previously found that ATCs express high levels of BAG3, a member of the BAG family of co-chaperone proteins, which is involved in various cellular processes, such as cell survival, proliferation, apoptosis and epithelial-mesenchymal transition. We have also showed that BAG3 protein interferes with HSP70-mediated delivery of BRAF to the proteasome and that its down-modulation, resulting in BRAF levels reduction, sensitizes thyroid cancer cells to apoptosis. The aim of this study is to investigate BAG3 role in ATC identifying and characterizing the entire set of BAG3 regulating protein partners. We used Stable-Isotope Labeling by Amino acids in Cell culture (SILAC) combined with mass spectrometry analysis to decipher BAG3 interactoma in 8505C ATC cell line harboring BRAF V600E mutation. Protein expression data from bag3- silenced compared to control cells allowed us to identify candidate targets of BAG3-mediated regulation in ATC cells. Total protein extracts obtained from wild type 8505C cells, BAG3 siRNA- and NT siRNA-treated 8505C cells were trypsin digested and analyzed by mass spectrometry, furthermore the mRNA extracted from the same cells has been analyzed by RTq-PCR. In the preliminary results we identified 6 proteins differentially expressed in BAG3-silenced samples compared to controls. Interestingly, in BAG3-silenced cells we detected SDPR, CAV1 and G3BP1 down-regulation, and FAM192A, PAI2 and HMGA2 up-regulation. These proteins are known to be associated to tumorigenesis through different biological processes. In particular our attention is focused on CAV1, PAI2 and HMGA2 that has been validated by RTq-PCR analysis. CAV1 and PAI2 proteins were analyzed by immunohistochemistry on thyroid tissues. In this study we identify BAG3/BRAF downstream proteins targets and these results may contribute to understand the molecular mechanisms that sustain ATC growth and metastatization and to identify novel prognostic and therapeutic targets.
Thyroid Cancer Thursday Poster Basic
The frequent initial manifestation of thyroid cancer is the appearance of a nodule, extremely common and in the great majority of cases (95%) it is simply hyperplasia or benign lesion. The most reliable diagnostic test for thyroid nodules is Fine Needle Citology (FNC), but cytological discrimination between malignant and benign follicular neoplasms remains difficult. The cytological analysis can benefit of molecular biology techniques more and more frequent in clinical routine diagnostics. The aim of our work was to study the molecular analysis by using a fast execution mutations panel related to genes B-Raf, Ras, Ret and Ret/PTC rearrangement on FNC washer to provide the clinician more precise accurate diagnostic indication useful to patient management. Until a few years ago, to detect mutations in thyroid informative genes, each exon of interest (Braf exon 15, and H-K-N-RAS exons 2 and 3) and Ret/PTC1 and Ret/PTC3 rearrangements had to be PCR amplified separately at a different annealing temperature followed by separate forward and reverse sequencing. This procedure was time-consuming and expenses and did not always was available a sufficient amounts of nucleic acids to perform it. Our rapid methodology studies more molecular markers of thyroid pathologies in a single experiment with one tube for Braf-ras multiplex, one tube for eight exons Ret gene multiplex and other two tubes to study RNA rearrangement, all together working at the same annealing temperature. PCR and sequencing analysis are used to determine the point mutations; RT-PCR method is used for the detection of the chimeric Ret/PTC1 and Ret/PTC3 transcripts in RNA extract from FNC washing. Actually there are new methodologies, as NGS sequencing, which simultaneously can test many point mutations and fusion genes, making the thyroid study more simple and fast but in this moment the procedure reported by us is very rapid and cheap and can also be used in small laboratories that do not have large equipment or highly skilled staff able to process the large amount of information that new technologies provide.
Thyroid Cancer Thursday Poster Translational
Somatic activating mutations of RET, predominantly codon M918T, are observed in ∼40% of sporadic medullary thyroid carcinomas (sMTC). Detection of these tumor-specific RET mutations may play an important role in patient care. The objective of this study was to test the clinical applicability of detecting the RET M918T mutation in plasma derived cell-free DNA (cfDNA) as a surrogate for analysis of tumor DNA and as a potential measure of disease prognosis. Samples were collected under an IRB-approved protocol from sMTC patients beginning 4/2014. We identified 47 sMTC patients with evidence of metastasis, elevated serum calcitonin, and a somatic RET M918T mutation. Plasma was prepared within 4 hours of collection and cfDNA isolated using a QIAamp circulating nucleic acid kit. The detection of the RET M918T mutation was performed with BioRad QX200 Droplet Digital PCR system (ddPCR). Positive detection was defined as >5 RET M918T copies/ml of plasma, while elevated expression was defined as an allelic fraction >1% of total RET cfDNA. Mutant RET cfDNA was detected in 15 of 47 (32%) RET M918T tumor positive patients, of these 13 met the elevated criteria. Serum calcitonin levels were not significantly different in patients with and without elevated plasma RET cfDNA (1538 vs 837 pg/ml median, P = 0.46) whereas significant differences were found for CEA levels (158 vs 15 ng/ml median, P < 0.0005). Median survival from time of sample collection was worst for patients with elevated RET M918T cfDNA (8.3 months vs undefined, P < 0.0001, 12 month median followup) with 8 of the 13 patients deceased within 12 months of sampling. Plasma-based detection of the RET M918T mutation by ddPCR was only 32% concordant with direct tumor analysis, suggesting a low rate of tumor DNA shedding in most sMTC patients. DNA shedding did not correlate with serum calcitonin but did with serum CEA levels suggesting it may better reflect active apoptotic cell death. Finally, the presence of elevated RET M918T cfDNA levels was strongly associated with a higher risk of death. We believe RET M918T cfDNA measurement may be a useful prognostic tool in sMTC patients.
Thyroid Cancer Thursday Poster Translational
Papillary thyroid carcinoma (PTC) consists of 80–85% in all is thyroid cancer. Recently molecular targeted drugs such as sunitinib and lenvatinib have been discovered and provided exellent prognostic improvement. However, in the clinical trial using these studies high incidence of withdrawal associated with adverse events were reported. Therefore, the development of molecularly targeted drugs to treat RAI-resistant thyroid cancer with minimal adverse events is needed. Our department is one of the largest involved in diagnosing malignant lymphoma in Japan, where about 5000 samples from all over Japan are delivered for diagnosis of hematological diseases. A 58-year old woman with cervical lymphadenopathy with a previous surgical history of PTC at the age of 57 received cervical lymph node biopsy to evaluate the possibility of malignant lymphoma, and the sample was sent to our institute. Hematoxylin and eosin staining of the sample showed that the lymph node had metastatic papillary carcinoma. In malignant lymphoma consultative cases, we routinely perform immunohistochemistry using L26 clone to evaluate the expression of CD20, a pan-B marker. Although this present case histologically showed metastasis of papillary carcinoma, most tumor cells are positive for CD20 on their surface. To eliminate the possibility that this phenomenon was a cross-reaction against molecules other than CD20, we performed an assessment using an antibody recognizing the N-terminus of CD20, which yielded the same result as tahte of L26. Based on the collective results, the diagnosis was metastasis of CD20-positive PTC in a cervical lymph node. Further investigation of CD20 expression in cases of PTC by using L26 and CD20N, showed tumor cells expressing CD20 in 5 PTC cases (23%) of the 22 cases including the present one. CD20 is commonly used as a B-cell marker and is an important target for molecular targeted therapy for B-cell lymphomas. Complement-dependent and antibody- dependent cellular cytotoxicities are thought to be important effector mechanisms of these drugs. This indicates that CD20-targeted therapy is effective against tumor cells with CD20 expression.
Thyroid Cancer Thursday Poster Translational
Lymph node metastasis(LNM) occurs frequently in papillary thyroid cancer(PTC). LncRNAs are a class of noncoding RNAs playing critical roles in cancer development. The report of lncRNAs in LNM of PTC is limited and the role of lncRNAs in LNM of PTC needs to be further investigated. Here, we confirmed the expression level of NONHSAT076754 in PTC with LNM using PTC tissues and explored the function and molecular mechanism of NONHSAT076754 in LNM of PTC using PTC cell lines. The expression level of NONHSAT076754 in PTC was detected by real-time PCR. Fluorescence in situ Hybridization was done to observe the subcellular distribution of NONHSAT076754. CCK-8 assay and colony formation assay were used to detect the proliferation ability while the wound healing assay and scratch test were done to investigate the migration and invasion ability of PTC cells after transfection. In addition, flow cytometry assay was conducted to study cell cycle and apoptosis. Moreover, the expression level of fibronectin-1 was detected by real-time PCR and western blot analysis before and after NONHSAT076754 was overexpressed or knocked down. NONHSAT076754 was significantly upregulated in PTC with LNM. The ability of migration and invasion were promoted by NONHSAT076754 in PTC cells. However, the proliferation, cell cycle and apoptosis were not affected by NONHSAT076754. Additionaly, fibronectin-1, as a cis target gene of NONHSAT076754, was confirmed to be upregulated in PTC with LNM. The expression level of fibronectin-1 was upregulated by overexpression of NONHSAT076754 and down-regulated by knock down of NONHSAT076754. NONHSAT076754 promotes migration and invasion through regulating fibronectin-1 in PTC, which indicates that NONHSAT076754 is a positive regulator in LNM of PTC. NONHSAT076754 is a promising novel diagnostic marker as well as a potential therapeutic target for LNM of PTC.
Thyroid Cancer Thursday Poster Clinical
Bone metastases in thyroid cancer are associated with a poor outcome, although the frequency of occurrence of these events in thyroid cancer is largely unknown. Patients diagnosed with thyroid cancer between 1991–2011 were identified using the linked Surveillance Epidemiology and End Results (SEER)-Medicare database. Using the International Classification of Disease, Ninth Revision (ICD-9) and Current Procedure Terminology 4 (CPT-4) codes we identified bone metastases and skeletal related event (SRE). SREs were defined as the occurrence of pathologic fractures, spinal cord compression, bone surgery or bone radiation. Descriptive analyses included occurrence of SREs based on cancer histology. Multivariable logistic regression was used to model the likelihood of bone metastases and SREs as a function of thyroid cancer histology, after adjusting for age, sex, race, stage, and tumor size. Of 30,063 patients in the SEER-Medicare registry, 1173 (3.9%) patients were identified with bone metastases and 1771 patients (5.9%) identified with an SRE. The likelihood of developing bone metastases was higher in follicular (OR 2.25, CI 1.85–2.74), Hurthle cell (OR 1.77, CI: 1.34–2.32) and medullary thyroid cancer (OR 2.16, CI 1.61–2.86) compared to papillary thyroid cancer. (p < 0.001) In addition, compared to papillary thyroid cancer, the likelihood of developing SREs was higher in follicular (OR 1.40 CI: 1.15–1.68) and medullary cancer (OR 1.62 CI 1.23–2.11) (p = 0.001). Age >65, male sex, regional and distant metastases were significantly associated with a greater likelihood of bone metastases and SREs. Tumor size (> 2 cm) increased the risk of bone metastases but did not seem to correlate with SREs. There was no significant difference in the occurrence of bone metastases or SREs between follicular (10.2%, 8.6%) and medullary thyroid cancer (10.5%, 9.0%). To our knowledge, this is the first population-based study evaluating the occurrence of bone metastases and SREs in patients with thyroid cancer. Patients with follicular and medullary thyroid cancers are especially vulnerable. This study emphasizes the importance of a tailored approach for the treatment of bone metastases and prevention of SREs based on tumor histology.
Thyroid Cancer Thursday Poster Clinical
Traditional diagnostic procedures in patients with differentiated thyroid cancer (DTC) are thyroid ultrasonography and FNAB. When clinically warranted, other image studies are recommended. To detect metastasis of lymph node (LN), utility of PET/CT is still limited. The aim of this study was to estimate the relationship between PET/CT and washout thyroglobulin of FNA(FNA-Tg) for diagnosing lymph node metastasis in patients with differentiated thyroid cancer (DTC). This retrospective observational hospital-cohort study enrolled consecutive 75 thyroid cancer patients with single or multiple suspicious cervical LNs (134 lesions) from May 2011 to December 2013 in whom FNAB, FNA-Tg measurement, and PET-CT had been performed. Final diagnoses were confirmed by histological examination of excised specimens or by follow-up ultrasonography for at least 6 month. Every patients were followed at least 2 years. Cases were divided by presence of suspicious LN detected on PET CT scan. There were no difference in age, sex, FNA-Tg between PET/CT positive and negative LNs. As a result, malignancy rate of LNs were 45.6% in PET/CT positive LNs. 67.2% of metastatic LNs detected on PET/CT scan. FNA-Tg and LN level was not significantly different between detected or non detected on PET/CT in malignant LNs. LNs which were detected on PET/CT but cytologic benign showed low FNA-Tg level except 6 cases. 1 case underwent surgical remove, and confimred malignancy. Other 5 cases were only evaluated by sonography, and showed no interval change. LNs detected on PET/CT with low FNA-Tg could be considered benign in DTC patients.
Thyroid Cancer Thursday Poster Clinical
Recently dynamic risk stratification has been approved to be more valuable than static anatomic staging system in non-medullary thyroid cancer and this notion has been also accepted in medullary thyroid cancer (MTC). The present study was designed to compare the clinical usefulness of response to initial therapy stratification with a traditional anatomic staging system. From August 1982 to December 2012, a total of 144 MTC patients underwent thyroidectomy in Yonsei University Hospital. Among them, 117 (82.2%) patients with complete clinical data and sustained follow-up were enrolled in this study. Clinicopathologic features and surgical outcomes were analyzed by retrospective medical chart review. Mean follow up duration was 85.78 ± 62.51 months. In this study, mean tumor size was 1.94 ± 1.40 cm and 22 (18.9%) patients had hereditary MTC, 95 (81.1%) patients had sporadic MTC. Stage I patients had highest probability of excellent response to initial therapy (92.1%). Stage IV patients had highest probability of biochemical and structural incomplete response to initial therapy (57.5% and 30.3%) and lowest probability of excellent response to initial therapy (12.1%). Response to initial therapy stratification and TNM staging system were significantly difference in statistically (p = 0.000). The TNM staging system provided risk stratification regarding to disease free survival (DFS), disease specific survival (DSS) and the probability of having no evidence of disease at final outcome, but did not provide risk stratification regarding to the probability of having biochemical persistent/recurrence disease at final outcome. However response to initial therapy stratification provided risk stratification regarding to not only DFS, DSS and the probability of having no evidence of disease at final outcome but also the probability of having biochemical persistent/recurrence disease at final outcome. In this study, we demonstrated that dynamic risk stratification with adjusted response to initial therapy system can offer more useful prognostic information than anatomic staging system in MTC.
Thyroid Cancer Thursday Poster Clinical
Papillary microcarcinoma (PTMC) is a small papillary thyroid carcinoma measuring 1 cm or less in diameter. Recently, incidence of PTMC has been increased due to an increase in the detection of subclinical disease such as small and low-risk carcinomas with ultrasonography and fine needle aspiration cytology. However, there is central neck lymph node metastasis in patients with PTMC without clinical evidence of metastasis by preoperative ultrasonography. We performed analysis to determine the influencing factors for central neck lymph node metastasis in PTMC although there was no clinical evidence of metastasis by preoperative ultrasonography. We analyzed retrospectively 625 patients with PTMC underwent thyroid surgery at Chosun University Hospital from January 2002 to December 2012. Finally, we included 587 patients who had no evidence of lymph node metastasis by preoperative ultrasonography. We reviewed medical records including clinical information and pathologic report. Central neck lymph node metastasis was found in 81 patients (13.8%) among total 587 patients. Lymph node metastasis occurred frequently in patients with following factors; female (p = 0.047), more than 0.5 cm in largest tumor size by pathologic reports (p = 0.001) and lymphovascular invasion (p < 0.001). In multivariate analysis, we determined significant factors for lymph node metastasis in patients without suspicious lymph node metastasis by preoperative ultrasonography as follows; female (p = 0.037), tumor size by pathologic reports (p = 0.002) and lymphovascular invasion (p = 0.005). We carefully suggest that must consider to perform central neck lymph node dissection in female patients with tumor size more than 0.5 cm and lymphovascular invasion in spite of PTMC.
Thyroid Cancer Thursday Poster Clinical
Continuous intraoperative neuromonitoring (CIONM) by vagal nerve stimulation seems to be a technological improvement. Although CIONM is a promising technology at the cutting edge of research in thyroid surgery, it still remains unclear whether IONM adds any value to the clinical outcome of transaxillary robotic thyroidectomy (RT). To the best of our knowledge, the study of standardized CIONM technique during transaxillary RT has not yet been demonstrated. The aim of this study was to assess the risk of recurrent larynageal nerve injury in transaxillary RT performed with or without CIONM. This study was performed from May 2015 to November 2015. We prospectively evaluated 50 patients with thyroid cancer who had transaxillary RT with or without nerve monitoring. Of those patients 21 were in monitored group and 29 were in unmonitored group. Laryngoscopy and voice function test were assessed before surgery and at 2 weeks, 3 months, and 6 months after the surgery. All procedures of CIONM during transaxillary RT were performed safely and effectively. Moreover, CIONM application was also performed safely on contralateral side even for total thyroidectomy. At first postoperative laryngoscopy, two patients (10%) in monitored group showed vocal cord palsy and 4 patients (13.9%) in unmonitored group. There was 1 loss of signal with corresponding unilateral transient vocal cord palsy. The voice function was not significantly different between the two groups. All patients with vocal cord palsy recovered completely at 3 months after surgery. CIONM in transaxillary RT is safe and feasible to test the functional integrity of the RLN. CIONM can help to give surgeons more confidence during surgery and might be helpful for advanced training in RT.
Thyroid Cancer Thursday Poster Case Report
A 59 years-old man with a history of Graves’ disease, treated with radioactive iodine (RAI) 30 years ago and euthyroid on levothyroxine, presented with a one year history of progressive hoarseness, lethargy and shortness of breath when supine. Physical exam showed he had a harsh but breathy voice, periorbital edema and stridor when supine. He had Pemberton's sign with facial plethora when arms were raised. The thyroid was non-palpable, and there was no cervical adenopathy. Laryngoscopy revealed paralysis of the right vocal cord. Chest X-ray demonstrated a right-sided mediastinal mass causing severe leftward tracheal deviation and compression. Neck and chest CT scans showed an 11 cm mass beginning in the right thyroid with intrathoracic extension to the level of the azygos vein. Fine needle aspiration biopsy was suspicious for thyroid cancer. Following extensive preoperative preparation, including fiberoptic awake intubation, the patient underwent uneventful total thyroidectomy utilizing a low cervical incision with hemi-median sternotomy. Pathology revealed a well-differentiated papillary thyroid cancer, columnar cell variant, measuring 10 cm with extensive necrosis. Margins were negative, with no lymphovascular invasion nor extrathyroidal extension.
At 1 month followup, the patient's hoarseness, facial edema, orthopnea, and positional stridor had resolved. Whole body I-123 scan showed avid tissue confined to the thyroid beds taking up 2.4% of administered radioiodine with no distant metastases. The patient was treated with 142 mCi I-131 RAI. Neck CT and ultrasound at 1 year followup showed no evidence of disease. Thyroglobulin (Tg) and anti-Tg antibodies (Ab) are progressively decreasing, with most recent Tg = 4.1 ng/mL and anti-Tg Ab = 23.7 IU/mL with a suppressed TSH. Dysphonia, facial edema, and/or orthopnea can indicate a recurrent laryngeal nerve palsy and vascular or tracheal compression, respectively, due to a mediastinal mass such as a thyroid goiter or cancer, even without palpable thyromegaly. Following a thorough history and physical exam, neck and chest CT (or MRI) is critical to ensure comprehensive preoperative planning for airway management and appropriate operative approach for adequate exposure.
Thyroid Cancer Thursday Poster Clinical
Studies have shown that surgical outcomes of thyroid cancer patients, and older patients specifically, are improved with a high-volume thyroid surgeon (>100 surgeries/year). However, age disparities in referral to specialist surgical centers still exist. Our objective was to delineate the factors that influence decision making regarding referral of older thyroid cancer patients (age >65) to high-volume thyroid surgeons. Members of the American College of Physicians, American Academy of Family Practice and Endocrine Society were randomly surveyed. A total of 269 physicians completed the survey (41.2% endocrinologists, 26.6% family physicians, 25.6% internists, 6.6% other). We found that patient preference (68.4%), transportation barriers (62.5%) and confidence in local surgeon (54.4%) were the most cited factors that decreased likelihood of referral of older thyroid cancer patients to a high-volume surgeon. Less frequently quoted factors were insurance restrictions (30.4%), patient inability to perform basic (27.7%) or instrumental (21.1%) activities of daily living, lack of social support (26.6%) and patient immobility (25.9%). When presented with clinical vignettes, both for a 65-year-old patient with comorbidities (atrial fibrillation, osteoporosis, congestive heart failure, chronic obstructive pulmonary disease) and an 85-year-old patient without comorbidities, endocrinologists (p < 0.001; p < 0.001 respectively), physicians in academic settings (p 0.033; p 0.028) and high-patient volume physicians (p 0.013; p 0.001) were more likely to refer to a high-volume surgeon. Physicians with fewer years in practice (p 0.031) were also more likely to refer an 85-year-old patient without comorbidities to a high-volume surgeon. Understanding the patterns of surgical referral of older thyroid cancer patients and the factors influencing these patterns is vital in identifying obstacles in the referral process. We found that physician specialty, practice setting, patient volume and years in practice influence the referral of older thyroid cancer patients to high-volume surgeons. This is the first step towards developing targeted interventions for this patient population.
Thyroid Cancer Thursday Poster Clinical
This study identified the prevalence and predictors for postoperative hypothyroidism after hemithyroidectomy in patients with papillary microcarcinoma. We retrospectively reviewed 803 patients who underwent hemithyroidectomy for papillary microcarcinoma from 2002 to 2015. The overall median follow-up period was 46 months (range, 6–153 months). Patients with known hypothyroidism or who were taking preoperative thyroid hormone replacement were excluded. Among the 803 patients, 537 (66.9%) developed hypothyroidism within 1 year after the hemithyroidectomy, and their mean levothyroxine replacement dose was 79.6 ± 34.1 mg/day. The prevalence of postoperative hypothyroidism was 313 of 364 (86.0%) after 3 years and 153 of 187 (81.8%) after 5 years, and their levothyroxine dosage did not change significantly during the follow-up period. Among patients who did not develop hypothyroidism within 1 year after surgery, 24 newly developed hypothyroidism within 5 years. However, only six patients who had hypothyroidism within 1 year after surgery were able to stop levothyroxine replacement within 5 years. These hypothyroid patients had higher preoperative thyroid stimulating hormone (TSH) levels compared with those of euthyroid patients (2.43 ± 1.55 vs. 1.73 ± 1.19 mIU/mL, P < 0.001). Age and presence of thyroiditis in a histological specimen were not significantly different between the two groups. A logistic regression analysis showed that preoperative TSH level and follow-up duration after hemithyroidectomy were independent predictors for developing hypothyroidism after adjusting for age, sex, body weight, and the presence of thyroiditis. TSH levels had greater value for predicting hypothyroidism in patients >45 years. The preoperative TSH cut-off values for predicting hypothyroidism within 5 years were 2.2 mIU/mL (95% specificity and 40% sensitivity) and 3.8 mI/mL (100% specificity and 13% sensitivity). A considerable number of patients who underwent hemithyroidectomy for papillary microcarcinoma developed postoperative hypothyroidism and most of them could not discontinue levothyroxine replacement therapy. Preoperative TSH level should be considered for predicting hypothyroidism before surgery.
Thyroid Cancer Thursday Poster Clinical
Anaplastic thyroid cancer (ATC) is a rare but rapidly fatal malignancy with poor outcomes despite aggressive therapy. An immune targeted approach with anti-PD-1 antibodies is more effective in tumors with high expression of the ligand, programmed death ligand-1 (PDL-1). Expression pattern of PD-1/PDL-1 and its impact on outcomes in ATC is largely unknown. This is a single center, retrospective study of ATC pts from 2003–15. Only pts treated with intensive multimodal therapy (surgery followed by chemoradiation) were included. Diagnosis of ATC was confirmed by expert thyroid pathologist. FFPE tissue sections were stained with PD-1 and PDL-1 antibodies. Staining intensity and percent of positively stained cells of total tumor cells and of tumor infiltrating leukocytes (TIL) were determined. Allred-like score was calculated, and a score of ≥3 considered positive. Demographic and clinical data was obtained from the medical record. Survival statistics were calculated using Kaplan-Meier method and SAS 9.4. A total of 48 pts with ATC were identified, of which 18 were excluded as they received palliative radiation alone. Of the remaining 30, tissue was available for 16 pts. Median age was 58 (range 37–83) yrs, and 11 (69%) were male. The most common AJCC stage was IVB (n = 13, 81%; IVA, n = 1; IVC, n = 2). PD-1 staining was positive in TILs in all tumors (n = 16, 100%) and predominantly negative in tumor cells (n = 15, 94%). In contrast, PDL-1 staining was positive in tumor cells of most pts (n = 13, 81%). Some of the TILs also expressed PDL-1 (n = 7, 44%). Both membranous and cytoplasmic staining was observed. At last follow up, 14 (of 16) pts have died. Pts with PDL-1-positive tumors showed numerically shorter overall survival (OS) when compared to PDL-1-negative tumors (median OS 5.8 versus 66.5 mos, HR 1.35, P = 0.6). Similarly, progression-free survival (PFS) was also numerically shorter for PDL-1-positive tumors (median PFS 4.1 versus 46.2 mos, HR 1.38, P = 0.6). PDL-1-positive expressing tumors showed numerically shorter PFS and OS in this homogenously treated ATC cohort. However, a larger sample is needed for a more reliable estimate. PDL-1 is frequently expressed in ATC making it an attractive target for immunotherapy.
Thyroid Cancer Thursday Poster Clinical
The purpose of this study was to evaluate the risk factors of central lymph node metastasis (CLNM) in T1NxM0 papillary thyroid carcinoma (PTC) and guide the clinical treatment. We retrospectively studied 300 patients (68 male, 232 female) with T1NxM0 PTC in Beijing Tongren Hospital between Aug. 2008 and Dec. 2013. Ultrasound, thyroid function, intra-operative findings and pathological data were collected and analyzed. 52 cases (among which 29 cases had unilateral lesions) underwent LN dissection of bilateral level VI and level VII, while the rest cases underwent the dissection in ipsilateral. The Logistic regression analysis was used to study the risk factors of CLNM. The maximum diameter of the tumor (Group A: <5 mm 46 cases, Group B: 6 mm ∼10 mm 140 cases, Group C: 11 mm ∼15 mm 72 cases, Group D:16 ∼ 20 mm 42 cases), the number of the lesion (234 single, 54 double, 12 three or more), the lesion location (58 upper part, 84 middle part, 56 lower part and 18 isthmus), Hashimoto's thyroiditis (82 cases) and sex were analyzed as potential risk factors. The difference of tumor diameter between preoperative thyroid ultrasound(U) and intra-operative specimen(P) was also compared. CLNM in T1NxM0 PTC were discovered in 51.52% (102/198) cases. Tumor diameter between patients with and without CLNM showed significant differences in Logistic regression analysis. The ultrasound tumor size showed a little larger than the intra-operative specimen, but had no significant differences. CLNM rate in cases with single nodule was: 31.62% (74/234), two nodules: 31.48% (17/54), three / more nodules: 41.67% (5/12). CLNM rate of upper part of the lobe was 41.38% (24/58), middle part of the lobe was 44.05% (37/84), lower part of the lobe was 57.14% (32/56) and isthmus was 50% (9/18). For 29 unilateral lesion cases who underwent bilateral dissection, only 3 cases(10.34%) had contralateral central lymph node metastasis. The diameter of tumor was associated with CLNM in T1NxM0 PTC. The contra-lateral level VI could be observed closely without dissection if no evidence of metastasis was found during surgery.
Thyroid Cancer Thursday Poster Clinical
Thyroid nodules are becoming more common. Due to the fact that few of these nodules harbour malignancy, further research is required to identify predictive markers of malignant thyroid disease. This study set out to understand the relationship between the levels of fT4 and fT3 and differentiated thyroid cancer. A case-control study was conducted with 228 patients, 142 cases and 86 controls, from the McGill University Teaching Hospitals between 2014 and 2015. Cases were defined as patients who underwent thyroid surgery and whose nodules were confirmed to be malignant on final pathology. Controls were defined as patients whose nodules were benign on final pathology. The serological levels of TSH, fT4 and fT3 were measured preoperatively and compared. Additionally, fT4 values were divided by fT3 values to create a variable called the fT4/fT3 quotient for each patient and an odds ratio was calculated. In cases, the mean TSH was 2.25 ± 0.360 U/mL, fT4 was 14.8 ± 0.689 pmol/L, and fT3 was 4.65 ± 0.463 pmol/L. For the controls, the mean TSH was 2.36 ± 1.68 U/mL, fT4 was 14.3 ± 1.71 pmol/L, and fT3 was 5.27 ± 0.957 pmol/L. Patients in the case group were more likely to have high TSH, while patients in the control group were more likely to have a low fT4. The OR for patients with TSH >4.4 U/mL was 2.13 (1.10, 4.09), for patients with TSH <0.4 U/mL it was 0.46 (0.25, 0.84). The OR for patients with fT4 > 16 pmol/L was 2.10 (1.21, 3.64), for patients with fT4 < 10 pmol/L it was 0.45 (0.23, 0.86). The OR for patients with fT3 > 5.5 pmol/L was 0.39 (0.16, 0.95), for patients with fT3 < 3 pmol/L it was 1.83 (0.34, 9.85). The average fT4/fT3 was 3.39 ± 0.206 for cases and 2.93 ± 0.467 for controls. The fT4/fT3 quotient was considered high if it was >3.3 (OR = 6.00 (2.94, 12.25)). In this study a direct relationship between high levels of fT4, and the presence of malignancy in a thyroid nodule was uncovered. Furthermore, low levels of TSH and fT4 seem to increase the likelihood that a thyroid nodule is benign. This has led to the finding that an fT4/fT3 ratio >3.3 increases the risk of malignancy by 3.6 times (p-value of 0.0013). Future research is required to reproduce this finding and determine the etiology of this relationship.
Thyroid Cancer Thursday Poster Clinical
In patients with differentiated thyroid cancer (DTC), stimulated thyroglobulin (sTg) levels by thyroid hormone withdrawal (THW) at remnant ablation (RA) and at 6 to 12 months are known to have good prognostic value. However, prognostic impacts of sTg levels by rhTSH at RA and at follow-up were not completely evaluatedThis retrospective study included consecutive DTC patients without initial distant metastasis from Jan 2006 to Dec 2011, who all underwent total thyroidectomy with prophylactic central lymph node dissection, followed by rhTSH-aided high-dose RA. sTg at RA (A-sTg) and sTg 6 to 12 months after RA, either by rhTSH or THW, were evaluated for optimal cutoff and prognostic values for detecting persistent/recurrent disease (PRD) Among 101 enrolled patients, 49 were followed up with rhTSH-based sTg (rhTSH-sTg) and 52 with THW-based sTg (THW-sTg) at 6 to 12 months after RA. Five patients were confirmed as PRD over the median follow-up of 62.9 months; 3 in rhTSH group and 2 in THW group. rhTSH-sTg were lower than THW-sTg in patients with PRD. The cutoff values of A-sTg, THW-sTg, and rhTSH-sTg for PRD were 5.0 ng/ml (sensitivity 80.0%, specificity 79%), 5.0 ng/ml (sensitivity 100%, specificity 98%) and 0.5 ng/ml (sensitivity 67%, specificity 83%), respectively. Under the rhTSH-aided ablation setting, sTg at ablation showed good prognostic value to predict RPD in DTC patients and had lower levels than that under THW.
Thyroid Cancer Thursday Poster Clinical
There is evidence that smoking may inhibit the development of TPO antibodies and prevent the development of chronic lymphocytic thyroiditis, which consequentially prevents against elevated TSH levels. The recent increase in the incidence of thyroid cancer is attributed mainly to papillary thyroid microcarcinomas (PTMCs). To date, no studies have examined the impact of smoking on the presentation and long-term outcomes among patients with a histological diagnosis of PTMC. Retrospective review of electronic medical records of all patients presenting to the UAMS Thyroid Center from January 2005 through December 2015 with a postoperative histological diagnosis of papillary thyroid cancer <10 mm in size. Only those patients with at least one year of postoperative follow-up were included. Patients with aggressive variants of papillary thyroid carcinoma (e.g. tall cell) were excluded. A total of 123 subjects were included in the analysis. The female to male ratio was 5 to 1. Less than a quarter of patients (21.6%, 27/123) were former (9.8%, 12/123) or current (12.2%, 15/123) smokers. There were no significant differences in patient age, gender, race/ethnicity, body mass index, alcohol exposure, family history of thyroid disease, concurrent Hashimoto's thyroiditis, and/or the presence of other (non-thyroid) cancer when comparing smokers and non-smokers. Smokers were significantly more likely to present with hyperthyroidism (11.1%, 3/27) compared to non-smokers (2.1%, 2/96; P = 0.036). Non-smokers (69.8%, 67 of 96) were significantly more likely to have a histological diagnosis of a PTMC >5 mm in size compared to smokers (40.7%, 11/27) (P < 0.001). When comparing smokers and non-smokers with PTMC, there were no significant differences in disease recurrence and/or cancer-related mortality Smoking may have a prohibitive effect on the growth of PTMC over time. The decline in cigarette smoking rates over the last few decades may partially contribute to the increased incidence of clinically detected PTMCs. Importantly, these findings should not be used to encourage smoking, as the health risks associated with this behavior far outweigh any potential proposed health benefits.
Thyroid Cancer Thursday Poster Clinical
To investigate the prognostic value of BRAF V600E mutation in the recurrence of non-invasive papillary thyroid cancer (PTC). From 2,638 patients at 11 medical centers with available clinicopathological data including information on tumor recurrence and patient mortality, 955 patients were identified with non-invasive solitary PTC defined as lack of multifocality, extrathyroidal invasion, and lymph node or distant metastases, including 768 females and 187 males with a median age of 46 years (interquartile range {IQR}, 36 to 57 years) and a median follow–up time of 64 months (IQR 30 to 116 months). The relationship between BRAF V600E mutation and tumor recurrence was retrospectively examined. Collective biochemical and structural recurrence occurred in 26/321 (8.10%) BRAF mutation-positive vs 14/634 (2.21%) wild-type BRAF patients of all tumor sizes (P < 0.001), with a hazard ratio (HR) of 3.89 (95% CI 2.03–7.46), which remained significant after adjustment for patient age and sex [HR 4.01, 95% CI (2.09–7.70)]. Significant association between BRAF mutation and PTC recurrence was seen in patients of tumor sizes >1 and ≤4 cm (P = 0.002, HR 3.10, 95% CI 1.49–6.45) and even more significant in tumors >2 and ≤4 cm (P = 0.001, HR 5.58, 95% CI 1.96–15.85). Structural recurrence in a large individual center was seen in 10/106 (9.43%) BRAF mutation-positive vs 4/336 (1.19%) wild-type BRAF patients of all tumor sizes (P < 0.001), with an adjusted HR of 9.41 (95% CI 2.93–30.19). Significant association between BRAF mutation and structural recurrence was also seen in tumor size >1 cm and ≤4 cm (P = 0.004, HR 5.69, 95% CI 1.75–18.54). Even stronger associations of BRAF mutation with structural tumor recurrence were seen when conventional PTC and follicular variant PTC were individually analyzed. Mortality was too low to analyze. BRAF mutation is significantly associated with recurrence of non-invasive PTC of tumor sizes >1 and ≤4 cm and can stratify these patients into higher- and lower-risk groups, which may help with better individualized decision making when considering the recent American Thyroid Association's recommendation for conservative treatment of such patients.
Thyroid Cancer Thursday Poster Clinical
A variety of primary thyroid carcinomas exhibit squamous differentiation on histologic examination. Diffuse sclerosing and cribriform morular variants show squamous morules while undifferentiated (anaplastic) thyroid carcinoma can show epithelioid or squamoid morphology. Nuclear immunostaining for p53 is present in undifferentiated carcinomas, however, p53 is also expressed in squamoid cells. We evaluated expression of p53, p40, and PAX8 in well-differentiated papillary thyroid carcinomas (PTC) and undifferentiated thyroid carcinomas (UTC) with squamous elements.12 carcinomas were identified: 7 UTCs (3 with a PTC component and 1 with squamous differentiation), 2 diffuse sclerosing variants with squamous morules, and 3 classic PTCs with squamous metaplasia. All were stained with p40, p53, and PAX8. Expression of these 3 markers was evaluated in the well-differentiated, undifferentiated, and squamous components of all tumors. Squamous components in all 6 carcinomas showed p53 positivity regardless of type, while 83% (5 of 6) were positive for p40. Differentiated PTC and UTC were both marked by p40 and p53 at rates ranging from 25–63%. PAX8 stained all well-differentiated PTCs and squamous areas of all carcinomas, but only 71% (5 of 7) of non-squamous UTCs. Neither p40 nor p53 are uniquely expressed in UTC. Conventional PTC without squamous features shows expression at 25 and 63%, respectively, compared to UTC at 43 and 57%. Squamous components of well-differentiated thyroid carcinomas exhibited even higher rates of expression (up to 100%). Furthermore, squamous components maintained expression of PAX8, and these components should not be mistaken for collision tumors, especially in metastatic settings. Caution should be used when using p40 or p53 to prove a diagnosis of UTC, particularly in the setting of squamous differentiation.
Thyroid Cancer Thursday Poster Clinical
BABA has been successfully adopted in the field of robotic thyroidectomy, not only for its' excellent cosmetic outcomes but also by its` proper oncologic safety. However, there are little information that BABA method also can be safely applied in patients with previous breast surgery history.
From the January 2010 to December 2015 in Seoul National University Hospital, total 1500 cases of BABA robotic thyroidectomy had been performed. Among them, 13 patients have a history of previous breast surgery. We retrospectively reviewed these patients and compared with control group using propensity score matching in preoperative clinical characteristics. Previous breast operations for patients are as follows: seven with excisional biopsy for benign breast lesions, four with breast conserving surgery for breast cancer and two with breast augmentation for cosmetic purpose. After propensity score matching, there were no statistic differences between breast surgery group and no breast surgery group in intraoperative parameters. The mean operation time and estimated blood loss of two groups are 180.6 minutes and 180.8 minutes (P = 0.985), 95.2 ml and 77.3 ml (P = 0.637). For the postoperative outcomes, there were no statistic differences in vocal cord palsy (P = 0.797), transient hypocalcemia (P = 1), permanent hypoparathyroidism (P = 0.589), total drainage amount (P = 0.190), mean drainage amount (P = 0.405) and symptom related to adhesion (P = 0.544). There is no patient presented wound complication in both group. Follow up imaging study for breasts in breast surgery group revealed that there were no differences in Breast imaging-reporting and data system (BI-RADS) score except breast lesion that underwent operation, before and after BABA thyroidectomy.
BABA approach for robotic thyroidectomy can be safely performed in the patients with breast surgery history. Prospective cohort study with long term follow up is still required to strengthen this small number retrospective study.
Thyroid Cancer Thursday Poster Clinical
Thyroid disease is common in the elderly, who experience a higher incidence and mortality related to its cancer. Most elderly patients are Medicare beneficiaries reported to undergo thyroidectomy by lower-volume surgeons and experience worse outcomes. The volume-outcomes relationship for thyroidectomy is evolving; the most recent recommended number of thyroidectomies performed per year is ≥25. The Center for Medicare and Medicaid Services releases yearly public-use files (CMS-PUF) detailing health care delivery in elderly patients. We used CMS-PUF to analyze national practice patterns of thyroid operations in the elderly to identify regions for targeting improvement. CMS-PUF (2014) were used to identify surgeons for 10 thyroid operation CPT codes. The CMS-PUF includes physicians who performed ≥10 thyroidectomies in Medicare Part B beneficiaries (MCB). Population and MCB data for 2014 were obtained from the United States Census Bureau and the Center for Medicare and Medicaid Services. Statistical analyses were performed with JMP Pro 12. We identified 186 surgeons who performed 3,292 thyroid operations in MCB in 2014. The mean number of thyroid operations per surgeon was 19 ± 13, and the median was 14 (range 11–97). Surgeons were 66% general surgeons and 34% otolaryngologists/other. A greater percentage of general surgeons performed ≥25 thyroidectomies per year compared to other surgeons (20% vs. 6%, p = 0.02), and mean operations performed by general surgeons were higher than other surgeons (19 ± 11 vs. 15 ± 6, p = 0.02). Overall, 90% of operations were total thyroidectomies and 10% were lobectomies. Lobectomies were more often performed by otolaryngologists/other than general surgeons (23% vs. 8%, p = 0.01). Twenty-five percent of states (n = 12) had no identified surgeon who performed ≥10 thyroidectomies per year in Medicare Part B beneficiaries. Regionally, the least amount of thyroidectomies performed by surgeons who perform ≥25 per year was in the Midwest (5% vs. 22%, p = 0.03). Differences in specialty and regional practice patterns are significant, and many states had no higher-volume surgeons. For the elderly, efforts to improve access to higher-volume surgeons on a regional and national level may improve outcomes.
Thyroid Cancer Thursday Poster Clinical
The association of surgeon procedure volume with clinical outcomes is well known, but the number of procedures defining a high-volume surgeon remains unclear. The objective of this study was to identify the point at which surgeon volume was associated with decreased 30-day complication rates for thyroid and parathyroid procedures after adjusting for multiple patient-level factors. Among 15,442 patients undergoing total thyroidectomy, hemithyroidectomy, and parathyroidectomy, we used generalized additive mixed models (GAMs) with random effects to ascertain cut points above which annual surgeon procedure volume was associated with lower complication rates. GAMs are useful when the response variable has a nonparametric distribution and the effect of predictor variables on the response variable is not linear. We assessed a composite outcome of 25 complications that included thyroid-specific surgical complications (hematoma, stridor, transient hypocalcemia, and vocal cord paralysis/paresis) and general surgical complications. Modeling was adjusted for demographics, health care use in the year before surgery, DxCG risk score and Charlson comorbidity index, and 26 thyroid-specific and general comorbidities. Among 7,624 patients undergoing total thyroidectomy, complications decreased above an annual surgeon procedure volume of 18.0 (90% CI, 11.2–27.1) cases. When annual surgeon volumes for hemithyroidectomies and parathyroidectomies were included in the model, the findings did not change. Similar surgeon volume inflection points were not observed among 4,969 patients undergoing hemithyroidectomies or 2,847 patients undergoing parathyroidectomies. Complication rates decreased when surgeons performed at least 18 total thyroidectomies per year. Annual volume of hemithyroidectomies and parathyroidectomies did not affect the relationship between annual surgeon total thyroidectomy volume and outcomes. Lower complication rates and smaller patient populations for hemithyroidectomies and parathyroidectomies precluded detecting inflection points for these procedures.
Thyroid Cancer Thursday Poster Clinical
ATA guidelines suggest checking post-op serum thyroglobulin (Tg) at 3–4 weeks and NCCN recommends checking between 2–12 weeks to determine the need for additional therapy or presence of residual disease. The optimal time is unknown. We aim to determine the nadir of unstimulated Tg level following total thyroidectomy. This is a prospective, observational pilot study. We enrolled 50 subjects >19 years old scheduled for total thyroidectomy and measured serum Tg, Tg ab, and TSH pre-op and post thyroidectomy at 7–14 days, 4 and 6 weeks, and 3 months in subjects with benign pathology and an additional 6 and 12 months in subjects with thyroid cancer. We compared time to Tg nadir between the groups, and rate of change post-op. There were 17 subjects in the benign group and 19 subjects in the malignant group. Fourteen subjects were excluded (7 had positive Tg Ab, 7 withdrew). Mean age was 53.3 ± 16.7 years in the benign group and 51.2 ± 16.8 years in the malignant group. Seventy percent of subjects were >45 years and 75% were females in both the groups. In the benign group, 100% of subjects had an undetectable Tg by 6 weeks post-op while in the malignant group, 93% had an undetectable Tg by 3 months, and 100% by 6 months post-op who have completed the study. There was a statistically significant higher pre-op Tg in the benign group (157.0 ng/ml compared to malignant of 56.4 ng/ml (p = 0.0315)). Only 5/17 (29%) subjects in the benign group reached nadir by 4 weeks while 5/19 (26%) reached nadir as early as 7–14 days post-op, 10/19 (52%) reached nadir by 4 weeks and 11/19 (57%) subjects reached nadir by 6 weeks in the malignant group. 3/5 (60%) subjects with malignancy that reached nadir at 7–14 days had preexisting thyroid disease and were on levothyroxine or anti-thyroid medications. There were no other significant predictors of time to Tg nadir in either group. Pre-op Tg levels does not predict time to nadir after thyroidectomy. The median time to nadir in the benign group was 6 weeks and 3 months post-op in the malignant group. 87% of subjects in both groups achieved nadir by 6 weeks. This suggest that measuring Tg at 6 weeks post-op is the optimal time frame to evaluate Tg nadir and determine the need for additional therapy.
Thyroid Cancer Thursday Poster Clinical
Thyroid cancer patients have quality of life and survivorship issues similar to those with more aggressive cancers despite better outcomes. The immediate impact of a thyroid cancer diagnosis is less well understood. Therefore, the objective of this study was to examine papillary thyroid cancer (PTC) patients' reaction to their diagnosis. We conducted and analyzed semi-structured interviews with PTC patients using modified grounded theory methodology. Interviews occurred as part of a randomized controlled trial preoperatively (n = 31) and 2 weeks (n = 28) post-surgery. All patients had PTC on final pathology. Patients diagnosed with PTC or an indeterminate thyroid nodule (ITN) prior to surgery had a strong, reflex desire to “get it out.” This theme was present in 48% of preoperative interviews (41% of PTC and 57% of ITN). There were no differences in age, gender, tumor size, or comorbidities between patients who did and did not have the “get it out” reaction. Diagnosis elicited emotions such as shock, anxiety, fear, and worry. Patients perceived thyroidectomy as the only possible solution to getting the cancer out and resolving their physical and psychological ailments. The wait between diagnosis and surgery was psychologically difficult, because the cancer was “still sitting there” and “could be spreading.” Patients described this waiting period as a life pause suggesting that thyroidectomy would return them to a normal state, and they would be “done with it.” The need to get the cancer out made some patients minimize the possibility of complications, because “those things…would come secondary.” To ameliorate stress during the wait, patients coped by researching and gathering information, self-reassurance, mindfulness, social support, worship, and distraction. Some patients were reassured by their prognosis and expressed “get it out”, but had less emotional response. Following PTC or ITN diagnosis, many patients have a strong, reflex desire to “get it out” that is elicited by the word “cancer.” Patients view their lives as on hold until the inevitable solution, total thyroidectomy, restores normalcy. Understanding this response will help us to better support patients' preoperative and decision-making needs.
Thyroid Cancer Thursday Poster Clinical
Lenvatinib (LNV) is a multi-kinase inhibitor which was FDA approved in 2015 for progressive RAI-resistant metastatic differentiated thyroid carcinoma (RMTC). We present biochemical, radiological, and clinical changes for every RMTC patient (pt) that we have started on LNV since March 2015. Six patients (4M:2F) had a total thyroidectomy followed by RAI remnant ablation and at least two additional RAI doses. Once RAI-resistance and progression were established we discussed the risks and benefits of LNV with pts and obtained consent. 5/6 pts received no RAI or external beam radiotherapy less than one year prior to beginning LNV. None had any prior anti-cancer medications. Each pt was started on 24 mg/day LNV and the dose was adjusted downward for serious adverse effects (SAE). Tumor response was assessed by changes in serum thyroglobulin (Tgb) and 18FDG uptake in the hottest lesion (SULpeak) according to PERCIST 1.0. A 30% reduction from baseline SULpeak in the target lesion was judged as a partial response (PR). Histology: 3 had papillary thyroid cancer; two had follicular carcinoma; and one had Hurthle cell carcinoma. Medians (range): age = 69 years (43–79); baseline Tgb = 2,151 ng/ml (21 - 14,600); final Tgb = 321 ng/ml (17 – 420); decline in Tgb = 81% (20–99%); duration of therapy = 11 months (3–14). Most common SAEs: fatigue (5/6); hypertension (4/6); weight loss (5/6); polycythemia (2/6); eosinophilia (4/6); rise in TSH (5/6); declines in WBC (3/6). SAEs in 4 improved with dose reductions down to 14 mg/d. Every pt had a fall in serum Tgb, and a partial metabolic response (PMR) based on PET. No PERCIST complete responses or progressive disease were noted up to 14 months on LNV. PMRs occurred in both soft tissue and bone metastases. In each of our 6 RMTC pts, LNV resulted in tumor responses and progression-free survival for up to 14 months, with SAEs that usually responded to dose reductions. LNV could be considered first line medical therapy for progressive RMTC.
Thyroid Cancer Thursday Poster Clinical
The rising detection of papillary thyroid microcarcinomas has generated challenges regarding management. We investigated the willingness of patients and referring physicians to pursue an active surveillance approach for small thyroid malignancies. Patients with biopsy-proven Bethesda V or VI thyroid nodules measuring 1.3 cm or smaller were offered enrollment in an IRB-approved active surveillance protocol or standard surgical resection. Enrolled patients were confirmed to have no suspicious lymphadenopathy, unfavorable nodule locations, or suggestion of poorly differentiated histology. Routine surveillance ultrasounds were performed every 6 months, with patients routed to surgery for growth >3 mm, development of lymph node metastases, or patient preference. Of 31 patients eligible for active surveillance, median age was 51.2 years, median nodule size was 0.9cm, and 77.4% were female. All referring physicians initially recommended thyroidectomy, with 51.6% agreeing that active surveillance was reasonable after discussion. All surgeons outside the protocol recommended thyroidectomy. Overall, 64.5% (n = 20) of patients agreed to enroll in the protocol. With median follow-up of 22.7 months, 100% of enrolled patients have remained in the study, with no patients developing growth or lymphadenopathy that would trigger surgery. Of the 35.5% who declined and underwent thyroidectomy, primary reasons included family pressure, fear of cancer, and perceived time commitment with active surveillance. All thyroidectomy patients had confirmed microPTC on histology, with one patient exhibiting temporary vocal cord paresis. No other complications, including seroma, hematoma, hypocalcemia, vocal cord paralysis, voice changes, hypertrophic scar, or keloid formation, were observed. To date, 64.5% of eligible patients have agreed to enroll in active surveillance. No enrolled patients have yet met growth criteria for surgery or requested to withdraw from active surveillance, supporting the concept that active surveillance is a medically reasonable option, and socially acceptable to patients. Further education of referring physicians is necessary to increase awareness of this novel approach to thyroid cancer management.
Thyroid Cancer Thursday Poster Clinical
Papillary thyroid microcarcinoma (mPTC) is usually associated with low risk of recurrence and excellent outcomes. Some patients with mPTCs, however, may develop lymph node metastasis and local recurrence. The independent predictive factors of recurrence for mPTC have not been clearly determined. We hypothesize that the risk of recurrence differs among patients with different initial presentation of mPTC: pathology-detected, imaging-detected and clinically-detected. We retrospectively reviewed 310 consecutive mPTC patients who underwent surgery between January 2000 and December 2010. Univariate and multivariate Cox proportional hazard models were used to calculate hazard ratio (HR) and 95% confidence intervals (CI). The adjusted disease-free survival curve was also used to compare the recurrence among the patients with different presentations. Most cancers were not suspected, but found on pathology (n = 126, 41%), followed by cancers that presented clinically with symptoms such as a nodule (n = 107, 34%) and lastly cancers that were discovered incidentally on imaging (n = 77, 25%). After a mean follow-up of 65 months (range 0–196), 20 patients had recurrences subdivided into local recurrence (n = 1), lymph node metastasis (n = 18) and distant metastasis (n = 1). Risk of recurrence was higher in the imaging-detected group (compared to the pathology-detected group HR 2.82, 95% CI 0.26 - 31.06) and the clinically-detected group (HR 19.17, 95% CI 2.55 - 144.03). After adjusting for number of lymph nodes metastasis, and microscopic extrathyroidal extension, the hazard ratio for recurrence was 2.46 (95% CI 0.22 - 27.24, P = 0.46) in the imaging-detected group and 10.81 (95% CI 1.38 - 84.74, P = 0.023) in the clinically-detected group. Our results suggest that initial presentation may be used to stratify mPTC patients for risk of recurrence. Clinically-detected cases have statistically significant higher risk of recurrence compared to pathology-detected cases. Imaging-detected cases may also potentially have a higher risk of recurrence.
Thyroid Cancer Thursday Poster Clinical
In MEN2A, American Thyroid Association-defined high-risk RET mutations (codon 634) are associated with earlier development of medullary thyroid carcinoma (MTC) compared to moderate-risk mutations. In the original classification, earlier age of MTC onset was equated with more aggressive disease. We hypothesized that age of presentation may not be a surrogate for MTC aggressiveness. Our institutional MEN2 database was queried for patients with MTC and an ATA moderate- or high-risk RET mutation. The primary outcomes (proxies for aggressiveness) were: (1) overall survival (OS) from diagnosis and (2) time to development of distant metastases (DM) from diagnosis. Cox models were built to determine factors associated with death or development of DM. 127 moderate-risk and 135 high-risk patients were included (n = 262). Mean age of diagnosis was 41.6 (moderate risk) and 25.6 years (high risk) (P < 0.0001). Mean age of death was 63.0 years (moderate risk) and 55.7 years (high risk) (P = 0.20). Moderate-risk patients had more T3/T4 tumors at diagnosis (P = 0.03), but there was no significant difference between groups for lymphovascular invasion, N stage, or M stage at diagnosis. There was no difference in the percentage of patients that developed DM (P = 0.46).
No difference was observed in OS for moderate- or high-risk groups (P = 0.40). On multivariable analysis for OS, increasing age [HR = 1.05 per year (95% CI = 1.03–1.08)], T3/T4 tumor [HR = 2.73 (1.22–6.11)], and M1 status at diagnosis [HR = 3.93 (1.61–9.59)] were significant; high-risk mutation was not significantly associated with OS (P = 0.40).
No difference was observed in development of DM for moderate- or high-risk groups (P = 0.33). On multivariable analysis for DM, only N1 status at diagnosis was significant [HR = 2.10 (1.03–4.27)]; high-risk mutation status (P = 0.38), age (P = 0.14), and T3/T4 tumor (P = 0.25) were not significant. Patients with high- and moderate-risk germline RET mutations have similar OS and DM after diagnosis of MTC and therefore similarly aggressive disease. Because “high-risk” connotes increased aggressiveness, future guidelines should consider RET mutation classification by disease onset (early vs. late) rather than categorizing risk (high vs. moderate).
Thyroid Cancer Thursday Poster Clinical
Postoperative hypocalcaemia is the most common complication after total thyroidectomy (TT) plus central neck dissection (CND) owning to the dysfunction of parathyroid glands. Thompson NW suggested the surgical concept of “meticulous capsular dissection” in 1973. Under the guidance of this concept, the incidence of hypoparathyroidism in TT can be decreased greatly. However, the exact method to preserve the inferior parathyroid gland (IPTG) in situ during central neck dissection (CND) still remains unclear. In this study, we presented a new operation concept for preserving IPTG in situ during CND, and evaluated its effectiveness. The study group consisted of 181 patients with primary PTC who underwent TT with CND using the new surgical concept “a layer of thymus-blood vessel-inferior parathyroid gland (TBP)”, from January 2014 to December 2014. The control group included 306 sex- and age-matched patients who underwent conventional TT with CND from January 2012 to December 2013. The proportion of IPTG preserved in situ and the incidence of postoperative hypoparathyroidism were analyzed. Age, sex, tumor size, multifocality, extrathyroidal extension, and number of harvested and metastatic central lymph nodes were not significantly different between the study and control groups. In the study group, the success rate of IPTG preservation in situ significantly improved (from 37.9% to 76.3% in the left; from 52.0% to 77.9% in the right) and the incidence of transient hypoparathyroidism significantly decreased (from 14.1% to 2.2%). This method could greatly improve the success rate of preservation of IPTG in situ, efficiently decrease the incidence of temporary postoperative hypoparathyroidism, and ensure the completeness of CND.
Thyroid Cancer Thursday Poster Clinical
Presence of pyramidal lobe in normal thyroid gland is reported from 15% to 75%. PTC (Papillary thyroid carcinoma) that primarily arose from pyramidal lobe is extremely rare. Furthermore, the incidence of hidden malignancy in pyramidal lobe after thyroidectomy for thyroid cancer has not been reported. This study intended to evaluate the PTCs that occur in pyramidal lobe. From the 2006 to 2015 in Seoul National University Hospital, total 1107 patients were performed thyroidectomy due to the PTC with pyramidal lobe resection, not only primary pyramidal lobe cancer but also incidental pyramidal lobe excision during other thyroid lobe cancer surgery. We split patients into two groups - group 1: pyramidal lobe dominant PTC and group 2: incidental pyramidal lobe PTC. 49 patients revealed PTC in their pyramidal lobe. Group 1 included 10 patients; five patients have solitary PTC in pyramidal lobe and five patients have primary pyramidal lobe cancer with smaller cancers in other lobes. Mean age of group 1 was 58 years, and tumor diameter was 0.7 ± 0.7 cm (mean ± standard deviation). Extrathyroidal extension was present in 8 out of 10, and microscopic lymphatic invasion was present in 3 patients. Group 2 included 39 patients who diagnosed pyramidal lobe cancer after thyroidectomy for other lobe cancers. Incidence of hidden pyramidal lobe cancer was 3.56%. This study reports the largest number of pyramidal lobe dominant PTC in single center. Mean size of pyramidal lobe dominant cancers were smaller than 1 cm but extrathyroidal extension rate was 80%. We also found 39 incidental cancers in pyramidal lobe after thyroidectomy. These results suggest that proper pyramidal lobe resection has oncologic values for treatment pyramidal lobe dominant cancer and remove hidden malignancy when doing other lobe thyroid cancer surgery.
Thyroid Cancer Thursday Poster Clinical
Needle assisted laparoscopic modified neck dissection through bilateral breast approach is a technique of selective neck dissection for levels IIA, IIB, III, IV, VB, VI. This technique can promote cosmetic effect in patients with N1b papillary thyroid carcinoma. In January 2016, a 26yo female patient with papillary thyroid carcinoma, her left side lateral lymph node was proven metastasis by FNA. After CT scanning and ultrasonic inspection preoperatively, the clinical staging was staging I cT1bN1bM0. we decided to perform total thyroidectomy and left modified neck dissection through the bilateral breast approach. The operation room setup and the steps to create the operation space were described in the previous videos. With the assisted of MiniLap and needle retractors, we started laparoscopic modified neck dissection. external jugular vein was separated first, so it will be protected more efficiently. Then we incision in front of the sternocleidomastoid muscle, dissected the carotid triangle, presenting the posterior belly of the digastric muscles, hypoglossal nerve (XII) and accessory nerve (XI), dissection the levels IIA, IIB and III lymph node. then continued by the intermuscular approach to expose the venous angle and ligature of the thoracic duct, the level IV lymph node were dissected. While identifying the transverse cervical artery and cervical nerves, we return to the level V then removed the specimen, completed the enblock modified neck dissection. Finally, we present the recurrent laryngeal nerves, parathyroids and other important structures mentioned earlier. There was scar less in the neck and the cervical sensory nerves were in fair preservation. The patient operated using this technique was hospitalized for 5 days without any postoperative complications. Needle assisted laparoscopic modified neck dissection through bilateral breast approach can give more cosmetic results and minimal invasion for young patients with lateral lymph node metastasis. Needle assisted laparoscopic modified neck dissection through bilateral breast approach can be consider for N1b papillary thyroid carcinoma without mediastinal metastasis. This technique can bring better cosmetic results and minimal invasion for young patients.
Thyroid Cancer Thursday Poster Clinical
Patient factors are known to influence extent of disease and outcomes in thyroid cancer, but the role of race/ethnicity independent of socioeconomic factors is unclear. This study aims to examine the association of race/ethnicity on papillary thyroid cancer (PTC) presentation as it relates to overall survival (OS). We also explore whether these differences can be explained solely by socioeconomic factors or hospital variation. Patients diagnosed with PTC from 2004 to 2012 were queried from the National Cancer Data Base. Differences in disease presentation and OS were evaluated across the four largest racial/ethnic groups in the U.S. [Caucasian, African-American (AA), Hispanic, Asian/Pacific Islander (API)] controlling for socioeconomic and hospital characteristics. Of 183,203 patients, 81% were Caucasian, 6% AA, 9% Hispanic, and 4% API. After adjusting for socioeconomic and hospital characteristics, compared to Caucasians, AAs were more likely to have tumors ‡4 cm (OR 2.11, 95% CI: 1.97-2.26) and distant metastasis (OR 1.75, 95% CI: 1.45–2.12) but less likely to have nodal disease (OR 0.80, 95% CI: 0.74–0.86), multifocal disease (OR 0.81, 95% CI: 0.78–0.85) or contiguous extension (OR 0.73, 95% CI: 0.63–0.84). In comparison, Hispanics were more likely to have more locally advanced disease with tumors ‡4 cm (OR 1.36 95% CI: 1.27–1.46), lymph node involvement (OR 1.30, 95% CI: 1.23–1.37), and contiguous invasion (OR 1.54, 95% CI: 1.40–1.70). APIs were more likely to have nodal disease (OR 1.25, 95% CI: 1.17–1.34), contiguous extension (OR 1.52, 95% CI: 1.34–1.73), and distant metastasis (OR 1.62, 95% CI: 1.31–2.00). On unadjusted OS analysis, AAs had worse OS while Hispanics and APIs had improved OS compared to Caucasians (all P < 0.001). On adjusted OS analysis, Hispanics (HR 0.64, 95% CI: 0.57–.071) and APIs (HR 0.61, 95% CI: 0.52–0.72) continued to have improved OS while AAs (HR 0.94, 95%CI: 0.86–1.04) had similar OS compared to Caucasians. Extent of disease at diagnosis differs across racial/ethnic groups. APIs and Hispanics have improved OS compared to Caucasians. These variations suggest that the diagnostic evaluation and surgical management of patients with PTC may differ according to race/ethnicity.
Thyroid Cancer Thursday Poster Clinical
The number of metastatic lymph nodes (LNs) and the rate of metastatic lymph node (LR) have been reported as predictors of recurrence in papillary thyroid carcinoma (PTC), while the role of LR or the number of metastatic LNs on the clinical response remains unclear. We aimed to compare the prognostic value of LR and the number of metastatic LNs on clinical response in PTC. A total of 384 PTC patients with lymph node (LR) metastases were enrolled in this study, response to initial therapy was classified as excellent, indeterminate, biochemical incomplete or structural incomplete response (ER, IDR, BIR or SIR). The receiver operating characteristic (ROC) curve was respectively employed to evaluate and compare the clinical value of the number of metastatic LNs and LR for predicting ER in different number of dissected LNs (DLNs). Multivariate analyses were further performed to explore the indicator for ER. In patients with ≤10 DLNs, LR presented higher area under the ROC curve (AUC) than the number of metastatic LNs in predicting ER (LR: 0.687, LNs:0.556, P = 0.0246), while it turns opposite in those with >10 DLNs. In the multivariate analysis, LR (OR = 1.037, P = 0.001) rather than the number metastatic LNs (OR = 0.752, P = 0.092) was an independent indicator for ER in addition to ps-Tg (OR = 1.056, P = 0.011) among patients with ≤10 DLNs. While in patients with >10 DLNs, the number of metastatic LNs (OR = 1.062, P = 0.044) turned to be independent factor for ER, apart from ps-Tg (OR = 1.071, P = 0.000) and gender (OR = 0.570, P = 0.023). LR appears to be a better negative predictor for ER than the number of metastatic LNs in PTC patients with ≤10 DLNs, while the number of metastatic LNs is superior to LR in those with >10 DLNs.
Thyroid Cancer Thursday Poster Clinical
Poorly differentiated thyroid carcinomas account for less than 15% of all thyroid malignancies. Nevertheless, they represent the second cause of death from follicular cell-derived thyroid cancer after anaplastic carcinomas.
To analyze the clinicopathologic characteristics and outcomes of poorly differentiated thyroid cancer (PDTC)Overall survival (OS), disease specific survival (DSS) and recurrence free survival (RFS) were calculated (Kaplan Meier). Clinicopathologic characteristics were analyzed between those who died and survived (X2). Factors predictive of disease specific survival were calculated by multivariate analysisA total of 101 patients with PDTC were treated from 1986 to 2010. The mean age at diagnosis was 60 ± 16.8 years and the female/male ratio was 1.9:1. The mean nodule size was 5.46 ± 3.55 cm; 61% presented with T4 and 25% with T3 status; 43.6% with N1 status and 32.4% with M1 status.
After a median follow-up of 4.68 years, the 5-year OS and DSS were 47.8 and 60.1% respectively. When stratified by pT4 and M1 status the 5-year DSS was 40.4 vs 72.6% (p < 0,001) and 28.9% vs 96.6 (p < 0,001). A trend towards a decrease of 5-year DSS with positive nodal status (45.6 vs 63.1%, p = 0.141) was observed. The 5-year local RFS and distant RFS were 72 and 49%, respectively.
Patients who died of the disease had bigger tumor size (> 40 mm 58.3 vs 41.7% p = 0,001), more frequently pT4 stage (51.7 vs 22%, p = 0.003), positive extra-thyroidal extension (84.9 vs 58.8%, p = 0,011), M1 status, either at diagnosis (46.7 vs 24.4% p = 0,001) or at the end of follow-up (60 vs 40%, p = 0.001). There were no differences in blood vessel invasion or in the histological pattern. Higher age at diagnosis, pT4 and M1 status at the end of follow-up were the only independent predictors of 5-year DSS (p = 0.001) in multivariate analysis. Positive M1 status was a stronger predictor than age and pT4 status (partial Eta Squared 0.882 vs 0.163 vs 0.119, respectively). Patients with PDTC are at an increase risk of death and recurrent disease. Distant metastasis, and not locoregional disease, is the major contributor to disease specific death.
Thyroid Cancer Thursday Poster Clinical
Cancer care expenditure in the United States continues to rise yearly and is projected to surpass $150 billion by 2020. Although thyroid cancer has a high survival rate, it is associated with potentially high costs of care due to surveillance imaging, biopsy, surgery and long-term medical therapy, similar to other cancers. Few studies have examined the psychological and economic costs experienced by thyroid cancer survivors. We seek to estimate the comparative prevalence of financial hardship among US thyroid cancer and non-thyroid cancer patients. The Agency for Healthcare Research and Quality Medical Expenditure Panel Survey (MEPS) with Experiences with Cancer databank was queried to identify thyroid and non-thyroid cancer survivors. The survey included questions regarding personal material financial hardship such as debt, need for loans and bankruptcy, and psychological economic hardship such as anxiety regarding bill payment. Thyroid cancer patients with a history of cancer other than thyroid cancer were excluded from the thyroid cancer group. Weighted response estimates were generated as previously performed in MEPS analyses and characterized using descriptive statistics and chi-squared analysis. Thyroid cancer survivors more commonly endorsed experiencing financial stress, either material or psychological, (48.6%; 33.5%, p < 0.001) and more frequently experienced concurrent material and psychological economic hardship (24.5%; 14.9%, p < 0.001) compared to non-thyroid cancer survivors. Psychological financial hardship was reported by 46.0% of all thyroid cancer survivors compared to 25.3% of non-thyroid cancer survivors while material hardship was reported at relatively similar rates among thyroid and non-thyroid cancer survivors, 27% and 23%, respectively. Thyroid cancer survivors in the United States are more likely to report significant material and psychological hardship after diagnosis than non-thyroid cancer survivors. These findings suggest that financial hardship related to thyroid cancer treatment, including psychological hardship, may be under-recognized in the medical community. We plan to follow-up these findings to further delineate the cause of financial hardship in thyroid cancer survivors.
Thyroid Nodules & Goiter Thursday Poster Case Report
Polycystic thyroid disease is a rare condition and has been described in adults in the setting of subclinical and clinical hypothyroidism. We present the first known case of a pediatric patient with diffuse macrocystic degeneration of the thyroid. Six-year-old previously healthy patient was evaluated after presenting with a 16-month history of an enlarging polycystic thyroid and hyperthyroidism. Markers of autoimmune thyroid disease including thyroid stimulating immunoglobulin, TSH receptor antibody, thyroid peroxidase antibody, and thyroglobulin antibody were negative. No family history of benign or malignant thyroid or cystic disease was present. The patient underwent a total thyroidectomy without perioperative complication. She remains euthyroid with thyroid hormone replacement therapy. To our knowledge, this is the first report of polycystic thyroid disease in the pediatric population associated with hyperthyroidism without evidence of autoimmune disease. Somatic activating thyrotropin-receptor gene mutations are known to cause non-autoimmune hyperthyroidism in children, however it is unknown if similar mechanisms are responsible for pediatric polycystic thyroid disease. Polycystic thyroid degeneration can occur in children and may result in a hyperthyroid state.
Thyroid Cancer Thursday Poster Clinical
Thyroglobulin (Tg) is specific of thyroid follicular cells and serum Tg levels have been used as a postoperative marker for residual or recurrent tumor in differentiated thyroid carcinoma (DTC). There are few studies accessing the predictive role of undetectable thyroglobulin (Tg) in patients with poorly differentiated thyroid carcinoma (PDTC). To analyze the Tg levels following total thyroidectomy and adjuvant RAI in PDTC patients and to correlate Tg levels with recurrencePatients with PDTC with no distant metastases at presentation and managed by total thyroidectomy and adjuvant RAI were identified from a database of 124 PDTC patients (cases from 1986 until 2011). A nonstimulated Tg level less than 1 ng per ml was used as a cutoff point for undetectable Tg levels. Association of patient and tumor characteristics with Tg levels was examined by X2 test. Overall survival, disease specific survival and recurrence-free survival (RFS) stratified by Tg level were calculated by Kaplan Meier plus log rank testTwenty-four patients had undetectable Tg and 15 had detectable Tg (median 30 ng/ml; range 4–27946 ng/ml) following surgery and iodine therapy. Patients with undetectable Tg were less likely to have positive nodal metastasis compared to those with detectable Tg (20.8 vs. 73.3% respectively; p = 0.005) and there was a trend to less extra thyroidal extension (20% vs 47.8 respectively; p = 0.082). Patients with undetectable Tg levels had a trend towards better 5-year overall survival (91.3 vs 65% respectively; p = 0.096) and better 5-year disease specific survival (90.9 vs 65% respectively; p = 0.009). Patients with undetectable Tg also had better 5-year recurrence-free survival (84 vs 32% respectively; p = 0.001) and regional control and distant control than patients with detectable Tg level (5-year regional recurrence-free survival 90.9 vs. 55.6%; p = 0.014 and 5-year distant recurrence-free survival 91.7 vs. 46.9%, p = 0.017). Undetectable postoperative plus iodine thyroglobulin levels in PDTC patients appear to predict a lower rate of both death and recurrence.
Thyroid Cancer Thursday Poster Clinical
To investigate the influence of lymph node metastasis on the change of positive TgAb in differentiated thyroid carcinoma (DTC) after initial treatment. We retrospectively analyzed the clinical data of 98 DTC patients with positive TgAb (≥115IU/ml) before radioiodine (RAI) therapy, all of whom underwent total or near total thyroidectomy, neck lymph node dissection and subsequent RAI therapy. Patients were divided into G1 (n = 83) and G2 (n = 15) according to the disappearance of positive TgAb or not after a mean follow-up of 21.0 months. Analysis of variance (ANOVA), X2 test and Mann-Whitney rank-sum test were applied to compare the basic clinical features between G1 and G2, including number of metastatic lymph nodes, lymph node metastasis rate and N- stage, dose of RAI ablation, etc. The receiver operating characteristic(ROC)curves were employed to evaluate the predictive values of TgAb levels (negative or positive) and optimal cut-off point. The multivariate analyses were further performed to explore the independent indicator for persistent positive TgAb. We retrospectively analyzed the clinical data of 98 DTC patients with positive TgAb (≥115IU/ml) before radioiodine (RAI) therapy, all of whom underwent total or near total thyroidectomy, neck lymph node dissection and subsequent RAI therapy. Patients were divided into G1 (n = 83) and G2 (n = 15) according to the disappearance of positive TgAb or not after a mean follow-up of 21.0 months. Analysis of variance (ANOVA), X2 test and Mann-Whitney rank-sum test were applied to compare the basic clinical features between G1 and G2, including number of metastatic lymph nodes, lymph node metastasis rate and N- stage, dose of RAI ablation, etc. The receiver operating characteristic (ROC) curves were employed to evaluate the predictive values of TgAb levels (negative or positive) and optimal cut-off point. The multivariate analyses were further performed to explore the independent indicator for persistent positive TgAb. N-stage was an independent indicator for disappearance of positive TgAb. A metastatic lymph node rate of higher than 0.24 might hold prognostic value in predicting disappearance of positive TgAb.
Thyroid Cancer Thursday Poster Case Report
Apatinib mesylate is an oral, novel tyrosine kinase inhibitor (TKI) selective targeting VEGFR-2. Previous studies have proved more than 30% of disease control rate in advanced gastric cancer while little has been reported for radioiodine refractory differentiated thyroid cancer (RAIR-DTC). Here, we report one case of the encouraging efficacy of apatinib in RAIR-DTC. This clinical trail was approved by the Ethics Committee of PUMCH. A 75-year-old male patient suffered from papillary thyroid carcinoma underwent thyroidectomy and lymph node (LN) resection. He was identified as progressive RAIR-DTC after two times of RAI therapy following surgery (5550MBq per therapy).
BRAFV600E mutation, TERT and VEGF were also detected positive in tumor tissue.
Apatinib (750 mg/day) was administrated orally with a cycle of 28 days. Both CT (RECIST 1.1) and 18FDG positron emission tomography / CT were used for tumor assessments after 1 cycle therapy. Meanwhile, Tg was monitored every 2 weeks. Adverse events were also collected during the therapy.
Partial response (PR) was achieved after 1 cycle therapy (from 29.0 to 18.9 mm in diameter). Significant decreases of 18FDG uptake (SUVmax from 18.99 to 4.0) and thyroglobulin level (from 10.95 to 4.64 ng/mL) were also observed after one cycle therapy. RAIR-DTC showed a 10-year survival less than 10%, which gained widespread concern. Abundant angiogenesis has been detected in RAIR-DTC in our previous study. Albert some TKIs showed efficacy in RAIR-DTC, drug resistance, multiply adverse events as well as high cost restricted the application in RAIR-DTC patients, especially in China. As a novel TKI inhibits VEGFR-2, apatinib could reduce VEGF mediated endothelial cell migration and proliferation, reaching to the anti-tumor effect.
Hand-foot-skin reaction (HFSR) was the most severe adverse event during the therapy. As the most common adverse event of TKI, our patients also acquired grade 3 HFSR, resulting in therapy suspension at the fifth week. After one-week drug withdraw, it receded to grade 1. We reported the rapid efficacy of apatinib in RAIR-DTC. Partial response can be achieved after only one cycle treatment.
Thyroid Cancer Thursday Poster Case Report
Primary thyroid lymphoma (PTL) is a rare entity, comprising less than 5% of all thyroid malignancies. As a lymphocytic disorder, Hashimoto's thyroiditis is known to increase the risk of transformation into lymphomas, where the most common is the Non-Hodgkin's variant. Here we describe a young patient who presented with a rapidly enlarging goiter. A 26 year old female with no significant medical history was referred to the Endocrine clinic for progressive neck enlargement causing dysphagia, dyspnea and hoarseness. Her thyroid was 6 times the normal size (left>right), firm and non-tender, and lacked discrete nodules or lymph nodes. TSH was 6.03 uIU/mL (0.28–3.89) and free T4 of 0.67 ng/dL (0.58–1.64). CT of her neck showed a large, left-sided 9 cm mass with retrosternal extension and causing tracheal deviation. Ultrasound revealed similar measurements with profoundly hypoechoic appearance. Other labs showed elevated thyroglobulin antibody of 2726 IU/mL (<40) and thyroid peroxidase antibody of 738 IU/mL (<35). Fine needle aspirate (FNA) revealed many large atypical lymphocytes, but flow cytometry was unremarkable. Core biopsy was pursued and was consistent with diffuse large B cell lymphoma (DLBCL). PET-CT scan showed abnormal FDG avidity only in thyroid and bone marrow biopsy was unremarkable. She was staged as IE. She received 3 cycles of rituximab, doxorubicin, cyclophosamide, vincristine, and prednisone (R-CHOP) and radiation. She achieved complete response. Neck ultrasound a year after therapy showed a heterogeneous thyroid without nodules or lymphadenopathy. With the exception of treatment of Hashimoto's, she continues to remain in remission. PTL poses a diagnostic challenge due to lack of a biochemical marker, non-specific radiologic findings, and inconclusive FNAs. In the setting of a rapidly enlarging neck mass, there should be a high level of suspicion for advanced thyroid carcinomas as well as lymphoma. A core biopsy is often necessary to establish the appropriate diagnosis, as the treatment of PTL differs significantly from follicular cell derived or medullary thyroid cancer. Once PTL is diagnosed, the patient should be promptly referred to medical and radiation oncology for further management.
Thyroid Cancer Thursday Poster Case Report
Mantle cell lymphoma (MCL) is a type of non-Hodgkin lymphoma (NHL). Extra nodal disease is often found in over 75% of these patients at initial presentation. Most common sites are: bone marrow, peripheral blood and the gastrointestinal tract. While 2% of all extra-nodal NHL present in the thyroid, there exists insufficient data to describe the incidence of MCL in the thyroid. A case series of 1400 patients revealed that <1% of thyroid lymphomas may be MCL. A literature search only yielded 2 published case reports; hence better understanding of the presentation and disease course is essential. A 65 year old female with a history of type 2 diabetes mellitus, was referred for a multinodular goiter (MNG) initially discovered in 2000. From 2000–2008, multiple fine needle aspirations (FNA) from the dominant right 2.7 cm nodule were consistent with Hashimoto's thyroiditis and flow cytometry was negative for monoclonal B or T cells. Her right nodule remained stable until 11/2014, when it was noted to have grown to 3.8 cm. Due to progressing dysphagia and neck discomfort, she underwent total thyroidectomy in 2/2015. Pathology revealed MCL with mantle zone growth pattern in the right thyroid and lymphocytic infiltrates in the left. A pre laryngeal lymph node was also found to have MCL. Flow cytometry showed monoclonal B cells comprising 9% of total cells. The Ki-67 index was found to be 10%. She was staged as IIE MCL and offered conservative management by medical oncology, given that she had no B symptoms, with plans to initiate chemotherapy if there is evidence of disease progression. Despite not receiving chemotherapy, there remains no evidence for disease progression at this time. MCL is considered to be an aggressive variant of the NHL. Though chemotherapy is the treatment of choice for MCL, a small subset of patients with low-grade disease may be observed. As in our patient, a Ki-67 index <10% suggests a favorable prognosis. Of note, the two previously reported cases of MCL in the thyroid also exhibited no aggressive disease. A diagnosis of primary MCL in the thyroid remains rare and therefore difficult to make, and such patients require close monitoring.
Thyroid Cancer Thursday Poster Case Report
With the increasing incidence of papillary thyroid cancer (PTC), long-term surveillance has become crucial in monitoring for recurrence and has led to a decrease in recurrence rate postoperatively. Recurrence, if it does occur, typically happens within the first decade after treatment. However, there are cases of recurrence of PTC many decades after treatment; this opens the debate of whether or not there needs to be a change in the guidelines for surveillance. The following is a case of a patient who, after a thyroidectomy, developed recurrence with metastases 50 years later. The patient is a 71-year-old man with a history of papillary thyroid carcinoma status post total thyroidectomy 50 years ago who presented with a new mass on the left side of his neck with hoarseness, weight loss and dysphagia. The patient did not have any follow-up nor did he receive radioactive iodine following thyroidectomy, as he was considered cured. On computerized tomography (CT) scan, the patient was found to have many pulmonary nodules bilaterally and left paratracheal lymphadenopathy. Positron emission tomography (PET) scan showed a 4-cm left thyroid mass and osseous metastatic disease of the left iliac crest. Fine-needle aspirate biopsy of the thyroid mass revealed cells that expressed thyroglobulin, TTF-1 and PAX8, and was diffusely positive for MOC31, CD7 and cytokeratin. The pathology is consistent with poorly differentiated anaplastic thyroid carcinoma with co-existing PTC. The lung nodules revealed a similar morphology on biopsy. This case displays an unusual timeframe for recurrence of PTC. In review of the literature, there have not been many documented cases of PTC recurring at 50 years, and additionally a recurrence as aggressive. This case also highlights the debate of whether or not there needs to be a change in the guidelines for long-term surveillance for recurrence, as this case appears to be the result of insufficient surveillance postoperatively. Newer studies in the literature have challenged older guidelines and have suggested more frequent cost-effective monitoring. This is a unique case of a recurrence of thyroid cancer in a much more aggressive manner after surgery, questioning guidelines for surveillance.
Thyroid Cancer Thursday Poster Case Report
Metastasis to the thyroid must always be considered when evaluating a thyroid mass in a patient with previous malignancy. Hyperthyroidism might mask the clinical picture and mimic Graves' disease or hot nodules.48 year old female recently diagnosed stage IIIC1 uterine carcino-sarcoma 8 months prior to admission, had surgery, chemo and radiation therapy. She reported symptoms of palpitation, sweating, heat intolerance and shortness of breath for one month, associated with a new right sided neck mass. Test results showed elevated free thyroxine 4 (free-T4 = 4.4 ng/dL) and low thyrotropin (TSH = 0.018 μIU/ml). CT neck showed a new 4.6 cm right thyroid mass consistent with thyroid metastasis and numerous new scattered, enlarged metastatic lymph nodes with ill-defined margins concerning for extra capsular spread of tumor. FDG CT PET done two months prior to admission showed no pathology in the thyroid. Patient was placed on Methimazole and prednisone, also underwent local radiation therapy to her neck for symptomatic relief. Patient was placed under hospice care and expired two days later. It is estimated that only 1 percent of all clinically detectable thyroid cancers are of metastatic origin. The most common primary sites are cancers of the kidney, breast, lung, gastrointestinal system, and melanoma. The mean interval from the diagnosis of the primary tumor to the development of the thyroid metastasis is 14 months, the range varying according to the histological type. Negative staining with anti-thyroglobulin and anti-calcitonin antibodies would exclude the thyroid as primary origin of the neoplastic cells. The association with hyperthyroidism is extremely rare, possible etiology is autoimmune activation of the thyroid by tumor cytokines, or due to metastasis induced destruction of thyroid cells and release of thyroid hormone. Despite poor prognosis, aggressive medical treatment such as radiotherapy and systemic chemotherapy may offer a better quality of life. The association of hyperthyroidism and metastasis to the thyroid is extremely rare. Nevertheless, a history of a previous malignancy must alert providers when evaluating a thyroid mass.
Thyroid Cancer Thursday Poster Case Report
Distant spread of papillary thyroid carcinoma (PTC) is seen in 2–10% of patients, two-thirds of which are pulmonary metastasis, one-fourth are skeletal metastasis, and kidney metastases are exceedingly rare. A 53 year-old African-American female presented to her primary care provider with hypertensive urgency and recently diagnosed kidney disease. She was referred to a nephrologist and a renal ultrasound revealed bilateral renal masses. Interestingly, the patient revealed that approximately twenty years earlier, she had thyroid surgery for what she believed was a benign goiter. The left renal mass was consistent with angiomyolipoma by radiographic criteria, however the right kidney mass was concerning for renal cell carcinoma. After discussion with urology about surgical options, the patient opted for partial nephrectomy. The pathology showed that the right renal mass stained positive for TTF1 and PAX8, and was negative for P504S; the final diagnosis was a follicular variant of papillary thyroid carcinoma. Given this diagnosis, the patient underwent workup up for primary thyroid cancer with thyroid ultrasound that showed bilateral enlarged lobes of the thymus with nodules involving both lobes. Fine needle aspirations of the nodules found in both lobes of the thyroid were negative for malignancy. Thyroidectomy was performed in stages; the right hemithyroidectomy was performed first without a finding of malignant cells. Left hemithyroidectomy then showed two foci of PTC within the thyroid parenchyma and one paratracheal lymph node involved with metastatic disease. Multiple CT scans have shown no definitive metastatic disease, although the patient does a have a stable subcentimeter lung nodule that is being followed. Following thyroid resection, the patient completed radioactive iodine treatment to insure total ablation of thyroid tissue. To our knowledge, there have been fewer than thirty cases of well-differentiated thyroid cancer spread to the kidney been reported in the literature. In conclusion, although metastasis of primary PTC to the kidney is very rare, it can be masquerade as a renal cell carcinoma by appearance on imaging tests.
Thyroid Cancer Thursday Poster Case Report
Papillary thyroid cancer (PTC) is usually indolent with good prognosis and long-term survival. We present a unique case of aggressive metastatic papillary thyroid cancer with unusual presentation course and recurrence. 62 year-old male lifetime non-smoker with history of asthma was initially evaluated by pulmonologist for incidental right lower lobe pulmonary nodule on CT abdomen. Physical exam and lab work showed no abnormalities. Follow up CT scan 1 year later showed increase in size of the nodule with new hypodensities in left thyroid. Thyroid Ultrasound revealed 10 × 7 × 9 mm nodule in right lobe and 13 × 8 × 12 mm nodule located in left lobe. PET scan showed metabolically active 25 mm right lower lobe lung nodule and 12 mm left thyroid lobe nodule suspicious for malignancy. Lung biopsy revealed metastatic PTC. Fine needle aspiration left thyroid was suggestive of a nodular goiter and right thyroid was suspicious for papillary carcinoma. He underwent total thyroidectomy with post- operative radioiodine ablation and right lower lung resection. Thyroid pathology revealed multifocal, bilateral Stage IV papillary carcinoma. Lung pathology report was consistent with metastatic PTC. Patient was started on TSH suppressive dose of levothyroxine. Follow up labs 2 years after the resection showed increase in anti-thyroglubin antibodies (TgAbs) with undetectable thyroglobulin and TSH levels. CT chest showed recurrent right lower lung tumor. He underwent another tumor resection and mediastinal lymphadenectomy. PET scan 6 months later, revealed metabolically active right lower lobe mass. He developed intermittent hemoptysis and is currently enrolled in a clinical trial involving tyrosine kinase (TK) inhibitor treatment. Elevated TgAbs was the only indicator of recurrent PTC in our patient. Therefore, it can be used as secondary tumor marker to monitor disease recurrence. Rearrangements in RET oncogene leads to dedifferentiated thyroid carcinoma. PTC has an excellent prognosis with five-year survival greater than 95%. About 5–10 percent are refractory to standard treatment. Treatment with mutation specific TK inhibitor can be beneficial in patients with recurrent disease.
Thyroid Cancer Thursday Poster Case Report
Thyroid Lymphoma (TL) is an uncommon type of thyroid cancer accounting for only 1%–5% of all thyroid malignancies. Diffuse large B-cell lymphoma (DLBCL) is the most common subtype (70%) followed by mucosa-associated lymphoid tissue (MALT) lymphoma (10%–23%). The incidence of TL as a manifestation of Chronic Lymphocytic Leukemia (CLL) is 3%–4% of all thyroid lymphomas with only 5 cases reported from 2005 to 2015. We report a case of CLL with TL. In 2/2013, a 41 year old man, with CLL treated by Oncology with fludarabine, cyclophosphamide and rituximab, was referred to Endocrinology for a multinodular goiter. He was clinically and biochemically euthyroid without thyroid autoimmunity. Physical exam revealed a nodular enlarged thyroid. CT showed a 4.0 × 2.9 cm right cystic mass with tracheal deviation. Sonography showed multiple right cystic and solid nodules with a dominant 3.1 × 2.7 × 2.8 cm complex nodule. FNA was benign with neither clonal B cell nor atypical T cell populations on flow cytometry. In view of tracheal deviation, hemithyroidectomy was considered but he was lost to follow up. In 7/2015 he returned to Oncology and started ibrutinib. CT showed the right complex lesion with tracheal deviation to be unchanged. He returned to Endocrinolgy. Repeat FNA was again cytologically benign but flow cytometry revealed clonal B cells, negative for CD 10, but expressing CD5, DIM CD 20, CD 23 and DIM surface lambda light chains comprising 88% of lymphocytes consistent with CLL. The immune profile was similar to that detected in a retroperitoneal lymph node biopsy done 6/2015. He responded well to ibrutinib with significant decrease in the size of lymph nodes and WBC count. However the size of the thyroid nodule remained stable on CT done in 3/2016. TL as part of CLL is rare. Diagnosis in our patient required a second FNA with flow cytometry. His TL has not responded to chemotherapy for CLL and may require surgery. CLL involving the thyroid is a rare disease, may not be associated with thyroid autoimmunity and can pose diagnostic difficulty. A high index of suspicion is needed to indicate to the pathologist the need to perform flow cytometry thus enhancing diagnostic accuracy. TL in CLL may not respond to chemotherapy.
Thyroid Cancer Thursday Poster Case Report
Insular thyroid cancer (ITC) is a rare type of poorly differentiated thyroid cancer with higher incidence of local recurrence, early cervical lymph node involvement, and distant metastases. Moreover, despite its moderate radioiodine avidity, the effect of radioiodine therapy often yields unsatisfactory results, and the management of ITC may require adjuvant radiotherapy. 66 years old male presented eight years ago with a 6 cm right thyroid nodule. Patient underwent right lobectomy with pathology revealing 3 cm insular variant papillary thyroid cancer with vascular invasion (pT2N0). This was followed by completion thyroidectomy (left lobe was free of cancer) complicated with laryngeal nerve paralysis and laryngeal nerve repair. Surgery was followed by external beam radiation therapy to the neck area and administration of 131iodine 150 mCi two years later given persistent detectable thyroglobulin levels. Post-treatment iodine scan failed to show iodine avid disease. Suppressed thyroglobulin levels remained detectable and relatively stable until recently when started to rise and peaked at 243 with stimulated values of 1061. A thyrogen stimulated PET/CT was initially nonlocalizing. Thyrogen stimulated PET/CT was repeated a year later and after careful review of images, it was noted that the FDG area in the lumbar spine, previously interpreted as chronic degenerative changes, appeared larger. MRI of the lumbar spine was suggestive for L1 metastatic disease. CT-guided biopsy confirmed metastatic thyroid carcinoma. Patient underwent five cycles of external beam radiation to the L1 vertebral body. Upon completion of treatment, his thyroglobulin trended down to 20's. Our patient presented with localized bone metastases eight years after initial diagnosis of insular variant papillary thyroid cancer and responded to local radiotherapy. Insular variant papillary thyroid cancer has a high risk of persistent/recurrent disease. Close surveillance is essential in the management of these patients.
Thyroid Cancer Thursday Poster Case Report
Spindle epithelial tumor with thymus-like differentiation (SETTLE) is a rare type of thyroid tumor. It occurs in young patients and mostly has an indolent clinical course. At diagnosis metastases are rare but many patients evolve with metastases at follow-up. A 16-year-old caucasian female presented swelling in front of neck since 4 years ago with a slow growth. At last 4 months, she added swelling in left lateral neck with fast growth and no pain. She denied erythema, obstructive symptoms and thyroid dysfunction symptoms. She denied headache, palpitations, bone pain and diarrhea. She had no history of radiation or a family history of thyroid cancer.
Physical examination revealed a nodule in middle of thyroid of 4 cm, firm and painless and a lymph node conglomerate in left lateral neck of 8 × 6 cm with no pain.
Thyroid ultrasound revealed a nodule in the left lobe who was solid, heterogeneous with multiple calcifications and size of 3.7 × 3.4 × 2.5 cm. It reported left lymph nodes with metastatic appearance of 2 or 3 cm. TSH was normal.
Fine needle aspiration cytology of thyroid nodule and left cervical lymph node reported a medullary carcinoma with lymph node metastases, bethesda category VI.
Central and left lateral lymphadenectomy and total thyroidectomy was perfomed.
Definitive histology reported:Proteinoid tumour, biphasic, with a mainly fusocelular component and another tubulopapillary epithelioid component attached with mucous glands. There are massive lymph node metastases in 5 of 41 lymph nodes. Immunohistochemistry (IHC) reported positive to cytokeratin cocktail, cytokeratin 7 and vimentin. IHC reported negative to TTF1, chromogranin, synaptophysin, calcitonin and α feto protein. Pathology report:SETTLE.
Patient added neck pain. Bone scintigraphy showed an increase uptake in backbone. Whole body CT Scan showed same lesions, further bilateral lung micronodules.
She received 44 Gy of external radiation therapy in backbone for 5 weeks. Currently she feels better. Unlike mostly cases, our case has metastasic disease at diagnosis. SETTLE is an unusual thyroid tumor as well as their metastatic disease at diagnosis. Histopathology is diagnostic clue.
Treatment and prognosis are challenging because there is no enough knowledge about this tumor.
Thyroid Hormone Action Thursday Poster Basic
We have previously shown the existence of murine and human TSH-β variants which are significantly expressed in bone marrow derived macrophages indicative of a local osteoprotective action (Baliram, R et al:154(12):4919-26: Endocrinology 2013; Baliram, R et al: ITC Florida, 2015). Both variants appear to have thyroid stimulating activity in TSH specific bioassay. To gain insight into how a subunit variant may have biologic activity we have examined the structure-function relationship of the human TSH-βv with the TSH-β wild type subunit using molecular dynamic (MD) simulation with the Charmm-gui server (Jo, S et al 29(11) 1859-65: J Comput Chem 2008; Lee J et al 12(1):405-13: J Chem Theory Comput 2016) and the NAMD software (Phillips JC et al 26(16);1781-802: J Comput Chem 2005) for 100 nanosecond run. Since no crystal structure of TSH itself is available, we modeled the wild type human TSH-β and TSH-βv using the published FSH structure as the template. The ectodomain (ECD) of the TSH receptor (TSHR) from residues 22-261, encompassing the entire leucine rich repeat region (LLR) with α helices and β pleated sheets, has been crystallized (Sanders J et al 17(5):395–410: Thyroid 2007) and we used this structure as the target in the MD simulations. These data showed that the wild type TSH-β subunit made contact with the middle and C- terminus of the LRR in a similar way to the interaction of the TSH-αβ heterodimer with the receptor ECD. Interestingly, the modelled TSH-βv subunit also retained its interaction with the ECD by contacting with surfaces on the α-helices and also binding to the C-terminal domain of the ECD. In all, the TSH-βv showed at least 9 contact points with the ECD, 3 of which formed hydrogen bonds and the remainder being polar and non-polar interactions of which lysine 58 (K58) and aspartic acid 203 (D203) are contacts with the TSH-βv and the wild type TSHβ. These molecular simulation studies of a novel human TSH-βv showed retention of 2 critical contact residues on the ECD indicating its ability to exert key conformational changes needed for TSHR signaling.
Thyroid Hormone Action Thursday Poster Clinical
Type 2 5′-deiodinase enzyme, as a commonly factor between thyroid and eye muscle tissues, plays an important role in the maintenance of intracellular T3 pool. The treatment of Graves' ophthalmopathy represents several times hard problem due to distinct autoimmune and inflammatory events in thyroid glands and orbits. In this study, the effects of drugs (methylprednisolone, pentoxifylline, beta-blocker and potassium iodate) were investigated on type 2 5′-deiodinase enzyme activities, which drugs are used for cure of hyperthyroid Graves' ophthalmopathy.
Type 2 5′-deiodinase enzyme activities were measured in human thyroid and porcine eye muscle supernatant fractions using 125I-T4 substrate and propylthiouracil. The radioactivities were measured after trichloracetic acid precipitation in gamma counter or displayed in autoradiography in the presence of various drug concentrations (1–1000 ng/ml). The results were exhibited in percent of enzyme activity given by the absence of drugs.
Methylprednisolone and pentoxifylline inhibited type 2 5′-deiodinase activities in the thyroid fraction but increased in the eye muscle fraction at the concentration of 1 μg/ml (94.27 ± 13.34% vs 108.87 ± 1.37% for methylprednisolone and 90.01 ± 6.15% vs 106.62 ± 2.52 %, P < 0.012 for pentoxifylline). Beta-blocker decreased type 2 5′-deiodinase activities, while potassium iodate increased them in both tissue-fractions (91.88 ± 4.55% vs 96.25 ± 1.5% for beta-blocker and 103.42 ± 1.46% vs 101.1 ± 15.19% for potassium iodate). Methylprednisolone, pentoxifylline and beta-blocker inhibited the binding of 125I-T4 to thyroid fraction in the ranges of 66 kDa and 29 kDa, but these inhibiting effects were weaker in eye muscle fraction. Distinct inhibitory effects of methylprednisolone and pentoxifylline on thyroid and eye muscle type 2 5′-deiodinase activities may explain their unexpected reactions in orbits.
Thyroid Hormone Metabolism & Regulation Thursday Poster Clinical
To evaluate differences in the prevention and management of hypocalcemia after thyroidectomy among surgeons. Surgeon members of the American Thyroid Association (ATA) and the International Association of Endocrine Surgeons (IAES) were surveyed by email in the spring of 2014. Descriptive analysis and adjusted logistic regression were performed on survey response data. Responses were received from 203 members of the ATA and 129 members of the IAES; 72% had been in practice for ≥10 years, 45% were based outside the US, 34% were in private practice, and 14% were trained in Otolaryngology.
26% of respondents test all patients for pre-operative 25 (OH) Vitamin D levels before thyroidectomy. 42% of respondents administer prophylactic oral calcium supplementation and 13% administer prophylactic oral vitamin D supplementation for all patients in the immediate post-operative period.
Post-operative PTH levels were used to assess for hypocalcemia by 53% of respondents, and more commonly performed by non-US surgeons compared to US-based surgeons (60% vs. 48%, p = 0.02).
29% of those surveyed occasionally admit thyroidectomy patients to trend calcium levels. Routine hospital admission was reported by 16% of respondents, a more common practice within Otolaryngology than General Surgery (33% vs. 13%, p = 0.004). This study identifies significant differences among surgeons in strategies to prevent and manage hypocalcemia following thyroidectomy. The development of evidence-based guidelines is warranted.
Thyroid Hormone Metabolism & Regulation Thursday Poster Clinical
T4 to T3 conversion in peripheral tissue comprises about 80% of serum T3 and the remaining 20% come from the thyroid gland. Therefore, it can be deduced that the patients who undergo total thyroidectomy has 20% lower T3 than that of whom has normal thyroid gland. Thus lowering levothyroxint (LT4) dose to increase serum TSH level to low normal (0.5–2.0 uIU/mL) according to the dynamic risk stratification (DRS) can be associated with weight gain. But there are insufficient data about the thyroid function or weight changes after lowering the dose of LT4 according to DRS in 2015 new ATA guideline. Between January 1st to December 31th 2013, 119 patients who start the lowering of the LT4 dose according to DRS were enrolled. By 1:1 matching with age and sex, 119 patients who did not change the LT4 dose during the study period were selected as a control group. Each thyroid function test and body weight at the time points (before surgery, before the start of lowering LT4 dose, after 6–12 month of the lowering of LT4 dose) were reviewed retrospectively. Baseline characteristics (age, sex and duration of follow up) of patient group and control group were not different. After the lowering of LT4 dose in study group, serum TSH level increased significantly (Wilcoxon rank sum test, p = 0.01) and serum free T4 level (Wilcoxon rank sum test, p = 0.01) and serum T3 level (Paired t-test, p < 0.001) decreased significantly. Interestingly, body weight significantly increased (Paired t-test, p = 0.004) after 6–12 month of the lowering of LT4 dose although the serum TSH level were in the lower normal range (< 3mIU/mL). In contrast, serum TSH level (Wilcoxon rank sum test, p = 0.994), serum fT4 level (Wilcoxon rank sum test, p = 0.543), serum T3 level (Wilcoxon rank sum test, p = 0.696) and bodyweight (Wilcoxon rank sum test, p = 0.604) did not change in control group. Even the serum TSH level was in the low normal range, we observed the weight gain after the start of lowering LT4 dose according to DRS in the new ATA guideline. Therefore, cautions and advices to the patients about weight gain are warranted when we start the lowering LT4 dose to release the suppression of serum TSH to maintain it in the low normal range.
Thyroid Hormone Metabolism & Regulation Thursday Poster Clinical
Levothyroxine (L-T4) is the treatment of choice for millions of hypothyroid patients and a limited serum TSH concentration represents the best marker to assess a successful treatment. Current guidelines recommend that L-T4 tablets should be taken in a fasting state, but this prescription is often cause of poor compliance to the therapy. Over the last few years, pharmaceutical companies have introduced in a few countries new, non-tablet L-T4 formulations, such as liquid and soft gel capsules. The results of a recent randomized, double-blind, placebo-controlled crossover trial, the “TICO” study, showed that a liquid L-T4 formulation can be ingested with breakfast, thus potentially improving therapeutic compliance. Aim of the present study was to compare TSH levels of hypothyroid patients treated with liquid L-T4 thirty minutes before or at breakfast.
We enrolled hypothyroid patients in stable euthyroidism on liquid LT4 (Tirosint® unit-dose vials, IBSA Farmaceutici Italia) treatment assumed half an hour before breakfast. The patients were invited to assume L-T4 with breakfast for 6 months. Individual L-T4 doses titrated during the first sequence period did not change during the second sequence. At the end of the second period TSH was re-checked.
761 patients (558/203 female/male, age 46.2 ± 10.8 years) were enrolled in the study. 498 patients were in replacement therapy for Hashimoto thyroiditis and 263 after thyroidectomy for the removal of histologically proven benign goiter. No difference of TSH levels was observed whether L-T4 was assumed at breakfast or half an hour before in a fasting state [2.54 ± 1.86 vs. 2.61 ± 1.79 (mIU/L), p = 0.455]. A sub-analysis was performed on 202 patients assuming a concomitant drug treatment (including proton pump inhibitors, calcium or iron supplements) or using fiber and soy milk products at breakfast. Again, no difference of TSH levels was observed [2.69 ± 1.96 vs. 2.63 ± 1.53(mIU/L), p = 0.732].
The present study confirms in a large set of patients that a liquid L-T4 formulation can be assumed directly at breakfast, thus potentially improving therapeutic compliance.
Thyroid Hormone Metabolism & Regulation Thursday Poster Case Report
Amiodarone-induced thyrotoxicosis (AIT) occurs in up to 10% of patients treated with amiodarone in the U.S., and is classified into types 1 and 2 based on underlying thyroid gland activity. Type 1 AIT is caused by increased thyroid hormone production stimulated by amiodarone's high iodine content. Type 2 AIT is due to a direct toxic effect of amiodarone on follicular cells, causing release of stored thyroid hormone. Determining the etiology of AIT is paramount, as treatment recommendations vary significantly based on underlying cause. A 73-year-old male with chronic systolic heart failure and ventricular arrhythmias presented after receiving multiple shocks from his implantable cardioverter defibrillator. There was no known history of thyroid disease. He denied exogenous thyroid hormone, but had been prescribed amiodarone for two years. He denied heat intolerance, diaphoresis, or diarrhea. Vital signs were normal. There was no exophthalmos or corneal injection. His thyroid was not enlarged and had no palpable nodules. Labs showed TSH <0.008 mIU/L (0.465–4.68) and free T4 2.11 ng/dL (0.78–2.19). Thyroid ultrasound was significant for a small gland with very low Doppler flow. Based on amiodarone use, lab evidence of hyperthyroidism, and low flow on ultrasound, he was diagnosed with type 2 AIT. His cardiologist was reluctant to discontinue amiodarone as he had previously failed multiple other antiarrhythmics. He was prescribed prednisone 30 mg daily which was slowly tapered. Thyroid function tests normalized on prednisone and remained stable during the taper. He currently continues amiodarone and remains euthyroid 18 months after discontinuation of glucocorticoids, however he will require continued monitoring of thyroid function. This is a case of type 2 AIT in a patient unable to discontinue amiodarone therapy due to severe cardiac arrhythmias. Discontinuation of amiodarone is preferred when AIT is identified, however rarely this is not possible. AIT recurs in up to 18% of patients with type 2 AIT who become euthyroid with treatment. This case underlies the importance of continued surveillance in patients with a history of AIT, particularly those in whom amiodarone cannot be discontinued.
Thyroid Imaging Thursday Poster Translational
Investigate factors related to echogenicity variability.
Evaluate the effect of nodule echogenicity on cytological/ histological diagnosis.
Prospective cohort design including 464 consecutive nodules submitted to fine needle aspiration biopsy between 2013/07 and 2016/03.
Echogenicity levels (ELs), in decibels (Db), were measured in thyroid parenchyma, in adjacent muscles, in the nodule selected for biopsy, and in a phantom, to define “normal thyroid” and “normal muscle”.
The ELs from thyroiditis and non-thyroiditis, and from male and female patients, were compared using Mann-Whitney U test.
The relationship between patients' age and muscle ELs was estimated using Pearson's correlation coefficient.
The differences in proportions of hypoechogenic (defined as nodule EL<thyroid EL; nodule EL<phantom thyroid EL; nodule EL< muscle EL and nodule EL< phantom muscle EL) vs hyper/ isoechogenic nodules in cytology/histology results were tested using chi-squared test.
The median (range) of Thyroid ELs, Muscle ELs and nodule ELs were −36,6 (51,8;-21,7); −43,9 (-58,1;-25,5), and −40,8 (-62,7;-22,8) respectively.
The median ELs from thyroiditis (-44Db) was significantly lower than non-thyroiditis' (-35Db) p <0.001.
No statistically significant difference in echogenicity was found between genders.
There was a weak, though highly significant, positive correlation between patients' age and muscle ELs (correlation coefficient 0,243, p < 0,001).
Hypoechogenic nodules relative to thyroid parenchyma were 3 times more likely than non-hypoechogenic nodules to have malignant cytology/histology (OR:3,16.IC: 1,088; 9,207. p = 0,02), as opposed to those relative to thyroid phantom, which were 5 times more likely (OR 5,2.IC:1,225; 22,2. p = 0,01), and to muscle, which were 2 times more likely (OR 2,3.IC: 1,166;4,715. p = 0,01). There is wide variability in the echogenicity of thyroid parenchyma and neck muscles. The presence of thyroiditis affects thyroid gland echogenicity and patients' age affects muscle echogenicity. The heterogeneity of the references affects nodules' ultrasound echogenicity evaluation.
Thyroid Imaging Thursday Poster Clinical
Ultrasound (US) features plays a crucial role in management of thyroid nodule. Despite the high diagnostic performance and suggested diagnostic criteria for malignant thyroid nodule, US features usually are operator-dependent. To improve the diagnostic performance of US, various types of US elastography, which measures the stiffness of nodule, had studied. Here, we present the prospective study of US elastography using the internal carotid artery as a pulsation source, which could present objective interpretation with proven inter- and intraobserver reproducibility. From May 2015 to Feb. 2016, we recruited subjects who were referred to perform FNA from primary physician (study ID: NCT02462512). During the period, elastography was performed on 172 nodules from 116 subjects before FNA. Among them, 48 nodules were not biopsied. Among 124 nodules, 13 nodules (10.4%) showed unsatisfactory or cystic fluid only. Finally, 111 nodules from 99 subjects were enrolled in the analysis. The mean maximum diameter of nodule was 11.5 ± 5.9 mm. Incidence of malignant nodule proven by cytology with/without pathologic report was 30.6% of total (34 malignant and 77 benign nodules). Cut-off value of 3.3, which maximized the geometric mean in detecting malignant nodules, was determined. Diagnostic performance of elastogaphy showed 55.9% sensitivity, 71.4% specificitiy, 46.3% positive predictive value, 78.6% negative predictive value (NPV) and 66.7% diagnostic accuracy. In benign and indeterminate nodules determined by B-mode, elastography showed 91.7% of NPV. Among 54 calcified nodules, 25 were considered as benign by elastography. 11 out of 25 calcified nodules were classified as indeterminateby US B-mode and all of them were benign. Other 14 calcified nodules were classified as suspicious malignant by US B-mode and 6 were proven to be malignancy. Elastography using the carotid artery pulsation as a compression source has a complementary role in management of patients with thyroid nodules. Especially, in benign and indeterminate looking nodules by US B-mode, it could decrease the number of FNA biopsies based on high NPV. Also, combination of elastography and US B-mode would be useful in management of calcified nodules.
Thyroid Imaging Thursday Poster Clinical
The incidence of thyroid cancer is increasing rapidly in recent years. In view of the variety of the biological behavior and clinical manifestation of thyroid cancer, there is inevitable defect for early diagnosis with a single technology. From November 2011 to February 2013, 307 cases of patients with a total of 367 thyroid nodules underwent conventional ultrasound (CUS), contrast enhanced ultrasound (CEUS) and ultrasound elastography examination before surgery. The sonographic features of these nodules were analysed. Binary logistic regression analysis was performed to screen out independent risk factors regarding thyroid cancer, and to establish multi-modality diagnostic model for thyroid nodules. The diagnostic performance of CUS, CEUS, ultrasound elastography and the multi-modality diagnostic model were assessed and compared. Six independent risk factors were included in logistic regression models: shape, echogenicity, vascular morphology, enhancement pattern, elasticity score, and age. Among all of the CUS characteristics, irregular shape had the highest diagnostic accuracy (80.7%), with a sensitivity of 88.9% and a specificity of 68.7%. Among all of the CEUS characteristics, heterogeneous enhancement had the highest diagnostic accuracy (78.7%), with a sensitivity of 82.0% and a specificity of 74.0%. Elasticity score had a diagnostic accuracy of 78.5%, with a sensitivity of 87.1% and a specificity of 66.0%. The multi-modality diagnostic model had a diagnostic accuracy of 86.9%, with a sensitivity of 93.5% and a specificity of 77.3%. The multi-modality diagnostic model improved the diagnostic accuracy compared with CUS, CEUS and ultrasound elastography. Independent risk factors for thyroid cancer include shape, echogenicity, vascular morphology, enhancement pattern, elasticity score, and age. The multi-modality diagnostic model was demonstrated to be effective in the diagnosis of thyroid nodules.
Thyroid Imaging Thursday Poster Clinical
FDG-avid thyroid incidentalomas (TI) are a common finding (2.5%) in patients imaged for staging or response assessment of malignancy and represent thyroid cancer in approximately 35% of cases. Consequently the 2015 ATA guidelines strongly recommend investigation of such nodules ≥1 cm with thyroid US and fine needle aspiration cytology (FNA) without considering the prognosis of underlying malignancy. This study aims to assess the overall and thyroid cancer specific survival in a large cohort of patients with FDG-avid TI with long-term follow-up. Retrospective review of 45 680 PET/CT scans performed at a comprehensive cancer center from January 2007 to January 2015 identified 2588 FDG PET/CT reports referring to the thyroid. After exclusion of non-avid thyroid nodules, diffuse FDG uptake, known thyroid cancer, abnormalities adjacent to thyroid and repeat studies, 501 patients with TI were identified for further analysis. Variables including age, gender, follow-up time >12 months, primary malignancy, overall survival, thyroid cancer-specific survival, FNA and histopathology were followed until January 2016.362 patients met the inclusion criteria with a median age 65 years (range 19–96), and median follow-up of 24 months (range 1–103). Lymphoid, lung and colorectal malignancy were the most common staging indications. Median overall survival from the primary malignancy was 24 months; no patients died from incidental thyroid cancer. Of 150 (30%) patients deemed suitable for further cytological or histopathological evaluation, 54 patients had thyroid cancer (52% papillary, 20% metastatic, 11% malignant on FNA, 9.2% hurthle cell carcinoma, 5.5% medullary and 2% follicular), yielding a malignancy rate of 36%. 78 nodules were benign and 18 indeterminate. Focal thyroid uptake in an additional 37 patients was reported as consistent with metastatic disease. Only 1 patient had structural incomplete response at completion of follow-up. Overall survival with FDG-avid TI was poor and not influenced by incidental thyroid cancer. The prognosis of underlying malignancy must be considered prior to investigation of FDG-avid TI and active surveillance may be appropriate in this group of patients.
Thyroid Imaging Thursday Poster Clinical
Transcutaneous laryngeal ultrasonography (TLUS) has been proposed as a noninvasive technique to examine vocal cords (VC). TLUS using lateral approach was recently suggested as a better approach compared to the anterior approach to improve VC visualization. The aim of this study is to compare the anterior and lateral approaches of TLUS in evaluating vocal cords function. This is a retrospective study for patients who underwent thyroid or parathyroid surgeries within 6 months period. Each patient was evaluated by both TLUS anterior and lateral approaches. All these patients underwent additionally flexible fiberoptic laryngoscopy (FFL). The sensitivity, specificity, accuracy, negative and positive predictive values (NPV and PPV), accuracy, and tests of equality for receiver operating curve (ROC) areas were calculated for both anterior and lateral approaches.149 patients were included and the mean age was 51.4 ± 15.31 years. 125 (83.9%) were women. Seven patients had unilateral VC paralysis confirmed by FFL. TLUS identified the paralytic cords only in five patients (71.4%). The sensitivity, specificity, and accuracy of anterior TLUS were 50.0%, 61.2%, and 61.1%. Lateral TLUS correctly detected right and left VC function in 79.2% and 83.9% of cases respectively, whereas anterior TLUS correctly detected 61.1% of them. The lateral approach (ROC area 0.65, 95% CI 0.16–1.00) was significantly superior to the anterior approach (ROC area 0.56, 95% CI 0.06–1.00) in detecting VC function (p < 0.001). TLUS utilizing the lateral approach has superior specificity, PPV, NPV, and accuracy compared to the anterior approach.
Thyroid Nodules & Goiter Thursday Poster Clinical
Thyroid cancer is one of the most common carcinomas in children. Prior to 2015, there were no guidelines regarding the features that determine the malignancy potential of nodules in pediatrics. The reporting of nodules was often incomplete leading endocrinologists to make assumptions in management decisions. The 2015 guidelines identified 5 concerning features that define malignancy potential of a nodule and their importance in determining management. We sought to evaluate the frequency in which pediatric ultrasound reports document the 5 concerning features of thyroid nodules in our institution. A retrospective database search was performed by pediatric radiologists to identify thyroid ultrasounds that detected a nodule 0.5 cm or greater in patients under 22yr from July 2014-October 2015. Reports were reviewed for documentation of the concerning thyroid nodule features including: hypoechogenicity, irregular borders, increased intranodular blood flow, microcalcifications, and abnormal cervical lymph nodes. Chart review was used to determine whether patients underwent an FNA biopsy of the nodule and the resultant pathology. 78 thyroid ultrasound reports documenting a total of 143 thyroid nodules (88 before 6/2015 and 55 after 6/2015) are included in this study. The median nodule size (largest dimension) was 0.8 cm. Only 5 (3.5%) nodules had all 5 concerning features documented. One of these nodules underwent FNA based on concerning features. Overall, 31 nodules underwent FNA. The indication for FNA was size alone in 21/31 (67.7%) and size plus concerning features in 10/31 (32%). Of nodules with concerning features documented, FNA was performed in 2/6 with irregular margins, 3/4 with calcifications, 7/13 with internal vascularity and 1/6 with concerning lymph nodes. Of the 31 nodules that underwent FNA, 6 had concerning pathology reports (4 with Bethesda III, 1 with Bethesda IV) and 3 ultimately underwent surgery. Upon review of over 100 nodules, a few had reported all 5 concerning features. Reporting of these features in pediatric thyroid ultrasounds should reflect the 2015 guidelines. A method for radiologists to standardize thyroid ultrasound reports to include all concerning features should be established.
Thyroid Nodules & Goiter Thursday Poster Clinical
Trans-axillary endoscopic thyroid surgery offers the advantage of a good cosmetic outcome; however, it requires a wider dissection field compared to the other endoscopic approaches or open surgery. Therefore, it might cause severe postoperative pain occasionally. To reduce the required dissection field, we perform trans-axillary single incision endoscopic thyroidectomy (SIET) with gas inflation. The aim of this study was to present a single surgeon's experience with SIET and to investigate the learning curve of SIET. Between June 2009 and September 2014, a total of 105 patients who underwent hemithyroidectomy for benign thyroid tumor via a SIET procedure were included in the present study. All of the procedures were performed by the same surgeon. Each patient`s operative outcomes were collected and retrospectively analyzed. The cumulative summation (CUSUM) analysis was used to assess the learning curve of SIET. No mortality or serious morbidity was observed during the study period. The adverse postoperative outcomes included wound hematoma (2 cases; 1.9%), transient skin paresthesia (5 cases; 4.76%), transient voice change (5 cases; 4.76%), skin pigmentation (1 case; 0.9%), and fibrous band of wound (1 case; 0.9%). The overall mean operative time was 105 minutes and the mean operative time in the experienced phase was 95 minutes. CUSUM analysis showed a decreasing trend at the 35th patient, suggesting that more than 35 cases were needed for the surgeon to gain proficiency. In 76.19% of the cases, patients showed extreme satisfaction with the cosmetic results. Our results showed reasonable surgical outcomes compared to previous studies on endoscopic thyroidectomy. The SIET procedure is safe and feasible for benign thyroid tumors, and has an acceptable learning curve for surgeons who are proficient in conventional endoscopic thyroidectomy.
Thyroid Nodules & Goiter Thursday Poster Clinical
Current surgical indications for Graves' Disease (GD) include intractability to medical and/or radioablative therapy, compressive symptoms and worsening ophthalmopathy. Due to chronic inflammation, total thyroidectomy (TT) in the setting of GD may be more technically challenging and lead to worse perioperative outcomes. For these reasons, endocrinologists may be discouraged from considering TT for treatment of GD. This study examines TT postoperative outcomes in patients with GD, and assesses its safety as an alternative definitive treatment in this patient population. A retrospective cross-sectional analysis was performed using the Nationwide Inpatient Sample database from 2006 to 2011. TT performed in patients with or without GD were identified. Demographic factors, comorbidities, and postoperative complications were evaluated. Chi-squared, student t-test, and risk-adjusted multivariate logistic regression were performed. Of 219,720 patients who underwent TT during the study period, 12,911 (5.9%) had GD. Patients with GD were younger than non-GD patients (mean 41.4 vs 53.0 years, p < 0.01). The GD cohort also had a higher proportion of women (83% vs. 78%, p < 0.01) and non-Whites (40.2% vs. 31.2%, p < 0.01). GD patients had significantly higher rates of postoperative hypocalcemia (12.8% vs 8.8%), hematoma requiring reoperation (0.7% vs. 0.4%), and longer mean hospital stay (2.6 vs. 2.3 days); p < 0.01. However, GD patients did not suffer higher rates of major medical complications (e.g. MI, stroke, ARF, VTE, shock), wound infection, vocal cord paresis, tracheostomy or autotransplantation of parathyroid glands. On risk-adjusted multivariate logistic regression, GD was independently associated with higher risk of postoperative hypocalcemia (AOR 1.35, 95% CI 1.3–1.4) and hematoma requiring reoperation (AOR 2.3, 95% CI 1.8–3.0). Despite higher rates of postoperative hypocalcemia and hematoma requiring reoperation, there is no increased morbidity resulting from major medical complications, vocal cord paresis, or tracheostomy in GD patients who undergo thyroidectomy. TT provides a safe and definitive treatment option for appropriately selected patients with GD.
Thyroid Nodules & Goiter Thursday Poster Clinical
Fine needle aspiration (FNA) is recommended for pre-operative evaluation of thyroid nodules. The Bethesda system for thyroid cytopathology classifies FNA results by risk of malignancy. However, 10–20% of nodules are indeterminate, classified as Bethesda III (B-III). Molecular testing may help clarify the malignancy risk in indeterminate nodules. We evaluated how molecular testing impacted surgical rates at our institution compared to repeat FNA. IRB-approved retrospective chart review was performed of all FNAs done at the University of Washington between 4/21/14 and 12/31/15. FNAs with B-III cytology were reviewed for molecular testing, repeat FNA, surgery, or monitoring by serial ultrasound. For patients who had molecular testing or repeat FNA, we reviewed outcomes and ultimate disposition. Of 650 FNAs performed, 48 (7%) were B-III. Molecular testing was performed on 35% of the B-III FNAs (n = 17), repeat FNA for 19% (n = 9), surgery for 15% (n = 7) and clinical follow up for 8% (n = 4). Eleven patients (23%) were lost to follow up. Of those who had repeat FNA, 3 were classified as B-III (2 had surgery with one follicular carcinoma, 1 followed by ultrasound), 4 benign, and 1 malignant. One was lost to follow up. Of 17 patients who had molecular testing, 11 had AfirmaTM, of which 9 were “suspicious” (82%). Of those, 5 had surgery with 2 confirmed malignancies (40%). Six patients had ThyroSeq® with 5 negative for mutations (83%). One patient had a mutation identified and is scheduled for surgery. Overall, 33% of patients who had repeat FNA underwent diagnostic surgery, compared to 35% with molecular testing. Malignancy rate was 22% for repeat FNA and 13% for molecular testing. Molecular testing after indeterminate FNA did not decrease the number of diagnostic surgeries compared to repeat FNA at our institution. Our study is limited by small numbers and lack of randomization. However, our data suggests molecular testing may not provide a significant benefit over repeat FNA in B-III nodules and more long-term data is needed to clarify the role of molecular testing at our institution.
Thyroid Nodules & Goiter Thursday Poster Clinical
Epidemiologic and clinical studies suggest that thyroid nodules can be palpated in 5% of individuals and detected in up to 60% of people who undergo thyroid ultrasound. thyroid cancer incidence has constantly increased all over the world including Saudi Arabia. the Bethesda system for reporting thyroid cytopathology (BSRTC) is widely used nowadays. From January, 2012 to December, 2014, a retrospective analysis was performed among 1188 patients (15–90 years old) who had 1433 thyroid nodules and FNAs at Prince Sultan Military Medical City, Saudi Arabia. All thyroid cyto-pathological slides and ultra sound reports were reviewed and classified according to th BSRTC.
Age, gender, cytological features and histological types of the thyroid cancer were collected from patients' medical chart and cytopathology reports. There were 124 total cases of malignancy on resection, giving an overall surgical yield of malignancy of 33.6%. The risk of malignancy for each Bethesda category ranged from 1–10% (the “benign category) to 94–100% (the “malignant” category). This comprehensive range shows the power of the Bethesda system to differentiate and determine the probability of malignancy.
The percentages obtained in our research were rather close to the figures reported in published studies: 25% versus 9–32% (non-diagnostic or unsatisfactory category), 9.3% versus 1–10% (the “benign and non- neoplastic” category), 14.3 versus 6–48% (AUS/FLUS), 69.2% versus 53–97% (the “suspicious for malignancy” category), and 96.7% versus 94–100 (the “malignant” category).
Among Bethesda, category IV found 47.2% risk of malignancy, which was higher than recently published meta-analysis by Bongiovanni et al whose reported 14–34% (FN/SFN). However, several studies showed a widest variation of risk of malignancy in category IV, some are higher (malignancy rate 50–67%) than the current findingsThe malignancy percentages obtained in our research were constantly and comparable with other published data in regard to risk of malignancy. For patients with follicular neoplasm/suspicious for follicular neoplasm (FN/SFN) and suspicious of malignancy categories, total thyroidectomy are indicted because of the substantial risk of malignancy.
Thyroid Nodules & Goiter Thursday Poster Clinical
The follicular neoplasm (FN) are usually diagnosed as suspicious follicular neoplasm (SFN) or follicular neoplasm (FN) in preoperative FNA and they are confirmed after thyroidectomy, but some of FN who are not suspicious cytology results were incidentally diagnosed after thyroidectomy. We analyzed the clinicopathologic characteristics of FN diagnosed after thyroidectomy. Patients who were diagnosed as follicular neoplasm (adenoma, n = 66; carcinoma, n = 4) after thyroidectomy were retrospectively analyzed. Their medical records about the results of preoperative cytology, ultrasonography and the cause of thyroidectomy decision were reviewed. The median age is 48.1 ± 14.2 years (range 21 ∼ 76) and two third (n = 44) were female. According to the guideline, 16 patients (35.7%) underwent thyroidectomy because suspicious cytology results (SFN/FN, n = 7; suspicious malignancy, n = 2; AUS/FLUS, n = 16).
27 patients were also underwent thyroidectomy without suspicious cytology results; 17 patients with benign cytology underwent thyroidectomy because of large tumor size (n = 12, 4.1 ± 1.3 cm by US), other malignant nodule (n = 4). 10 patients with non-diagnostic FNA results were included, because large tumor size or gradually tumor size increase (4.7 ± 1.3 cm by US), other malignant nodule (n = 3) The follicular neoplasms are usually diagnosed with cytology examination preoperatively, but many FN were incidentally diagnosed after thyroidectomy although benign cytology result. The large or growing thyroid nodules although benign cytology should be considered to the surgical diagnosis to rule of follicular neoplasm.
Thyroid Nodules & Goiter Thursday Poster Clinical
Surgical procedures for various thyroid and parathyroid diseases are common, and the incidence of thyroid malignancies increases with age, necessitating surgical intervention for older patients. We aim to evaluate the safety of thyroid and parathyroid surgeries in patients over 80 years of age. This is a retrospective review of all octogenarians who underwent thyroid or parathyroid surgery at a North American institute, over a five-year period by a single surgeon. Those patients were compared to a randomly selected control group of younger patients who underwent the same procedures. We collected demographics clinicodemographical data, procedure type, length of hospital stay, and perioperative complications. 22 octogenarian patients (mean age: 83.6 ± 2.98 years, females 63.6%) were compared to 233 younger patients (mean age: 53.1 ± 12.43 years, females 65.7%). The overall postoperative complication rates in the octogenarian group were significantly higher (OR 5.38, 95% CI 1.68–17.23, P = 0.005). Postoperative complications included transient hoarseness (OR 4.54, 95% CI 1.10–18.80, P = 0.037), and transient post-operative confusion (OR 31.13, 95% CI 1.23–786.86, P = 0.04). Hypocalcemia, wound infection, hematoma and seroma were not higher in octogenerians (P > 0.05 for all). There was a tendency to keep octogenarian patients over 24 hours postoperatively (OR 11.35, 95% CI 2.78–46.25, p = 0.04). Risk of complications was associated with increasing age by one year (OR 1.03, 95% CI 1.00–1.06, p = 0.036), and the odds of length of stay over 24 hours by 5% (OR 1.05, 95% CI 1.00–1.09, p = 0.038). Patients over 80 years of age undergoing thyroid and parathyroid surgery tend to have a higher risk of overall complications rates and a longer post-operative hospital stay compared to younger patients. Thorough counselling in octogenarian patients should be performed. However, further multi-institutional studies with are warranted.
Thyroid Nodules & Goiter Thursday Poster Clinical
Recent ATA and AACE guidelines have explicitly sought long-term outcome data regarding cytologically indeterminate nodules with Afirma GEC ‘benign’ results. A PubMed literature search for relevant original publications through May 22, 2016 was performed. Six published clinical utility studies reported a median follow-up time of 7 months or longer, including 3 studies with ≥13 months follow-up (median 13, 19, and 26 months). The three studies include 411 GEC ‘benign’ results and the longest reported follow-up time was 44 months. Among these studies with median follow-up >1 year (including 2 multicenter and 1 single center), 85% of GEC ‘benign’ patients avoided surgery on average. One study included histopathology results and reported 1 cancer among GEC ‘benign’ nodules (1.1%). Compared with cytopathology-benign nodules, there was no statistical difference in the proportion of nodules demonstrating growth (p = 0.80) or cancer detection (p = 0.16). Another multi-center study reported no statistical difference in the rate of follow-up ultrasound evaluation (p = 0.70) or thyroid surgery (p = 0.59) among GEC ‘benign’ vs cytopathology benign nodules. Among cytologically benign nodules, guidelines indicate that nodules requiring follow-up should typically be re-evaluated within 12–24 months. GEC ‘benign’ nodules appear to behave like cytologically benign nodules and are managed similarly during long-term follow-up. More than 400 patients with GEC ‘benign’ results are described in the literature, with durations of follow-up sufficient to sustain their clinical observation until re-evaluation according to recent guideline recommendations. Most GEC benign nodules remain unoperated, and a low prevalence of cancer is reported among them.
Thyroid Nodules & Goiter Thursday Poster Clinical
Radiofrequency ablation (RFA) is a promising, effective, and low-risk approach to management of benign thyroid nodules (TNs). This technique has been shown to reduce volume of TNs and improve compressive and cosmetic symptoms in Italy and South Korea. The aim of this study is to assess effectiveness, tolerability, and rate of complications of RFA in a series of patients with benign thyroid nodules in the U.S. Ten patients with benign TNs were retrospectively evaluated after RFA. The included patients declined surgical resection or were poor surgical candidates. TNs were proven benign by fine-needle aspiration biopsy. The nodules were either increasing in size or causing compressive symptoms and ≥3 cm in one diameter. TN volume, compressive and cosmetic symptoms and thyroid function were evaluated at baseline and following RFA. All TNs significantly decreased in size after RFA. The mean decrease in volume was from 23.15 mL to 11.3 mL with a mean decrease of 52% about 6 months after RFA. In 5 out of 10 patients, the TNs were growing from their reference size. In one patient with toxic adenoma, subclinical hyperthyroidism resolved by 4-month follow-up (TSH normalized from 0.03 to 2.7 mIU/L). Compressive symptoms resolved in 7 patients and improved in the other 3 patients. Cosmetic concerns improved in all 5 treated patients. One patient developed vasovagal hypotension during the procedure and required overnight observation. Three out of 10 patients developed mild neck discomfort, swelling, bruising and dysphagia. These symptoms completely resolved within 2–5 days. Overall the treatment was well tolerated by all patients. In the US population RFA of benign TNs performs as well as documented in centers from Europe and Asia. It is an effective and safe procedure that leads to reduction of TN volume with improvement in compressive symptoms and cosmetic concerns. RFA could be effective in management of toxic adenomas and it may be an alternative to conventional treatments for benign TNs. RFA carries a very low rate of adverse events and might be particularly effective for patients for whom surgery or radioactive iodine therapy are contraindicated or undesirable.
Thyroid Nodules & Goiter Thursday Poster Clinical
ThyroSeq v2 performance has not been independently validated for indeterminate thyroid nodules. In this study we aim to assess the performance of ThyroSeq v2 in our institution. We also estimated the impact of reclassifying the encapsulated non-invasive follicular variant of papillary thyroid carcinoma as “non-invasive follicular thyroid neoplasm with papillary-like nuclear features” (NIFTP) on its performance. We analyzed retrospectively our institutional experience with ThyroSeq v2 on Bethesda category III (B-III) or IV (B-IV) specimens until April 2016. Sensitivity (Sn), specificity (Sp), negative predictive value (NPV) and positive predictive value (PPV) with exact binomial 95% confidence intervals were calculated on 100 consecutively resected thyroid nodules (51 B-III and 49 B-IV) until April 2016. A mutation or rearrangement was identified in 29 nodules and suspected in 3 due to overexpression of ALK of MET; all 32 were considered test-positive. The other 68 nodules were test-negative. The overall Sn, Sp, PPV and NPV are 67% (45%–84%), 79% (68%–87%), 50% (32%–68%) and 88% (78%–95%), respectively. Performance would be relatively worse (p > 0.05) for the B-III than B-IV category with Sn 45% (17%–77%) vs. 85% (55%–98%); Sp 73% (56%–85%) vs. 86% (71%–95%); PPV 31% (11%–59%) vs. 69% (41%–89%); and NPV 83% (66%–93%) vs. 94% (80%–99%), respectively. Considering NIFTPs benign, the overall rate of malignancy would drop from 24% to 15% and the Sn, Sp, PPV and NPV would be 73% (45%–92%), 75% (65%–84%), 34% (19%–53%) and 94% (86%–98%), respectively. The prevalence of cancer would drop from 22% to 10% in B-III and from 27% to 20% in B-IV, if NIFTP are considered benign. The Sn, Sp, PPV and NPV in that scenario, would be 40% (5%–85%), 70% (54%–82%), 13% (2%–38%) and 91% (77%–98%) for B-III; and 90% (56%–100%), 82% (66%–92%), 56% (30%–80%) and 97% (84%–100%) for B-IV. Considering NIFTP benign would increase the NPV and decrease the PPV in both indeterminate categories. The performance of ThyroSeq v2 in our institution is worse than priory described among B-III specimens for which it may not be clinically useful.
Thyroid Nodules & Goiter Thursday Poster Case Report
Radioiodine treatment is the most common treatment in the United States for Graves' Disease. Several complications are recognized and widely reported in the literature. However, recurrent laryngeal nerve (RLN) palsy and subsequent vocal fold paralysis are very rare complications. To our knowledge, this is the sixth case of RLN reported in the literature after I-131 administration. The study design is a case report of a patient seen at a tertiary care center. Our patient was a 48-year-old male who presented to us with complaints of hoarseness and left vocal fold paralysis three weeks after 18 mCi I-131 treatment for hyperthyroidism. CT scan with contrast showed no masses or structural lesions, but video stroboscopy showed complete paralysis of the left vocal fold. The patient underwent injection laryngoplasty with Cymetra and experienced significant improvement in his voice as shown with acoustic parameters. Four months later there was complete recovery of the patient's vocal fold paralysis and full return of voice function. Our patient presented to us with complete paralysis of the left vocal fold after receiving no surgery and having no masses or neoplasms. His only intervention prior to presentation was I-131 administration. The fact that our patient eventually fully recovered from RLN palsy and subsequent vocal fold paralysis months after I-131 administration suggests an inflammatory etiology for the injury. Although I-131 acts via beta-particle radiation damage to the tissue with maximum spread of a few millimeters from the site of action, our case demostrates that very rarely RLN damage may occur from this intervention. Rarely mentioned in specialized thyroid texts, this complication is not recognized in many general otolaryngology and endocrinology texts. It is important for endocrinologists, otolaryngologists, and other practicioners to recognize RLN palsy as a rare but potentially dangerous side effect of radioiodine treatment.
Thyroid Nodules & Goiter Thursday Poster Case Report
Parathyroid carcinoma is very rare, nevertheless, the objective of this case is to make providers think of parathyroid carcinoma when patient presents with very high PTH and calcium levels, along with a palpable neck mass. A 49-year-old woman presented with polyuria, polydipsia and constipation for 3 weeks. The patient had history of Graves' disease and goiter, status-post total thyroidectomy 8 years ago. Currently taking Levothyroxine 150 mcg daily. On physical exam she looked dehydrated, had a neck surgical scar with a palpable 3 cm fixed, solid and non-tender right sided mass. Test results showed normal levels of free thyroxine 4 (free-T4) and thyrotropin (TSH), but markedly elevated calcium level of 17.2 mg/dl with intact parathyroid hormone (i-PTH) of 979 pg/ml. Parathyroid SPECT/CT revealed evidence of possible parathyroid adenoma in the region of the prior right thyroid lobe. CT neck with contrast confirmed presence of a 2.9 × 2.7 cm mass. Patient underwent surgical resection. The mass was ovoid, encapsulated and weighted 4.3 grams. Pathology was compatible with parathyroid adenoma. Parathyroid carcinoma should be suspected if intractable symptomatic hyperparathyroidism, serum calcium of 14 mg/dL or greater, and a palpable neck mass is present. The serum PTH level is also significantly elevated, commonly 3 to 10 times the upper limit of normal. The diagnosis is confirmed with histological examination. A palpable neck mass is evident in 40–70% of parathyroid cancer cases. This is in contrast to benign parathyroid tumors which are almost always non palpable. Our patient had total thyroidectomy which probably made her parathyroid adenoma palpable on physical exam. Sonographic features of parathyroid carcinoma is more likely to be heterogeneous, lobulated, and larger. In contrast, parathyroid adenomas are more likely to be homogenous, smooth, and smaller. Fine needle aspiration (FNA) prior to initial operation is not recommended due to possible tumor rupture and seeding. Parathyroid carcinoma should always be in the differential diagnosis when patient presents with very high PTH and calcium levels. A palpable neck mass should not be mistaken with a thyroid nodule and FNA must be avoided.
Thyroid Nodules & Goiter Thursday Poster Case Report
Unilateral Graves' Disease (GD) is rare. GD can co-exist in 4.5% of multinodular goiters (MNG). We report a patient with unilateral left-lobe GD in a MNG. A 66 year old woman initially presented at age 61 with positive anti-TPO and TSI, thyroid storm and cardiac decompensation in 2011. Thyroid scan showed an enlarged left lobe and suppressed right lobe; 24-hr uptake was 66.3%. Ultrasound (U/S) showed an enlarged heterogeneous hypervascular left lobe (7.9 × 4.5 × 3.8cm) and a normovascular right lobe (4.0 × 1.3 × 1.1cm). After acute treatment she was switched to methimazole (MMI), and was maintained on MMI with difficult control of thyroid levels. Infrequent follow-up led to several episodes of hypothyroidism and subclinical hyperthyroidism without adverse drug effects. Repeat U/S showed a large left lobe with two nodules (largest 1.6 × 1.8 × 1.7cm) with low internal vascularity and hyperemic surrounding gland. The smaller right lobe had low-to-normal blood flow and contiguous nodules. She declined FNA. Follow-up thyroid U/S and neck examinations were stable.
In August, 2015, she was euthyroid, but had positional stridor with neck flexion, dyspnea and dysphagia. On neck CT scan was an enlarged left thyroid lobe with rightward tracheal deviation and minimal tracheal narrowing. At total thyroidectomy operation the left lobe was impinging on the trachea and extending substernally. The 157-gram thyroid surface was bosselated. Cut sections showed nodules with focal hemorrhage and calcification. Histopathologic examination of the left lobe showed variously-sized follicles lined by cuboidal follicular cells. Rare follicles with scalloped colloid and pseudopapillae lined by tall follicular cells were present, findings consistent with treated GD.
Only 8 cases of unilateral GD, including ours, have been reported worldwide in the English literature. Our patient displayed the unique co-existence of a bilateral MNG with unilateral, left-lobe GD. Initial complications of thyroid storm with cardiac decompensation, and eventual stridor, dyspnea and, dysphagia were sequelae of unilateral GD in a MNG. This is the first report of the rare unilateral GD in a MNG, and the challenges of long-term management.
Friday, September 23, 2016
Thyroid Cancer Friday Basic
New therapeutic approaches are needed for patients with thyroid cancer refractory to radioiodine treatment. Bromodomain and extraterminal domain (BET) proteins interact with acetylated histones to facilitate gene transcription. JQ1 is a small molecule that competes with acetylated histones for binding to BET proteins, thereby inhibiting the BET-activated transcription of the Myc gene. Through suppressing of the Myc transcription program, JQ1 shows potent anti-tumor effects in hematological cancers and some solid tumors. We examined anti-cancer efficacy of JQ1 using the ThrbPV/PVKrasG12D mouse model that spontaneously develops anaplastic thyroid cancer and examined the signaling pathways critical for tumor cell proliferation. The ThrbPV/PVKrasG12D mouse expresses a mutated thyroid hormone receptor β (designated as TRβPV) and mutated KRAS(G12D). JQ1 markedly prolonged survival of ThrbPV/PVKrasG12D mice and inhibited thyroid tumor growth. Global differential gene expression analysis showed that JQ1 suppressed the Myc transcription program by inhibiting mRNA expression of the Myc gene. JQ1-suppressed Myc expression was accompanied by chromatin remodeling as evidenced by increased expression of histones and hexamethylene bis-acetamide inducible 1, a suppressor of RNA polymerase II transcription elongation. Molecular analyses showed that JQ1-induced reduction of MYC protein abundance in thyroid tumors was concurrent with decreased cyclin-CDK4-Rb-E2F3 signaling, critical for tumor growth. BDR4 is a BET protein that plays a central role in cellular growth control. We stably expressed TRβPV and KRAS(G12D) in rat thyroid follicular PCCL3 cells. Using ChIP analysis in PCCL3 cells stably expressing TRβPV and KRAS(G12D), we found that JQ1 inhibited the recruitment of BRD4 to the promoter complex of the Myc gene as the mechanism for JQ1-mediated suppression of the Myc mRNA expression. The reduced MYC protein level inhibited tumor cell proliferation. Our preclinical findings suggest that BET inhibitors could be an effective agent to reduce thyroid tumor burden for the treatment of refractory thyroid cancer.
Thyroid Cancer Friday Translational
TERT promoter mutations, which create the ETS binding site to upregulate TERT, strongly predict poor clinical outcomes of papillary thyroid cancer (PTC). A single nucleotide polymorphism (SNP), rs2853669, in the TERT promoter was reported to disrupt the ETS2 binding site to downregulate TERT. We tested whether this SNP affected the prognostic role of TERT promoter mutations in PTC. Genetic variants were examined by PCR and Sanger sequencing of genomic DNA from PTC in 608 patients (427 women and 181 men) aged 47 years (interquartile range-IQR 37–57) with a median follow-up time of 75 months (IQR 36 to 123). Their relationship with clinical outcomes was analyzed. Luciferase reporter assays were performed to determine the promoter activities of TERT promoter with various genetic variants. When analyzed irrespectively of the SNP status, TERT promoter and BRAF V600E mutations were each associated with PTC recurrence. TERT promoter mutations displayed a strong association with PTC recurrence in the absence [hazard ratio (HR) 2.12, 95% confidence interval (CI) 1.10–4.12] but not in the presence (HR 1.17, 95% CI 0.56–2.41) of the variant SNP after adjustment for all the conventional clinicopathological characteristics. As shown previously, coexisting TERT promoter and BRAF V600E mutations were synergistically associated with PTC recurrence than either mutation alone. In this group of patients, the variant SNP also showed a strong protective effect against tumor recurrence compared with the wild-type allele (HR 0.30, 95% CI 0.11–0.82). The variate SNP showed similar protective effects against TERT promoter mutation-associated PTC mortality. Luciferase reporter assays showed that TERT promoter mutations increased the promoter activities compared with the wild-type, which was significantly reduced by the coexisting variant SNP introduced in the TERT promoter. The variant allele of rs2853669 significantly reduces the impact of the TERT promoter mutation, whether alone or in coexistence with BRAF mutation, on the aggressiveness of PTC and represents a novel genetic factor that can help refine TERT promoter mutation-based risk stratification of PTC.
Thyroid Cancer Friday Translational
The liver mitochondrial glycerophosphate dehydrogenase (mGPDH) has been found to be a molecular target of metformin. There are no data on expression of mGPDH in thyroid cancer. The goal of this study was to analyze the expression of mGPDH in papillary and follicular thyroid cancer (PTC and FTC) and to examine the effect of metformin on thyroid cancer growth and expression of mGPDH in a metastatic mouse model.
We analyzed mGPDH expression in 48 human thyroid tissue samples (8 normal, 16 FTC and 24 PTC). For quantification of staining 200 cells in 3 different areas were examined and percentage of positive cells was scored: 0 – no staining; 1 − <25% of cells; 2 − 25–50% of cells; 3 – >50% of cells.
We used NOD. Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice which develop lung and liver metastases after tail vein injection of human FTC cells transfected with a linearized pGL4.51[luc2/CMV/Neo] vector. The mice were randomly assigned into 2 groups: placebo (P) treated with water via gavage (n = 21) and metformin (MF) - treated with 12.5 mg MF in 250 ul of water via gavage (n = 20).
We analyzed tumor growth by weekly imaging with Xenogen IVIS and expression of mGPDH in metastases by immunostaining. The intensity of mGPDH staining was significantly higher in patients with thyroid cancer compared with normal thyroid tissue (p < 0.001). There was no difference in mGPDH staining between PTC and FTC (p = 0.13).
After 4 weeks of treatment with metformin the tumor burden was significantly smaller in animals treated with metformin as bioluminescence increased 59.8+/- 56.7 times in MF group and 160.7+/-243.3 times in controls, p = 0.047. The cross-sectional analysis of lung and liver tissues revealed that MF group had lower rate of liver metastases (MF 36% vs. P 89%, p = 0.023). The intensity of mGPDH staining in metastases was significantly reduced in MF as compared to placebo group, (p = 0.0148). Treatment with metformin delays progression of thyroid cancer metastases in vivo and is associated with down-regulation of mGPDH in metastatic lesions. The molecular target of metformin, mGPDH, is overexpressed in thyroid cancer and may serve as a biomarker of response to metformin treatment in thyroid cancer.
Thyroid Cancer Friday Translational
Two key regulators of cellular growth, differentiation, and survival are members of the PI3K signaling pathway and histone deacetylases (HDAC). It has been previously shown that the PI3K-AKT pathway is constitutively activated in thyroid cancer. Also, a recent study demonstrated that the expression of some HDACs is higher in thyroid cancer as compared to benign tumors. Inhibition of both the PI3K-AKT pathway and HDACs has been shown to induce differentiation of thyroid cancer cells. Thus, the aim of this study was to evaluate the simultaneous targeting of these pathways in thyroid cancer cells. CUDC-907 is a first-in-class compound that functions as a dual inhibitor of HDACs and the PI3K-AKT pathway. We investigated the effect of this drug on differentiation markers of thyroid cancer cells using 6 cell lines, and its effect on growth and metastasis in vivo. CUDC-907 treatment in multiple thyroid cancer cell lines increased thyroglobulin, thyroid stimulating hormone receptor (TSHR), PAX8 and sodium iodide symporter (NIS) expression. We next tested the effect of CUDC-907 treatment on HDACs 1, 2, 4 and 6 expression. We found that HDAC2 levels were reduced in all six cell lines with CUDC-907 treatment. We then determined the HDAC2 expression level by immunohistochemistry using a thyroid tissue array. HDAC2 was significantly higher in thyroid cancer (papillary, follicular, anaplastic) as compared to benign tumor and normal thyroid tissue, and it was the highest in anaplastic thyroid cancer samples.
Lastly, we tested the growth inhibitory effect of CUDC-907 in an in-vivo metastatic mouse model of thyroid cancer. CUDC-907 treatment significantly reduced tumor growth and metastases. Our results show that CUDC-907 treatment leads to an upregulation of thyroid differentiation markers in thyroid cancer cells, and effectively inhibits growth and metastasis in vivo, by inhibiting PI3K signaling and HDAC2 expression. Thus, CUDC-907 may be an effective agent to evaluate in a clinical trial for advanced and metastatic thyroid cancer.
Thyroid & Development Friday Clinical
Congenital primary hypothyroidism (CPH) impairs infant growth and development. The American Academy of Pediatrics (AAP) recommends: 1. measuring TSH in all newborns so that infants with CPH, defined as serum TSH ≥20 mIU/L, are diagnosed by 14 days of life 2. initiating immediate treatment with the goal of serum TSH <5 mIU/L within one month of starting thyroxine replacement.
To assess whether the diagnosis and treatment of infants with CPH in Utah corresponded to AAP Guidelines, TSH measurements obtained between 2006 and 2015 in 4394 children <2 years of age were reviewed. TSH was measured using a third generation chemiluminescent immunoassay. Data analysis consisted of calculating percentages and ranges by TSH and age. The number of TSH measurements per infant varied between 1 and 18. An infant's first TSH measurement was designated the initial TSH and all subsequent measurements for an infant were termed subsequent TSH measurements.82 of the 4394 (1.9%) infants referred for TSH measurement had an initial TSH ≥20 mIU/L. 43 infants (1.0%) were found to have an initial TSH ≥20 mIU/L by day 14 of life. 39 infants had a delayed diagnosis of CPH, defined as an initial TSH ≥20 mIU/L in an infant older than 14 days. 42 infants were inadequately treated, identified as an initial TSH ≥20 mIU/L and the finding of one or more subsequent TSH values >5 mIU/L one month or more after the initial TSH. In 16 infants, ages 28–367 days, an initial TSH was <20 mIU/L and a subsequent TSH was ≥20 mIU/L. In these 16 infants, the age at which the first TSH ≥20 mIU/L occurred ranged between 92 and 690 days. 3 of these16 infants had a TSH ≥20 mIU/L on more than one determination. Delayed diagnosis of CPH occurred in 39 out of 82 (48%) infants referred for TSH immunoassay. Based upon TSH >5 one month or more after the initial TSH ≥20 mIU/L, 42 out of 82 (51%) of CPH infants were inadequately treated. These findings indicate that the management of CPH in Utah between 2006 and 2015 did not meet AAP Guidelines for Newborn Screening and Therapy of Congenital Hypothyroidism and may result in increased long-term disability due to the delayed diagnosis and inadequate treatment of CPH.
Thyroid Hormone Metabolism & Regulation Friday Clinical
TPOAb positivity during pregnancy is present in 5.6% to 22.1% of all women. Various cut-offs for TPOAb positivity are reported (range:15–143 IU/L). Cut-offs can be based on a fixed manufacturer cut-off or a population-based cut-off. In order to increase specificity, we investigated the threshold at which TPOAb levels begin to affect thyroid function and the thyroidal response to hCG. We used data from two Dutch prospective cohorts. hCG, TSH, FT4 and TPOAbs (manufacturer cut-off >60 IU/L) were measured once in 5435 pregnant women (<18 weeks) from Generation-R, and twice in 1663 pregnant women from HAPPY (<18 & at median 32 weeks; manufacturer cut-off TPOAbs >35 IU/L). We investigated the association of TPOAb with TSH, FT4 and the thyroidal hCG response using multivariable linear regression models adjusting for age, smoking, BMI, parity, ethnicity education and fetal sex. There was a positive association of TPOAbs with TSH and a negative association of TPOAbs with FT4 during early pregnancy, in both studies (both P < 0.001). TSH levels were already higher from TPOAbs of ∼10 IU/L onwards while FT4 levels were lower from ∼30 IU/L onwards in both studies. During late pregnancy, the association of TPOAbs with TSH was attenuated by ∼60% and TSH became higher from TPOAbs of ∼35 IU/L (P < 0.001). There was no association of TPOAbs with FT4 during late pregnancy.
In contrast to TPOAb negative women, there was no association of hCG with TSH or FT4 in TPOAb positive women in both studies (P-difference <0.001 & 0.036). The lack of association between hCG and TSH became apparent from TPOAbs of ∼10 IU/L while the lack of association of hCG with FT4 became lower from ∼30 IU/L in both studies.
As compared to early pregnancy, the association of hCG with TSH was attenuated by ∼60% in late pregnancy while hCG was not associated with FT4. TPOAbs affect maternal thyroid function during pregnancy already well below manufacturer or commonly used cut-offs in both early and late pregnancy. TPOAbs have a stronger effect on maternal thyroid function during early pregnancy than late pregnancy. This is most likely due to the fact that TPOAbs impair the thyroidal response to hCG, which also already occurs from levels below commonly used cut-offs.
Thyroid & Development Friday Clinical
Maternal hypothyroidism and/or hypothyroxinemia have been associated with a child's poor neuropsychological development. Previous research on whether maternal gestational thyroid dysfunction affects childhood sensory and linguistic development, is however lackingThe Northern Finland Birth Cohort 1986 included all births within a year (9362 women, 9479 children) from the two northernmost provinces of Finland. Maternal serum samples (n = 5791) were obtained in early pregnancy (mean ± SD 10.7 ± 2.8 weeks' gestation) and they were analyzed for TSH, free T4 and thyroid peroxidase antibodies (TPO-Abs). Parents evaluated child's sensory and linguistic development at age of 7 via a questionnaire, and the data was supplemented with medical chart review. The prevalence of child's sensory and linguistic impairments were compared between mothers with and without gestational thyroid dysfunction. Children with an intelligence quotient ≤85 were excluded from analysis. Of 5391 mothers, 1024 (19.0%) children had some sensory or linguistic impairment. There were no statistically significant differences in prevalence of child's outcomes between mothers with and without thyroid dysfunction. However, children of hypothyroid and hypothyroxinemic mothers had a trend of an increased prevalence of any vision impairment (10.8% and 11.7%, respectively) compared to those of euthyroid mothers (6.5%). All results remained same after excluding mothers with positive TPO-Ab concentrations and prematurely born children. Our novel results did not associate maternal thyroid dysfunction during pregnancy with parental reported sensory and linguistic development impairment. A trend of a higher prevalence of vision impairment was seen in children of hypothyroid and hypothyroxinemic mothers, and this finding merits further research.
Thyroid & Development Friday Clinical
The effects of maternal subclinical hypothyroidism on pregnancy outcomes are not clear. We performed a retrospective cohort study to assess potential associations between maternal thyrotropin (TSH) levels in pregnancy and adverse obstetric and perinatal outcomes. Data for women aged ≥18 yrs with a singleton gestation who were seen for prenatal care at Boston Medical Center from 1/1/2003–5/22/2014 and their infants were obtained from electronic medical records. Women with thyroid disease or thyroid medication or lithium use were excluded. Maternal demographics, pertinent medical and obstetric history, and serum TSH levels from the first prenatal visit were used to predict adverse obstetric and perinatal outcomes. Trimester-specific ranges were used to define normal TSH values: 0.1–2.5 mIU/L in the 1st trimester, 0.2–3 mIU/L in the 2nd trimester, and 0.3–3 mIU/L in the 3rd trimester. Birth weight ≤2500 g was considered to be low. Prematurity was defined as gestational age (GA) at birth <37 weeks. A total of 5,823 pregnant women with TSH values during pregnancy (mean age 29.3 ± 6.0 yr, 16% white, 60% black, 13% Hispanic) and their 5,823 fetuses and infants (mean GA at birth 38.6 ± 3.2 wks, 52% male, mean birth weight 3.2 ± 0.7 kg) were included in the analyses. Among the pregnant women, 3,718 (64%) had TSH measured in the 1st trimester. 377 (6.5%) of all pregnant women had elevated trimester-specific TSH values (median(range) 3.33(2.51–22.38) mIU/L). Obstetric complications occurred in 3,192 (55%) women and perinatal complications occurred in 3,729 (64%) newborns. Elevated serum TSH levels in any trimester of pregnancy were associated with increased risk of prematurity compared to normal serum TSH values (β-estimate 0.38, p-value 0.048, odds ratio 1.5). Elevated serum TSH concentration did not predict preterm labor, fetal loss, placental abruption, pre-eclampsia/eclampsia, gestational hypertension, gestational diabetes, cesarean section, neonatal death, neonatal respiratory distress syndrome, congenital malformation, neonatal admission to intensive care unit, or low birth weight. Serum TSH concentration above the trimester-specific ranges in pregnancy were associated with increased risk of prematurity in offspring.
Autoimmunity Friday Poster Basic
A recent randomized clinical trial has provided evidence for a beneficial effect of the anti-oxidant agent selenium in mild Graves orbitopathy (GO). The aim of the present study was to determine the cellular mechanisms by which selenium acts in GO, by investigating its effects in cultured orbital fibroblasts. We established primary cultures of orbital fibroblasts from 6 GO patients and 6 subjects without GO. Cells were treated with H2O2 to induce oxidative stress, after pre-incubation with selenium or, as a control, with methilcysteine (MCys). The following tests were performed: measurement of oxidative stress [glutathione disulfide (GSSG) in cell media], cell proliferation, hyaluronic acid (HA) and pro-inflammatory cytokines (TNFa, IL1b and IFNg) in cell media. H2O2 induced oxidative stress (increase in GSSG release) and fibroblast proliferation, which were significantly reduced by selenium, but not by MCys. H2O2 did not affect HA release, which was however significantly reduced by selenium, but not by MCys. H2O2 determined an increase in the release of TNFa, IL1b and IFNg, an effect that was significantly reduced by selenium limited to TNFa and IFNg. Whereas the effects of selenium were similar in GO and control fibroblasts concerning oxidative stress and cytokine release, they were exclusive to GO fibroblasts concerning proliferation and HA release. Selenium protects orbital fibroblasts from oxidative stress which provides a cellular basis for its effects in patients with GO.
Autoimmunity Friday Poster Clinical
The sonographic thyroid volume (TV) is associated with age, body surface area (BSA), TSH (thyroid stimulating hormone) and free thyroxine (FT4) in euthyroid children although remains unknown in children with autoimmune thyroiditis (AIT). Similarly, there is no data if hypothyroid children have diastolic hypertension (DHTN) as reported in adults.
2. To assess if DHTN is associated with hypothyroid pediatric patients.
Out of 73 hypothyroid patients, 8 patients had elevated BP, none of them had DHTN. Only one patient had elevated diastolic BP in the pre-HTN range (90–94 percentile for age, gender and height) at diagnosis. TV in children and adolescents with AIT correlated with age, weight, height, BSA, and FT4. The incidence of DHTN does not seem to be increased in pediatric hypothyroid patients.
Autoimmunity Friday Poster Clinical
Measurement of anti-thyroperoxidase autoantibodies (TPOAb) and anti-thyroglobulin autoantibodies (TgAb) has been commonly performed to detect Hashimoto's thyroiditis. However, the relationship between thyroid autoimmunity and histological findings is still unclear. To clarify the relationship between these antibody titers and histological thyroiditis, thyroid histology was analyzed retrospectively. Eighty-five patients with a pathological diagnosis of papillary thyroid cancer (PTC) or Hashimoto's thyroiditis were randomly selected. The thyroid tissue was studied using the opposite lobe which didn't have cancer. We excluded patients with Graves' disease and multiple cancers. Serum levels of TPOAb and TgAb were measured by electrochemiluminescence immunoassay. Patients were divided into four groups: (I) TPOAb and TgAb positive (n = 25), (II) TPOAb positive only (n = 14), (III) TgAb positive only (n = 23), (IV) both antibodies negative (n = 23). Histological findings were graded as follows: (a) lymphocytic infiltration, (b) lymphoid follicles, (c) eosinophilic change, (d) fibrosis. We divided the severity of histological findings of Hashimoto's thyroiditis into four groups, Group A: no findings, Group B: (a) alone, Group C: (a)+(b) or (a)+(c), Group D: (a)+(b)+(c)+(d). All cases in the group I (TPOAb and TgAb positive) showed moderate to severe histological inflammatory changes (Group C and D). Of these, 40% had fibrosis. In the group II (only TPOAb positive), 86% was Group C and D. Of those, one case had no inflammatory changes and another case had only lymphocytic infiltration. In the group III (only TgAb positive), 82% was Group C and D, 13% had no inflammatory changes at all and 4% had only lymphocytic infiltration. In those with TPOAb and TgAb negativity, 96% had no inflammatory changes or only lymphocytic infiltration. TgAb and TPOAb are equally useful indicators of histological inflammation in Hashimoto's thyroiditis.
Autoimmunity Friday Poster Clinical
TSH receptor (TSHR) antibodies (Ab) can be measured with binding or bio-assays. Sensitivity and specificity of five binding and two bio-assays were compared. TSHR blocking (TBAb) -and stimulating (TSAb) Ab were measured with reporter bioassays. Blocking activity was defined as percent inhibition of luciferase expression relative to induction with bovine TSH alone (cut-off >40% inhibition). TSAb was reported as percentage of specimen-to-reference ratio (SRR% >140%). TSHR-binding inhibitory immunoglobulins (TBII) were measured with two ELISA (Kronus and Dynex), as well as with three automated assays (Kryptor, Cobas, and Immulite). A total of 80 patients (median age 42 years, range 23–73 years, 64 (80%) female) with autoimmune thyroid diseases, involving 60 patients with Graves' disease (GD), 20 patients with Hashimoto's thyroiditis (HT) and 20 euthyroid healthy controls (C) were included. C tested negative in all assays (specificity 100%) while all 60 hyperthyroid patients with GD were positive in the TSAb bioassay (sensitivity 100%). Among the GD patients, 20 showed low TSAb positivity (SRR% 140–279), but were TBII-positive in only 20 (100%), 7 (35%), 9 (45%), 11 (55%), and 18 (90%) using the Kronus, Dynex, Kryptor, Cobas and Immulite, respectively. In 20 moderate TSAb-positive (SRR% 280–420) patients, TBII tested positive in 20 (100%), 14 (70%), 13 (65%), 16 (80%), and 19 (95%), respectively. The high (SRR% >420) TSAb positive patients were TBII positive in all testings. All 20 hypothyroid HT patients tested TBAb positive (sensitivity 100%) in the bioassay while they tested TBII-positive in 20 (100%), 18 (90%), 20, 20, and 18, respectively. Results obtained with two luminometers correlated for TSAb-positive (r = 0.99, p < 0.001), TBAb-positive (r = 0.88, p < 0.001), and C (r = 0.86, p < 0.001). None of the binding assays differentiated between TSAb and TBAb. Bioassays for TSHR Ab are more sensitive than the automated binding assays and exclusively differentiate between stimulatory and blocking antibody activity.
Autoimmunity Friday Poster Clinical
The clinical utility and relevance of TSH receptor (TSHR) blocking antibodies (TBAb) in patients with autoimmune thyroid disease (AITD) remains a matter of debate. The prevalence of TBAb in a large AITD collective, the corresponding thyroid functions and retest repeatability were investigated. Serum TBAb and stimulatory Ab (TSAb) were measured with reporter bioassays. Blocking activity was defined as percentage inhibition of luciferase expression relative to induction with bovine TSH alone (cut-off >40% inhibition). TSAb activity was reported as percentage of specimen-to-reference ratio (SRR% >140%). All samples were measured for TSHR binding inhibiting immunoglobulins (TBII). A total of 1135 unselected and consecutively followed patients with AITD (mean age 39 ± 18 years, 920 (81%) female) as well as 302 euthyroid healthy controls (28 ± 8 years, 155 female) were investigated. All controls were negative for TBAb (bioassay specificity 100%). In contrast, the prevalence of TBAb positive patients with Hashimoto's thyroiditis and Graves' disease was 67/767 (9%) and 15/368 (4.1%), respectively. Thyroid function significantly correlated within TBAb inhibition: the higher, the more hypothyroid. Thirty-nine (48%), 33 (40%), and 10 (12%) of 82 were hypothyroid, euthyroid, and hyperthyroid, respectively. Of 40 patients with TBAb >60% inhibition, 32 (80%) were TBII positive. TBAb positivity highly correlated with both thyroperoxidase (94%) and thyroglobulin (93%) autoantibodies. Ten patients were detected both TBAb and TSAb positive while Graves' orbitopathy was present in two. In repeating measurements (3–5 times), all samples with a percentage inhibition of TBAb above 50% were accurate and reproducible, whereas samples shortly above the cut-off (40–50% inhibition) tended to fluctuate in approximately 20%. Serum TBAb levels were measured with best accuracy in this TBAb bioassay, proving more sensitive than the binding assay. TBAb determination is clinically useful with emphasis in diagnosis and management of patients with Hashimoto's thyroiditis.
Autoimmunity Friday Poster Clinical
There are two methods for the measurement of TSH receptor (TSHR) autoantibodies (Ab); a competitive binding inhibition assay for TSH or monoclonal Ab against TSHR (TBI) and a bioassay for thyroid stimulating Ab (TSAb). Both are useful to diagnose Graves' disease (GD) and to decide the termination of anti-thyroid drugs (ATD). TBI is commonly used, but since it is a binding assay, it detects non-stimulating Abs in addition to stimulating Ab. TSAb was measured in GD patients during the course of illness when the titer of TBI was considered not reflecting the clinical GD conditions. TBI and TSAb were assayed using commercial kits (TRAb: Roche Diagnostic, Germany, TSAb: Yamasa, Japan). When necessary, TSH blocking Ab was assayed using the same TSAb Kit (TSBAb). We experienced several interesting patients in whom a stimulating Ab switched to a blocking Ab or vice versa during the course. These include a 56 year-old female patient with GD who became severe hypothyroidism spontaneously by appearing a blocking Ab, a 43 year-old female patient who was very severe hypothyroidism with Hashimoto thyroiditis + blocking Ab and then became GD two years later, or a 44 year-old female patient who was initially GD, but three months later became hypothyroidism due to a blocking Ab and became again GD two years later from then with disappearing a blocking Ab and appearing a stimulating Ab. Besides these patients, we found several GD patients in whom a stimulating Ab disappeared, but a neutral Ab, that is, non-stimulating and non-blocking Ab, remained. All of them had been treated with ATD and had remained euthyroidism for a long time but ATD could not be stopped because of high titer of TBI. We measured TSAb and TSBAb, both of which were negative in each patient. ATD was stopped and the patients have kept euthyroidism. TBI assay detects stimulating Ab, blocking Ab, and also neutral Ab that does not enhance nor inhibit the thyroid function. The stimulatory potency of the neutral Ab is considered similar to that of TSH. Although ATD is generally unable to stop when the titer of TBI is high, it may be necessary to see whether TBI is expressing the real stimulating Ab by measuring TSAb together.
Autoimmunity Friday Poster Case Report
Neonatal Graves disease is a rare, life threatening condition, occurring in 1–5% of neonates born to mothers with Graves disease. Maternal derived, transplacental TSH receptor stimulating antibodies are considered the cause of the neonatal hyperthyroidism. Several treatments have been used, however no evidence based guidelines for evaluation or treatment exist. We describe two cases of Neonatal Graves. CS was born to a G2P2 mother with poorly controlled Graves disease (TSI >500%) prior to delivery, requiring hospitalization and methimazole therapy. CS was born at 24.6 weeks, BW of 485 grams. Labs at birth and 1 week of age showed low TSH and low FT4. On DOL 19 CS developed tachycardia, apnea, hyperthermia and respiratory distress. Labs showed: low TSH (<0.02 uIU/ML), elevated FT4 (5.3 NG/DL). Methimazole and atenolol were started, CS received 6 days of treatment. After discontinuation, CS developed rebound hyperthyroidism requiring 19 days additional treatment. TSH and FT4 normalized by DOL 84.
EC was born to a G2P1 mother with prior history of Graves disease with post-ablative hypothyroidism on levothyroxine. Fetal tachycardia developed in the third trimester concerning for fetal hyperthyroidism, Mom was started on methimazole and back on levothyroxine. EC was born at 38.3 weeks, BW of 3.209 kg. Labs were not drawn after birth, EC was discharged home on DOL 3. EC presented to the ER on DOL 12 with tachycardia, respiratory failure and hypotension, labs showed: low TSH (<0.02 uIU/ML), elevated FT4 (6.3 NG/DL), TSI (408%). Methimazole and propranolol were started, EC received 66 days of treatment. On day 27 levothyroxine was added for FT4 of 0.8 NG/DL. Neonatal hyperthyroidism often manifests in the first 10 days of life, disease resolution depends on clearance of maternal antibodies from neonatal circulation. Thyroid function tests on day of life 3–5, 7 and 14 can detect hyperthyroidism. TSI level should be obtained at birth. Methimazole, in combination with beta blockers and levothyroxine, are relatively safe and effective treatments for neonatal hyperthyroidism. Serial labs can detect iatrogenic hypothyroidism. Most patients improve rapidly; however long term complications of thyrotoxicosis can occur.
Autoimmunity Friday Poster Case Report
Pretibial myxedema (PTM) is an uncommon extra-thyroidal manifestation of Graves' disease (GD). Elephantiasic PTM is the most severe form and occurs in less than 1% of cases. Management of severe PTM remains challenging. We present a case of progressive PTM resistant to treatment. Eventually Rituximab (RTX) was used with some apparent subsequent improvement. 50 year-old male with a history of GD and mild Graves' orbitopathy (GO) with mild PTM in 2007 and treated with radioiodine X 3. He became hypothyroid and maintained on levothyroxine. His TSH receptor antibody (TRAb) level remained elevated at >250 U/L. During the subsequent years he developed worsening non-pitting plaques with orange peel-like appearance on both lower legs and dorsum of his feet to a grossly disfiguring degree (see Williams Textbook of Endocrinology, 13th edition 2016 page 382, Figure 12-7B). The surface of the foot lesions appeared nodular and elephantiasic. His GO stabilized and did not require treatment. A skin biopsy showed increased mucin deposition in the dermis and his skin lesions worsened despite topical betamethasone, triamcinolone injections, hyaluronidase and even a trial of octreotide. In May of 2015 he had a therapeutic trial of 500 mg RTX IV X 2 at 6 weeks apart and this resulted in modest improvement in swelling and a decrease in shoe size. TRAb level fell to 25 U/L in December 2015. PTM results from accumulation of glycosaminoglycans in the dermis secreted by fibroblasts. The main pathogenic mechanism is proposed to be due to fibroblast stimulation by TRAb as occurs in GO given that both have histologic similarities. Additionally, the so called neutral variety of TRAb (directed at the cleavage region of the TSH receptor) may play a role in the development of extrathyroidal manifestation. Cleavage region TRAb neither stimulate nor block TSH binding but can induce target cell apoptosis. The evidence to support this hypothesis is the higher apoptotic rate observed in the orbital fibroadipose tissue of GO patients and probably in PTM. The pathogenesis of PTM is complex and requires further study. There is no consensus on management. However, RTX should be considered in refractory cases.
Disorders of Thyroid Function Friday Poster Translational
Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder affecting one in 3000 to 4000 newborn babies, and can result in severe neurodevelopmental impairment if treatment is delayed. Since the introduction of newborn screening program in 1988, about 1,000,000 newborn babies have been screened and more than 300 cases identified in Saudi Arabia. Molecular characterization of genetic defects in these cases has not been systemically studied. The present study investigates the mutational spectrum of genes involved in CH among 50 patients. Genomic DNA from 50 CH patients was extracted from peripheral leukocytes and was sequenced by whole exome sequencing. The candidate mutations were verified by Sanger sequencing. Mutations were identified in 46% of patient (23/50) in the following genes: TG, TPO, IYD, DUOX2, SLC26A4, NKX2-1, and TSHR. TG mutations were found in 12 of 23 (52%) mutations identified. Many of them are novel: c.7294C>T, p.Q2432X, c.2176 + 1G>A, and c.4426T>C, p.C1476R, and occurred more than once. Novel TPO mutations were found in two patients: c.1187_1188insGCCG, and c.1237delG:p.E413fs. Novel TSHR mutations were found in 3 patients: two having c.C820T, p.R274W, and one carrying c.1556G>A, p.R519H. Novel DUOX2 mutation (c.G2649C, p.M883I) was found in one patient. One patient was found to have two novel NKX2-1 mutations: c.793_794ins GGCGGCGGG, and c.760-886del127. Mutation spectrum in Saudi CH patients is quite unique and narrow, reflecting the consanguineous nature of the population. The data would provide valuable information for genetic counseling. It is still challenging to find genetic defects in the remaining 50% patients.
The project is supported by KACST grant# P-L-10-0051
Disorders of Thyroid Function Friday Poster Clinical
Overt hypothyroidism (oh) might worsen prognosis in critically-ill elderly patients. However, difficult interpretation of thyroid function tests (TFT) due to non-thyroidal illness (NTI) has led to discouragement of screening for thyroid dysfunction during hospitalization, thus hampering the detection of a hypothyroid condition. Our aim was to detect hypothyroidism in critically-ill elderly patients and evaluate its influence on prognosis. We consecutively included all patients >60 y admitted to the hospital ward (n = 451). TFT were done on day 1 and 8. Thyroid dysfunction was categorized as oh (TT4 < 4.5μg/dl, T3 < 0.8 ng/dl, TSH >5mU/l) and subclinical hypothyroidism (sch) (TT4:4.5–13μg/dl, T3:0.8–1.9 ng/dl, TSH >5mU/l), overt hyperthyroidism (OH) (TT4 > 13μg/dl, T3 > 1.9 ng/dl, TSH <0.3mU/l) and subclinical hyperthyroidism (SCH) (TT4:4.5–13μg/dl, T3:0.8–1.9 ng/dl, TSH <0.3mU/l), euthyroidism (eu) (TT4:4.5–13μg/dl, T3:0.8–1.9 ng/dl, TSH:0.3–5.0mU/l) and NTI(T3 < 0.8 ng/dl, TT4 and TSH within normal range or any combination of hormones outside the previous categories). Adult Comorbidity Evaluation (ACE-27), and intra-hospital mortality were recorded. The association between mortality and TFT categorization were studied by Cox-Regression. According to TFT results, out of 451 patients (77.0 ± 7.9years, 54%females) 76% were categorized as NTI, 4% oh, 10% sch, 1% SCH and 9% eu. Patients classified as oh were older and presented higher ICU requirement and mortality (all p < 0.05). In multivariate analyses, oh patients showed significantly higher mortality rates than NTI in a model adjusted by ACE-27, sex and age (HR 3.6(1.3–9.6), p < 0.01). At day 8, 194 patients remained at the hospital and had their TFT reevaluated. From the initial 20 patients with oh at day 1, two died, 8 were discharged and 10 remained hospitalized by day 8. Eight patients out of the 10 remained in the oh category. At least 5% of this elderly population presented oh at day 1 and 80% remained with oh by day 8. Overt hypothyroidism during hospitalization was associated with elevated mortality. Further studies would reveal if hypothyroidism should be diagnosed/treated or if this particular combination of altered TFT are merely a bystander in critically ill patients with worse prognosis.
Disorders of Thyroid Function Friday Poster Clinical
There is currently no report on the usage of short-course prednisone as a treatment for moderate to severe SAT. Our study evaluated the effectiveness and safety of this treatment. Fifty cases of moderate to severe SAT were enrolled. Patients in the experimental group received 30 mg prednisone daily for one week. The control group was treated with 30 mg prednisone, then, the dose was reduced by 5mg/week prednisone from the second week until the sixth week. All patients were followed up for six months after their treatment was discontinued. The primary endpoint was the differences in efficacy and recurrence rate at the end of treatment between the two groups. Secondary endpoints included differences in thyroid and adrenal function, blood glucose concentrations, blood pressure, bone metabolism, and lipid levels between two groups. No significant differences were observed in age, gender, SAT severity score, erythrocyte sedimentation rate, iodine absorption rate at 3 h and 24 h, systolic and diastolic blood pressures, parathyroid hormone, levels of C-reactive protein, FT3, FT4, TSH, glycated albumin, triglycerides, total cholesterol, cortisol, peripheral blood glucose between the two groups at baseline (P > 0.05 for all). Primary endpoint: The efficacy in the two groups was 69.2% and 75%, respectively, and no significant difference was found. The recurrence rates were 30.8% and 25%, respectively, with no significant difference between them (P > 0.05). Secondary endpoints: Systolic blood pressure (P < 0.05) and parathyroid hormone levels (P < 0.05) were significantly different between the two groups at the end of treatment. No differences were observed in glycated albumin, peripheral blood glucose, triglycerides, total cholesterol, cortisol, and diastolic blood pressure (P > 0.05 for all). This study is the first to evaluate the efficacy and safety of one-week treatment with prednisone and the standard six-week therapy for moderate and severe SAT, and it is by far the study with the shortest prednisone treatment for SAT. Our study demonstrated that the short-course prednisone treatment was as effective as the standard treatment for SAT, and had similar recurrence rates. Furthermore, the short-course treatment had fewer side effects with respect to bone and blood pressure.
Disorders of Thyroid Function Friday Poster Clinical
Hypothyroidism is found in about 2% of the population with a mean age of diagnosis in the 50s, and the disease is 10-fold more common in women than in men. The most common reason for Hypothyroidism is Hashimoto's Thyroiditis (HT), which typically responds well to life-long replacement with oral Levothyroxine. A 35 y/o female patient mother of 3 with HT for 21 years is presented, with very abnormal thyroid hormome levels. Her current meds are Levothyroxine 500mcg QD and Cytomel 50 mcg TID. She has all the classical symptoms of clinical Hypothyroidism. She is s/p Cholecystectomy for stones, has Migrains, has nausea and diagnosed with reflux. She also takes Omeprazole and Ondasterone. Physical Exam is consistant with HT. Lab:TSH 396 uIU/mL, Free T3 0.89 (N 2.18–3.98 pg/mL), Free T4 0.26 (N 0.76–1.46 ng/dL), Thyroid Peroxidase Ab >600 IU/mL (N 0–34) Thyroglobulin Ab 1422.9 (N 0.0–0.9 IU/mL), Antigliadin Abs, IgG 2 (Negative 0–19), Antigliadin Abs, IgA 22 (Weak Positive 20–30). Patient referred for swallowing study that was normal, and then instructed to take 300 mcg Levothyroxine daily intravaginally. Patient repeated lab 4 weeks later and recent Free T4 was 0.73, and TSH 199.00. Patient stated that she is not feeling any different, and therefore told to increase the Levothyroxine dose to her original 500 mcg daily. The intravaginal route for administring oral medications is used often in patients receiving Bromocriptine for hyperprolactinemia, when that medication causes severe nausea. In difficult to control cases with HT, or in patients with any GI condition impeding normal absorption of Levothyroxine, the intravaginal route of administration should be entertained. More data from this patient will be generated, and based on her initial response, we are certain that she will attain Euthyroid State.
Disorders of Thyroid Function Friday Poster Clinical
The effects of levothyroxine dose adjustments on patient satisfaction with drug therapy and physician care have not been described previously.
The primary objective of our study was to measure those effects among 2 groups of subjects:
Similar to prior studies, subjects had a high prevalence of concomitant GI conditions that can adversely affect levothyroxine performance: GERD (34%); lactose intolerance (11%); IBS (8%); GI surgery (6%); and H. pylori infection (2%). Results showed a strong correlation between the frequency of levothyroxine dose changes and reduced patient satisfaction with treatment, treatment convenience, symptom control and physician performance.
Disorders of Thyroid Function Friday Poster Clinical
Hemithyroidectomy theoretically preserves thyroid function. However, some patients who underwent hemithyroidectomy have hypothyroidism and require thyroid hormone replacement. We evaluated the incidence and predictive factors of postoperative hypothyroidism after hemithyroidectomy. We identified 324 patients who were preoperatively euthyroid and underwent hemithyroidectomy from January 2008 to December 2011 for papillary thyroid microcarcinoma, retrospectively. Age, sex, preoperative TSH, surgicla site, the presence of thyroid auto-antibodies and lymphocytic infiltration in histology were analyzed for the association with of thepostoperative hypothyroidism. The incidence of postoperative hypothyroidism was 56% (192/342). Of them, 185 (96%) patients presented subclinical hypothyroidism and 7 (0.04%) patients presented overt hypothyroidism. Patients requiring levothyroxine supplementation were 44 patients (13%) including all overt hypothyroid patients and 37 subclinical hypothyroid patients. Most of postoperative hypothyroidisms were developed within 12 months from operation (149/192, 77.6%). Preoperative TSH levels >1.7 and age >55 showed significant correlation with the postoperative hypothyroidism (Odds ratio (OR) = 1.24, 95% confidence interval (CI) 1.18–1.29, p < 0.001 and OR = 1.01, 95% CI 1.00–1.01, p = 0.390, respectively). They were also correlated with the development of hypothyroidism within 12 months from operation (OR = 3.27, 95% CI 2.46–4.66, p < 0.001 and OR 2.32, 95% CI 1.53–3.43, p < 0.001, respectively). However, only preoperative TSH showed significant association with development hypothyroidism after 12 months from operation. (OR = 2.32, 95% CI 1.53–3.43, p < 0.001). When we categorized patients into 4 groups according to the preoperative TSH value and the age, 80.4% of patients in the high risk group (preoperative TSH >1.7 and age >55), and 28.8% patients in low risk group (preoperative TSH <1.7 and age <55) developed postoperative hypothyroidism. Preoperative TSH level and age were significant predictors of the development of hypothyrodisim after hemithyroidectomy. Close monitoring and follow-up of thyroid function is needed for patients with high preoperative TSH or old age.
Disorders of Thyroid Function Friday Poster Clinical
Subacute thyroiditis is an uncommon cause for thyrotoxicosis that classically presents with anterior throat pain, elevated ESR, and decreased uptake on I-123 scan. Most patients have restoration of euthyroidism with supportive measures for pain. We present here a case of subacute thyroiditis with an atypical clinical course. A 39 year old female presented with acute onset fatigue, fever, and right-sided neck pain. She was initially diagnosed with a viral URI and managed with supportive care. However, she developed progressive thyrotoxic symptoms and odynophagia. Her thyroid was enlarged and tender, and evaluation showed TSH <0.01 mIU/mL, fT4 2.7 ng/dL (NL 0.93–1.7 ng/dL), and an ESR of 128 mm/hr. She was diagnosed with subacute thyroiditis and had initial improvement with prednisone 40 mg daily.
2 weeks later the patient's thyrotoxic symptoms recurred and were worse than at initial presentation. At this time, her thyroid was no longer tender on exam. Further evaluation demonstrated an elevated TRAb, and I-123 scan revealed diffusely increased uptake, consistent with Graves'. She was started on methimazole. While this patient's initial presentation was most consistent with subacute thyroiditis, with clinical improvement after prednisone, she subsequently developed worsened thyrotoxicosis with findings diagnostic of Graves'. In 1967, Volpe et al observed a relationship between subacute thyroiditis and thyroid autoimmunity. Several potential mechanisms by which thyroid infection may lead to autoimmunity have been proposed, including molecular mimicry (i.e virus or bacterium epitopes resembling self-antigens), the induction of HLA-DR expression on thyroid cells (enabling the presentation of thyroid self-antigens to APCs), or superantigens (robust T cell activation and induction of auto-reactive T cells) (cite Davies). Several cases of Graves' disease occurring after subacute thyroiditis have been described (cite Bartalena), but Graves' had occurred 2 mo-8 years after subacute thyroiditis, later than our patient's course. While the development of two distinct etiologies for thyrotoxicosis is uncommon, this unusual occurrence may be explained by the induction of thyroid autoimmunity due to thyroid inflammation.
Disorders of Thyroid Function Friday Poster Case Report
A 44-year-old woman presented to the ER complaining of abdominal pain, nausea, vomiting, diarrhea, shortness of breath, palpitations and pedal edema for the past one month. On exam positive findings included anxiety, tachycardia (HR 140s), hypertension (BP 162/97) and mild proptosis. She was diagnosed with hyperthyroidism one year prior but was not on any treatment. Initial labs revealed a suppressed TSH 0.041 (RR 0.270 - 4.200) with FT4 4.18 (RR 0.93 - 1.70), T3 237.3 (RR 80.0 - 200.0) and abnormal liver function tests: AST 49 (RR 15 - 46), ALT 17 (RR 9 - 52), bilirubin 2.1mg/dl (RR 0.2 - 1.3), and alkaline phosphatase 135 (RR 38 - 126). The patient's Burch-Wartofsky score was borderline for thyroid storm (25). The thyroid U/S showed normal thyroid gland without nodules. She was diagnosed with Graves' disease and treatment was initiated with propranolol 40 mg TID, methimazole 40 mg BID and cholestyramine 4g QID. On day 3 of hospitalization the patient was found to have worsening transaminases (AST 718; ALT 219) so methimazole was discontinued and dexamethasone 2 mg BID and L-carnitine 1g TID were prescribed. Nevertheless patient's clinical status deteriorated and it became more consistent with thyroid storm. While the etiology of the patient's hepatic dysfunction was most likely multifactorial, neither methimazole nor PTU could be used at that point due to the potential risk of deteriorating patient's hepatic failure. The decision was made to start SSKI and perform plasmapheresis. She underwent 2 sessions of plasmapheresis with dramatic improvement in her LFTs (after 1st round AST 1034 –>114, after 2nd round down to 24, ALT 585–>210, after 2nd round –>77) and thyroid hormone levels (FT4 0.93–>2.73–>1.51 and T3 237–>70. Patient also had improvement in her mental status with resolution of her diarrhea and tachycardia. She was discharged home on methimazole 20 mg daily and outpatient follow-up. Thyroid storm is a rare and life-threatening state due to thyroid hormone excess. This case illustrates the perfect situation wherein the treatment option of plasmapheresis should be considered as an alternative measure when a patient cannot tolerate conventional medical treatment.
Disorders of Thyroid Function Friday Poster Case Report
About 2–17% of Myasthenia Gravis (MG) patients also have Graves Disease (GD). Both GD and MG have autoimmune components. The treatment of hyperthyroidism with methimazole (MMI) can exacerbate MG symptoms either by its immunomodulatory property or, by inducing hypothyroidism, via the “see-saw” and “reverse see-saw” phenomenon. A 21 year old African American woman presented with unintentional weight loss of 35 pounds, palpitations, heat intolerance, and diplopia. She was diagnosed with hyperthyroidism secondary to GD and started on MMI 60 mg and propranolol 20 mg.
A month later, she returned with dysphonia, dysphagia, increased oral secretions, and generalized weakness. The thyroid was diffusely enlarged with positive bruit and she had extreme weakness of all extremities and facial muscles. Ultimately electromyography (EMG) and elevated Ach receptor Abs were consistent with MG. CT thorax revealed thymic hyperplasia. Initially, TSH was <0.008, anti-TPO - 317.4 units/mL, TSI - 403% and TSHR AB - 19 IU/L. MMI dose was progressively decreased to 5 mg daily for persistently low T3 /T4 levels and muscle weakness. T4 continued to be low so, Levothyroxine 100mCg was started. A block and replace method was chosen to maintain euthyroidism and to prevent exacerbation of muscle weakness from hypothyroidism.
MG symptoms improved on this regimen but she continued to have dysphagia and was started on plasmapheresis and prednisone. She received 4 cycles of pheresis with improvement in muscle strength. She was discharged on MMI 10 mg and Levothyroxine 75 mcg daily. She is clinically euthyroid and has returned to work. Thymectomy is planned in the near future. Both MG and GD can present with neuromuscular weakness. A positive relationship between the clinical and immunological activities of these diseases has been described. MMI has an immune modulatory effect on T cells and may induce an auto antibody response against Ach receptors causing increased muscle weakness in patients with MG. Iatrogenic hypothyroidism may also exacerbate the MG weakness. Providing replacement therapy with levothyroxine allows for a safer regimen, prolonged euthyroidism and prevents myasthenic weakness.
Disorders of Thyroid Function Friday Poster Case Report
It is rare for young adults to have cerebral vascular accidents (CVA) due to Graves' disease, especially without evidence of atrial fibrillation (AF). We present a case in which the combination of Graves', a Chiari network (CN) and patent foramen ovale (PFO) resulted in a large CVA in a young man. 27 year old male presents two days after a motor vehicle accident complaining of left side hemiparesis and paresthesia. Head CT notable for a large right middle cerebral artery infarct. Hypercoagulable factor testing, electrocardiography, transthoracic echocardiogram and telemetry were unremarkable. He endorsed increase in anxiety, appetite, heat intolerance, defecation, tremor and some weight loss over the past year. Examination and laboratory studies further support the diagnosis of Graves' disease: TSH <0.02, Free T4 4.01 (0.61 – 1.79 ng/dL), Total T3 3.80 (0.60–2.20 ng/mL), Thyroid Stimulating Immunoglobulin: 423% (0–139%). Transesophageal echocardiogram showed in the right atrium a CN with vegetation or thrombus distal to the CN, the atrial septum had a small PFO with a trivial right to left shunt. He was discharged to a rehabilitation center on apixaban, methimazole and propranolol. CN is a reticulated network of fibers in the right atrium; it is present in 2% of the population and generally is asymptomatic. CN has been associated with atrial thrombi; and specifically linked to strokes when part of a structural triad: CN, an atrial septal aneurysm and a PFO. This case is unique in that it describes a paradoxical embolism in the setting of a CN, PFO and Graves', without any atrial septal aneurysm. It is ambiguous whether paroxysmal AF (pAF) contributed to thrombus formation in this patient, since CN has been linked to thrombus formation independent of arrhythmia. We propose that this patient was predisposed to atrial thrombus formation by his CN, and his thyrotoxicosis potentiated this risk resulting in his large paradoxical stroke. Young adults presenting with Graves' disease and stroke should undergo a thorough investigation for other coinciding triggers to determine the exact and complete etiology of the stroke.
Disorders of Thyroid Function Friday Poster Case Report
Primary hypothyroidism is usually treated with oral levothyroxine. There are a few reported cases responding only to parenteral treatment. We present two cases of hypothyroidism refractory to oral therapy.
Disorders of Thyroid Function Friday Poster Case Report
Poor medication adherence is the main cause of low efficacy of pharmacological therapy and it is more common in chronic diseases. After inorganic iodine 38 mg/day, a 41-year-old devorced working primipara with Graves' disease, 30 mg methimazole (MMI) (Thyroid 2015;25:43–50) off for one week, saw family physician on her dullness, headache, and general edema. Butterfly rash, serum albumin 1.6 mg/dL, apparent proteinuria 5.5 g/day, as well as downregulated white blood cell count 3.1 × 10*3/microL implied the diagnosis of active lupus nephritis. She was positive for anti-nucleic ( × 80) and double strand-DNA IgG (25 IU/mL) antibodies. According to kidney biopsy confirmed as diffuse lupus nephritis with 2/25 fibrocellular crescents and focal segmental subepithelial deposits, class IV-G, A > C in the International Society of Nephrology/Renal Pathology Society System 2004, 40 mg predonisolone (PSL) was initiated (Modern Rheumatol 2012;24:618–25). TSH was suppressed under 0.01 microIU/mL with TRAb 14.9 IU/L, so 30 mg MMI was restarted.
Although PSL could reduce to 5 mg on titrating to 200 mg cyclosporine A (CSA) for 15 months with sustained negative ds-DNA IgG, thyroid function had been more overwhelmed. In parallel with titrating CSA, TSH, fT3, and fT4 levels were under 0.01 microIU/L, 14.3 pg/mL, and 4.22 ng/dL, respectively. With TRAb 28.2 IU/L, endocrinologist referred thyroid consultant to discuss on inorganic iodine readministration. Detected she had taken not 30 but 5 mg MMI, consultant simply restarted 15 mg MMI. It is possible scenario that the patient was not taking the prescribed MMI. Given the fact that she had been taking multiple similar-appearing oral medications including CSA, fexofenadine, fluvastatin, lansoprazole, methimazole, PSL, sulfamethoxazole/trimethoprim, and telmisartan, it is easy to imagine her being confused about which medication to take (N Engl J Med 2014;371:2321–7). Alternatively, in younger population than 60 years of age, and who live within the most socioeconomically deprived areas, they are reported to be lower adherence levels measured with modified Morisky scale (Int J Clin Pharm 2014; 36:202–11). Medication adherence monitoring system should be established for endocrinology outpatients.
Disorders of Thyroid Function Friday Poster Case Report
Acute suppurative thyroiditis (AST) is a rare entity, accounting for only 0.1–0.7% of all thyroid diseases. The mainstay treatment is early initiation of IV antibiotics and prompt surgical drainage. This case demonstrates the use of antibiotics alone with complete resolution of AST. A 25-year-old man presented with a two week history of worsening painful left neck swelling, dysphagia, sweats and weight loss in the setting of severe tooth pain. On exam, he was febrile and tachycardic. Neck exam revealed a 7 cm tender left neck mass. Imaging confirmed 6.6 × 4.3 × 12.1 cm complex solid and cystic mass extending from the angle of the mandible to the thoracic inlet. Laryngoscopy showed left vocal fold paralysis and purulent drainage in the hypopharynx. FNA of the mass confirmed purulent content. Laboratory data revealed WBC of 13.9 103/uL, suppressed TSH <0.01 mIU/L with free T4 2.69 ng/dL (0.60–1.82 ng/dL). Intravenous vancomycin and clindamycin were started then changed to ampicillin-sulbactam when cultures grew streptococcus viridans. Drainage of the abscess was discussed, however conservative management was elected. After antibiotics, repeat imaging showed no drainable collection and clinically patient had significant reduction in neck swelling. There was complete resolution of fever, pain, dysphagia and vocal cord paralysis. Thyroid function tests normalized. He was discharged on amoxicillin-clavulanate to complete 6 weeks of therapy. Due to financial constraints, evaluation to confirm a brachial cleft anomaly was not pursued. AST is rarely encountered the prompt of the appropriate antibiotics alone may be an option for acute management. Although in our case there was complete resolution of all symptoms including vocal cord paralysis with conservative treatment, identification of brachial cleft cysts is important because of the increased risk of recurrent infection without surgical correction of the anomaly. Acute suppurative thyroiditis may be managed with antibiotics alone in the acute setting, but a complete evaluation to assess the need for surgical excision for branchial cleft anomalies is important to prevent reoccurrence.
Disorders of Thyroid Function Friday Poster Case Report
Thyroid dysfunction frequently results from high doses of radiation to the neck. Hypothyroidism is more common after radiation, while hyperthyroidism is rare. Other sequelae include prolonged thyroiditis, goiter and thyroid cancer. We present a case of a patient with a history of Hashimoto's hypothyroidism since 2006 who presented with Graves' disease after being treated with 36 gY of radiation to the neck for lymphoma.75-year-old Hispanic female with hypothyroidism was found to have a low TSH, thus her levothyroxine was stopped. About 1 month later, she presented to the ER with complaints of palpitations, shortness of breath and compressive symptoms. In addition, she had significant weight loss, heat intolerance and dysphagia. On exam, her temperature was 97.3 F, heart rate of 120 bpm and BP of 135/70 mmHg. She appeared anxious and her neck was enlarged. Labs revealed her TSH was undetectable, free T4 of 2.63 and total T3 of 3.30. Thyroid stimulating immunoglobulin (TSI) was >500% (<122%) and TPO antibody was 5188.0 (0.0–9.0 IU/L). Thyroid ultrasound revealed the gland was enlarged. Propranolol 40 mg q6 hours and methimazole 40 mg were started. She was referred to endocrine surgery and total thyroidectomy was performed. The etiology of thyroid abnormalities seen in patients after irradiation to the neck includes vascular damage, parenchymal cell damage and autoimmune reactions. Several mechanisms exist. Release of antigen subsequent to radiation thyroid damage promotes production of thyroid-antibodies causing autoimmune thyroiditis, and Graves' disease may develop even in patients previously receiving thyroxine as in our patient if TSI are produced. Thirty-three % of the patients with Graves' hyperthyroidism had received thyroxine before onset, which was seen in our patient. Finally, radiation may result in cytotoxic activity to the gland. In conclusion, hyperthyroidism is a rare complication after radiation to the neck; the incidence being approximately 0.5%. In our patient, hyperthyroidism appeared 4 years after radiation therapy. Therefore, it's necessary to monitor thyroid function indefinitely following radiation therapy, not only for detection of hypo-function, but also for hyper-function.
Disorders of Thyroid Function Friday Poster Case Report
Less than 1% of patients with hyperthyroidism develop dilated cardiomyopathy with systolic dysfunction. This condition generally is reversible once euthyroid state has been achieved. Herein, we present a case of a 43-year-old male with hyperthyroidism induced cardiomyopathy. A 43-year-old male, with history of HTN, TBI, presented to the ED with acute chest pain, shortness of breath and abdominal discomfort. Vitals: 98.1F; 16 rpm, 148/81 mmHg with a regular pulse of 79 bpm. He was in mild distress due to pain, but otherwise his examination was unremarkable. Laboratory measurements were consistent with mild leukopenia of 3400/uL (3.8–10.6), negative troponin; ECG showed sinus rhythm with non-specific T wave changes. A trans-thoracic echocardiogram showed moderately dilated left ventricle, anterolateral hypokinesia and systolic dysfunction with EF of 35%. Cardiac catheterization showed widely patent normal coronaries. Additional investigation revealed: TSH <0.01 uU/mL (0.27–4.2). Endocrinology was consulted: patient denied prior thyroid disorders or symptoms of weight loss, bowel changes, tremulousness. Exam was negative for exophthalmos, thyromegaly, hyperreflexia or tremors. Additional labs showed: free T4 2.35 ng/dL/L (0.5–1.39), T3 291 ng/dL (48–178), TSI elevated at 490% (normal, <122%). Patient was transferred to the cardiac step down unit, where he was managed with ACE inhibitor, ASA, metoprolol and methimazole and has a pending follow up with repeat TFTs and echocardiogram. Sign and symptoms of congestive heart failure are common in hyperthyroidism, but dilated cardiomyopathy with impaired systolic dysfunction is rare. The exact mechanism remains unclear, but there are multiple factors likely to contribute to left ventricular systolic dysfunction. In summary, we suggest in this report, in addition to high output heart failure, some patients can develop low output heart failure, manifesting as cardiomyopathy with decreased systolic function. Rarely, some patients can present with chest pain only. Treatment of hyperthyroidism usually restores cardiac function.
Disorders of Thyroid Function Friday Poster Case Report
Alternating hypothyroidism and hyperthyroidism is an unusual clinical entity that may occur in patients with TSH receptor antibodies. A 41 year old female was referred for abnormal thyroid function tests. Patient endorsed insomnia, headaches, intermittent palpitations and weight loss for the past 3 months. No family history was reported. Initial thyroid tests showed: TSH <0.03 mU/L (0.5–4.8) and free T4 0.88 ng/dL (0.8–1.8). Initial I-123 thyroid scan showed a suppressed uptake at 2.5% (10–30%). Thought to be subacute thyroiditis, the patient was not initiated on any medications. 4 months later, the patient endorsed fatigue, hair loss, dry skin, and a 20-pound weight gain. Repeat testing found: TSH 54, free T4 0.61, and TPO antibodies greater than 8000 IU/mL (0–35). Sonography done at the time was consistent with Hashimoto thyroiditis. She was started on weight-based levothyroxine. Five months later her hyperthyroid symptoms reappeared and thyroid values revealed an undetectable TSH. The patient denied any additional thyroid replacement doses. Levothyroxine was stopped. Five months later, she again developed symptoms of hypothyroidism and thyroid values revealed a TSH of 28.9. While the patient exhibited symptoms of thyrotoxicosis, TSH receptor antibodies were found positive at 76% (<16%). Repeat thyroid scan showed a 45% homogenous uptake (10–30%) and thus, she was treated with 15 mCi of I-131. Two months after treatment, thyroid testing showed a TSH of 116.7 and decreased TSH receptor antibodies at 42%. Levothyroxine was resumed. The literature has established that autoimmune thyroid disorders are associated with two different types of TSH receptor antibodies, namely thyroid stimulating immunoglobulin (TSAb) and TSH receptor blocking antibody (TbAb). TsAb are detected in patients with Graves' disease, while TBAb may be present in some patients with a hypothyroid phenotype. Recent studies show that both antibodies can coexist in one patient, and the thyroid function is very much dependent on the balance between these two types of antibodies. This leads to a clinical phenomenon where a single patient can fluctuate between hyperthyroid and hypothyroid states as demonstrated in this case.
Iodine Uptake & Metabolism Friday Poster Translational
There is no consensus on the association between dietary iodine uptake and Differentiated Thyroid Cancer (DTC) risk so far. Our aim was to evaluate this association using pooled data from 5 population-based case-control studies carried out in French Polynesia, New Caledonia, Cuba and France (2 studies). We interviewed 2162 DTC cases and 2571 controls by face-to-face interview, using the standardized dietary uptake questionnaire and the photo booklet from Epic cohort. Dietary iodine content was estimated from French food composition table CIQUAL, and for typical Cuban, French Polynesian and New Caledonian food, iodine content was estimated from measurements performed specifically for this study. The odds ratio (OR) stratified by age, gender and studies, and adjusted for smoking status, ethnicity, education level, number of full term pregnancies, body surface area, radiotherapy for previous cancer, first-degree relative thyroid cancer history and energy uptake were estimated. Overall, we did not evidence a significant association between dietary iodine uptake and DTC risk whatever classified the population sample according to the Iodine Global Network classification or by quartile of the value distribution of dietary iodine uptake in controls for each study, nevertheless, we did find a significant heterogeneity among studies (P-heterogeneity = 0.002). In the study performed in French Polynesia, higher dietary iodine uptake was significantly associated with lower DTC risk (p-trend = 0.04), whereas the significant association was inverse in other studies (p-trend = 0.005). Furthermore, we observed DTC risk increased significantly with increasing number of full term pregnancies among the iodine deficiency women (p-trend <0.0001), and an similar but less strong association was observed among women who had optimal or more than adequate iodine uptake (p-trend = 0.02). Higher dietary iodine uptake may reduce DTC risk in French Polynesia, however, it may increase DTC risk in New Caledonia, Cuba or France. For pregnant women who had iodine deficiency, increasing dietary iodine uptake may reduce their risk of suffering from DTC.
Thyroid & Development Friday Poster Clinical
Since the diagnosis made by different ultrasound radiologists varied much, and the published of 2015 ATA Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer provied a accurate gudide in thyroid ultrasound, systematic trainings are in need. Thirty-eight ultrasound radiologists who had little experience in thyroid ultrasound were enrolled in the study. Four of them were randomly selected as the intensive group and the other 34 participants were defined as control group. All participants finished a questionnaire about their demographic data and ultrasound experience and took a test of basic knowledge, the identification of sonographic thyroid nodules and cervical lymph nodes images at the beginning. Then all of them received a series of systematic lectures about ultrasonic diagnosis of thyroid nodules within a month in order to identify the characters of malignant and benign thyroid nodules. Meanwhile, the intensive group took an additional training by learning from the specialist of thyroid ultrasound in outpatient for 9 times (half day for once). And in the end, all participants took another same test as the beginning one. The efficacy of the training was assessed by comparing the results of the two tests. There were significantly difference between the results of basic knowledge, the identification of sonographic thyroid nodules and cervical lymph nodes images tests before and after the whole training (P < 0.01, P < 0.01, P < 0.01). Before the training, the grades of between intensive group and control group had no statistical difference (P > 0.05). After the training, the grades of basic knowledge, the identification of sonographic thyroid nodule images of the two group are significantly different (x(_)±s: 59.35 ± 9.03 vs 69.50 ± 7.00, 133.79 ± 18.88 vs 161.50 ± 9.75; P<0.05); While the grades of the identification of sonographic cervical lymph images had no statistical difference. (x(_)±s: 80.50 ± 6.46 vs 77.32 ± 8.36; P > 0.05). The systematic lectures on ultrasonic diagnosis of thyroid nodules are useful for ultrasound radiologists who had little experience in thyroid ultrasound, and the short-term training would have greater value.
Thyroid & Development Friday Poster Case Report
Lingual thyroid is a rare embryological anomaly. It occurs in about 0.3% of all thyroid diseases and the incidence is reported to be 1:100000. This developmental abnormality is usually asymptomatic but there have been approximately 400 symptomatic cases reported in literature, of which approximately 30 cases with malignant transformation. A 44 year old woman presented to clinic with one year of worsening dyspnea on exertion, snoring, and fatigue. She denied dysphagia. She has had a lingual thyroid since childhood and was on levothyroxine ages 7 to 16 and during pregnancy ages 20 to 23. On exam the lingual thyroid was not visible and no thyroid was palpable in the neck. A serum thyrotropin level was 2.830 uIU/ml (normal range, 0.360 to 3.740). MRI neck with and without contrast revealed a well-defined enhancing soft tissue mass located in the base of the tongue that displaces the epiglottis posteroinferiorly and causes airway narrowing and absence of thyroid gland in the thyroid bed. Because of her obstructive symptoms, she underwent a transoral robotic resection of the mass without complications. Pathology showed benign thyroid tissue, consistent with ectopic lingual thyroid. She was started on thyroid hormone replacement therapy and is doing well. This case demonstrates how lingual thyroid can progress to severe compressive symptoms 35 years after diagnosis, requiring aggressive intervention. Lingual thyroid is usually asymptomatic. However, during puberty, pregnancy and menopause the ectopic thyroid tissue can increase in size causing compressive symptoms, explaining why it is more common in females. Patients should be made aware of such potential complications. Due to its rarity, management is varied and controversial. Medical therapy with thyroid hormone may be chosen for those with mild symptoms and elevated TSH to reduce gland size. Radioactive iodine ablation can be done in select patients. Surgery is more effective and indicated in cases of severe symptomatology or suspicion for malignancy. Clinicians need to weigh the risks and benefits of each therapeutic intervention in the context of the clinical picture. More case reports and studies are needed to determine guidelines for management.
Thyroid Cancer Friday Poster Basic
Two-thirds of papillary thyroid carcinoma (PTC) possess the BRAFV600E oncogene and thus constitutive MAPK pathway activity. A hallmark of most cancers is the somatic activation of telomerase. Recently, non-coding oncogenic mutations (C228T and C250T) were discovered to activate TERT transcription. These mutations are abundant in MAPK-driven cancers such as PTC, and they create ETS factor binding sites that apparently sensitize TERT to MAPK-mediated activation. However, this mechanism has not yet been thoroughly examined.
In this study we sought to determine which ETS factors are expressed by thyroid cancer cells, and to compare their trans-regulatory effects upon TERT. ETS gene expression in NThy, TPC1, SW1736, C643 cell-lines and thyroid tissue was ascertained by real-time qRT-PCR. Transcriptional activity was measured by gene reporter assay. Briefly, the wild-type and C228T TERT gene promoters were cloned into a pGL3 luciferase reporter, and ETS genes were cloned from human thyroid cDNA into pCMV-HA. NThy were transiently transfected, and 24 hrs post-transfection promoter activity was measured. Measurement of ETS gene expression within all three thyroid carcinoma cell-lines, revealed a significant up-regulation (>2-fold, P < 0.01) of four ETS genes: ETS1, ETV5, ELK1 and ELK3. The other ETS genes that were measured showed no significant difference to the levels found in either non-tumorigenic NThy cells or healthy thyroid tissue controls. Gene reporter assays revealed that overexpression of ETS1 in NThy cells stimulated both the C228T and wild-type TERT promoter by 1.7-fold (P < 0.001), as compared with their respective empty vector controls. Similarly, ETV5 overexpression also stimulated both mutant and wild-type TERT promoter by 2.5-fold (P < 0.001). However, in contrast, overexpression of both ELK1 and ELK3 potently repressed (>90% reduction, P < 0.001) the transcriptional output of both TERT promoters. Our findings reveal an unexpected divergence in the trans-regulation of TERT by ETS family members expressed in thyroid cancer cells. The unexpected discovery of ELK-mediated TERT repression warrants further investigation, and could potentially be a target for future therapeutic approaches.
Thyroid Cancer Friday Poster Basic
Papillary thyroid cancer (PTC) is the most common type of thyroid carcinoma. The mechanism of PTC has unraveled numerous genes recurrently mutated, but the discovery of abnormal expression of new metastasis suppressor genes in thyroid cancer using genomic efforts has been slow. It's important to pay more attention to PTC as metastatic dissemination of thyroid cancer cells represents a significant clinical obstacle to curative therapy. We performed a combined analysis of massively parallel whole-transcriptome sequencing of paired PTC tumor and normal tissues in 20 patients, and found serum deprivation response (SDPR) was significantly down-regulated in thyroid cancer. Real-time PCR analysis was performed to assess the expression of SDPR in primary PTC samples and matched adjacent normal thyroid tissue samples. PTC cell lines with transfection of small interfering RNA were utilized to investigate the functions of SDPR gene, including cell proliferation assays, colony formation assays, migration assays and invasion assays. SDPR was significantly down-regulated in primary PTC tissue compared with adjacent normal tissue both in the local cohort and TCGA cohort. Reduced expression of SDPR was associated with larger tumor size, more serious lymph node metastasis and advanced AJCC stage in both cohorts. Kaplan-Meier analysis indicated that patients with lower SDPR expression had a shorter recurrence-free survival (p = 0.001) in TCGA cohort with 473 thyroid cancer patients. Multivariate Cox analysis revealed that SDPR expression (hazard ratio [HR], 0.74; 95% CI, 0.56 to 0.96, p = 0.025) and AJCC stage (HR, 1.58; 95% CI, 1.15 to 2.18, p = 0.005) were independent predictors of worse RFS in TCGA cohort. Moreover, cell proliferation and colony formation were promoted in PTC cell lines after downregulating the expression of SDPR. Downregulation of SDPR significantly enhanced the migrate and invasive capacity of PTC cell lines. In conclusion, we identified SDPR as a novel tumor suppressor gene in PTC, utilizing RNA sequencing. Our study indicated that SDPR gene has important clinical and biological implications and may act as a potential prognostic marker and a druggable target in PTC.
Thyroid Cancer Friday Poster Basic
ATC is a rare aggressive tumor arising from the follicular cells of the thyroid gland. The average survival time is four to nine months after the diagnosis and, at present, there are no curative therapies. BAG3 is a member of the BAG family of co-chaperone proteins, and also known as a member of the HSP70 co-chaperones family. BAG3 abundance is constitutively high in ATC cells and it was demonstrated involved in cancer maintenance inhibiting NFkB sequestering in the cytoplasm. BAG3 was shown to have therapeutic effects against ATC solid tumors. ATC cells mice xenografts were treated with BAG3 small interference (si)-RNA by intra-tumor injections. After 90 days of treatment mice treated with BAG3-siRNA showed significative reduction of solid tumor volume. This study is focused on the depiction of the molecular insights of BAG3 constitutive hyper-expression and the effects of its silencing in ATC cells, by a quantitative proteomics approach. Quantitative proteomics analysis of BAG3 silenced ATC cells allowed to detect 54 up-regulated proteins and 37 down-regulated proteins. Basing on bibliographic research, we focused the attention on Serpin (PAI2) up-regulation and Caveolin down-regulation that were confirmed by western blot and quantitative PCR. The presence of these proteins was monitored in cancer biopsies with different degrees of aggressiveness. PAI2 presence was detected in higher aggressive cancers (Papillary 100%, Follicular 80%, Anaplastic 75%) making this protein a possible biomarker. No significative results were found in biopsies for Caveolin.
Proteomics data were used to perform pathway analysis using the software Ingenuity Pathway Analysis (IPA). This approach allowed to highlight the downstream effectors of BAG3, helping to better understand its selective high abundance in ATC cells. IPA data-mining allowed also to give information concerning the causal role of BAG3 silencing on the associated phenotype and also to discover ATC cells upstream effectors that could be responsible of cell resistance to the siRNA therapeutic treatment. The present work could be considered the discovery phase of a wider system biology study addressed to obtain a holistic model describing the role of BAG3 in ATC cells.
Thyroid Cancer Friday Poster Basic
Medullary thyroid carcinoma (MTC) originates from the small population of neuroendocrine C-cells of the thyroid gland. Surgery remains the only curative treatment. The human REarranged during Transfection (RET) proto-oncogene is recognized as the key driver of MTC tumorigenesis. This has previously been targeted by tyrosine kinase inhibitors (TKIs) but efficacy has been modest. MicroRNAs (miRNAs) are small non-protein coding RNAs and cancer biology can be modified by targeting miRNA expression. Progress of miRNA studies in MTC has been hampered due to the lack of normal control C-cell tissue as a differential expression comparator.
Thyroid Cancer Friday Poster Basic
To investigate impact of YAP siRNA on cell proliferation, migration, invasion, cell cycle, apoptosis and autophagy of BCPAP and KI cell. CFSE detected cell proliferation change of papillary thyroid cancer cell lines BCPAP and K1 after YAP siRNA; Transwell detected migration and invasion of BCPAP and K1 cell after YAP siRNA. Detected BCPAP and K1 apoptosis with Annexin-AV / PI double staining after YAP siRNA; PI assay YAP siRNA impact on BCPAP and K1 cell cycle, Western Blot detected protein expression; Western Blot detected BCPAP and K1 cells autophagy marker protein LC3-I, LC3-II and autophagy-related protein Atg12, Atg16, Atg5, autophagy Belcin1 expression after YAP siRNA treatment. YAP decreased expression can inhibit BCPAP and K1 cell proliferation; YAP decreased expression can inhibit BCPAP and K1 cell migration and invasion. Apoptosis results show that inhibition of YAP expression had no effect on apoptosis of BCPAP and K1, but can contribute to both G0 / G1 phase arrest; this process is accompanied by a transcription factor and C-MYC Foxo3a downregulation, cycles key regulatory proteins p21 and p27 upregulation; In BCPAP and K1 cells, LC3-I protein is slightly higher than LC3-II. siRNA YAP may inhibit both cell LC3-1 and LC3-II protein expression, which LC3-I is particularly significant, resulting in LC3-II / LC3-I value increase, this process is accompanied by the relevant trigger autophagy change of Beclin1 and autophagy nucleation and extension related Atg5-Atg12-Atg16 complex expression. YAP siRNA in BCPAP and K1 cell could inhibit proliferation and arrest cell cycle in G0 / G1 phase and is accompanied by p21 and p27 upregulation, C-MYC and Foxo3a regulation. Moreover, YAPsiRNA can promote cell autophagy.
Thyroid Cancer Friday Poster Basic
Stem/progenitor cells finalize their homing by selective access and anchorage within their specialized niches. Tumor tissue may represent a special target for the homing of stem/progenitor cells providing unprecedented access to solid and invasive cancers. To explore the potential homing of human thyroid progenitor cells to thyroid cancers we have examined the interaction between our model PAX8/NKX2-1 transfected human embryonic stem (ES) cells, which have the characteristics of thyroid progenitor cells (Ma R et al. Thyroid. 2015), and anaplastic human thyroid cells (the T238 cell line) using in vitro cell migration. Initial studies using an agarose gel system demonstrated marked outgrowth of the thyroid progenitor cells towards the anaplastic cells with almost no outgrowth towards human fibroblasts (293T cells) after 3 days of culture. Using a more sophisticated Boyden transwell system we were able to quantitate and observe the fluorescent cells migrating through a separation membrane at a rate of 75 cells/well over 3 days when migrating towards the thyroid cancer cells compared to almost no migration towards the fibroblasts. Specificity studies with liver hepatoma cells (Hep G2 line) showed that the human thyroid progenitor cells had high specificity for thyroid cancer with almost no migration towards the hepatoma cells. These results showed that, PAX8/NKX2-1-hES cells migrated to anaplastic thyroid cancer cells with high specificity. This exceptional tropism towards thyroid tumor cells may allow the delivery of tumoricidal thyroid progenitor cells to provide potent anticancer efficacy.
Thyroid Cancer Friday Poster Basic
The effects of thyroid-stimulating hormone (TSH) and thyroid hormones on the development of human papillary thyroid cancer (PTC) remain poorly understood. The study population consisted of 741 histologically confirmed PTC cases and 741 matched controls with pre-diagnostic serum samples stored in the Department of Defense Serum Repository (DoDSR). Concentrations of TSH, total T3 (TT3), total T4 (TT4), and free T4 (FT4) were measured in serum samples. Conditional logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs). Compared to the second tertile within the normal range, TSH level below the lower bound of the normal range was associated with an elevated risk of PTC (OR = 2.65, 95% CI: 1.27, 5.52), while the TSH level above the normal range was associated with a borderline increased risk of PTC (OR = 1.58, 95%CI: 0.97–2.56). The risk of PTC decreased with increasing TSH level within the normal range (Ptrend = 0.0001). The observed associations between TSH and PTC varied by gender, histological subtypes, and tumor size. A suggestive protective effect of higher TT3 levels on PTC risk was observed among men. No significant associations were observed between serum concentrations of TT4 and FT4 and risk of PTC and its subtypes. Our study found a significantly increased risk of PTC associated with TSH level below the normal range and a suggestive increased risk of PTC associated with TSH level above the normal range. Future studies are warranted to elucidate underline mechanisms and identify initial causes of abnormal TSH level.
Thyroid Cancer Friday Poster Translational
Recently we described the feasibility of molecular testing using routine air-dried FNA smears. Subsequent retrospective studies showed variable impact of molecular testing especially with regard to the mutation rates in follicular carcinoma and the risk of malignancy (ROM) for RAS positive samples. Now we prospectively analyzed the impact of molecular testing in a routine diagnostic setting in Germany over a period of two years. Molecular testing was done for 195 atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS), 278 follicular neoplasm/suspicious for a follicular neoplasm (FN/SFN), 55 samples suspicious for malignancy, and 36 cytologically malignant samples. For 322 of these nodules histology and for further 74 nodules follow-up of > one year was available. PAX8/PPARG and RET/PTC rearrangements were detected by qPCR, while BRAF and RAS mutations were detected by pyrosequencing.99.6% and 89.9% of samples were satisfactory for the DNA and RNA based analysis, respectively. In the AUS/FLUS group 58% of cancers were identified by the detection of 2 BRAF, 4 NRAS, and 1 RET/PTC3 mutation, in the FN/SFN group 27% of cancers were identified by the detection of 2 BRAF, 1 HRAS, 4 NRAS, and 1 RET/PTC3 mutation. The presence of a BRAF and RET/PTC mutation was associated with cancer in 98% and 100% of samples respectively, whereas the presence of a RAS mutation was associated with cancer in only 35% of samples (with a higher malignancy risk for NRAS mutations (67% and 33% in AUS/FLUS and FN/SFN, respectively) in comparison to HRAS mutations (0% and 20% in AUS/FLUS and FN/SFN, respectively). While FNAs with an AUS/FLUS diagnosis alone had a 21% ROM, it increased to 44% for mutation-positive test outcomes. In the FN/SFN group, with an 18% ROM, the detection of a mutation resulted in a 40% ROM. Our data show that BRAF and RET/PTC mutations are highly specific for cancer. In contrast, the impact of RAS mutation detection is limited. In summary, the current mutation panel strongly needs an improvement by the addition of further cancer specific mutations and further markers for RAS positive cases.
Thyroid Cancer Friday Poster Translational
Advances in genomic technology have enabled evaluation of indeterminate thyroid nodules for cancer-associated DNA mutations and fusions. Likewise, genome-wide transcriptome analysis on RNA has enabled gene expression “signatures” to be developed with high sensitivity and modest specificity. However, Next-Generation Sequencing (NGS) has yet to be exploited as a platform for combining the knowledge from both RNA expression and DNA variation to build stronger classifiers that more accurately diagnose thyroid nodules from fine-needle aspirates (FNA). We developed a robust pipeline for capturing transcriptional data, mutations, variants and fusions all from the same RNA. Our goal was to determine the feasibility of adding richer genomic content to train a genomic classifier to improve the specificity of diagnosing benign nodules while maintaining high sensitivity. FNA from 88 patients were collected preoperatively and nucleic acids isolated. Patients underwent thyroidectomies and surgical tissue was diagnosed by histopathology experts. The cohort included 44 malignant (PTC, HCC, FC, MTC, and WDC-NOS) and 44 benign nodules (BFN, FA, HCA, LCT, NHP, and HTA). Training (n = 58) and testing (n = 30) sets were defined by carefully balancing cytology and histology, and classifier training was conducted in a blinded manner. Samples were subjected to NGS with 15ng of RNA input. Classification models were evaluated in cross-validation according to overall AUC. The best model was then selected to analyze the test set. Over 2000 differentially expressed genes, 1400 sequence variants and 9 fusion-pairs were used to train several models. The best model uses an Ensemble score (median probability) from three models (SVM, LASSO, Random Forest). In the test set, this classifier yielded an overall AUC of 0.88, with a sensitivity and specificity of 93% and 80%. Classifiers with high sensitivity and improved specificity can be developed from a combination of features generated using our NGS assay. Although this feasibility study is based on a relatively small data set, the principles of how counts, variants and fusions can be effectively combined has been demonstrated. Efforts are underway to apply this approach to a larger cohort.
Thyroid Cancer Friday Poster Clinical
Social support is important for recovery and quality of life after thyroid cancer surgery, but difficulties arise when there are mismatches between patient support needs or expectations and the support they receive. We evaluated these mismatches after thyroid cancer surgery and their implications for recovery. We conducted semi-structured qualitative interviews with patients at three time points: preoperatively (N = 29), and 2 weeks (N = 22) and 6 weeks (N = 17) postoperatively following surgery for papillary thyroid cancer as part of an ongoing randomized clinical trial. We used a grounded theory approach to develop a coding structure based on a representative subset of interviews. Emergent themes were assessed by the study team and conflicts resolved by consensus. We evaluated 3 domains of social support: emotional, tangible, and informational. Patients felt that emotional social support (having someone to talk to and work through the emotional impact of cancer surgery) was critical to quality of life. However, when friends and family were too pushy or failed to understand their emotional support needs, these efforts were counterproductive and created stress for patients. Most patients appreciated tangible (transportation, providing meals, help with housework) and informational support (finding information about cancer and treatments), but numerous respondents indicated difficulties arising from ill-informed efforts to provide support. These included phone calls from friends and family immediately after surgery during the period of maximal voice discomfort. For patients used to coping with problems on their own, an overabundance of tangible support caused distress rather than comfort, and post-surgical communication difficulties made it hard for patients to help their networks adjust the style and frequency of support. Effective social support following thyroid cancer surgery requires more than a willingness of family and friends to be helpful. Physicians should help patients identify their support needs and communicate expectations of support to family and friends after thyroid cancer surgery. This can reduce stress and conflict while enhancing quality of life.
Thyroid Cancer Friday Poster Clinical
Among the tools currently used for diagnosis of MTC, Fine Needle Aspitarion (FNA)-cytology accuracy is low, failing in up to 50% of cases, and preoperative serum calcitonin (sCT) measurement has low positive predictive value in some clinical (chronic kidney failure) and laboratorial conditions (heterofilic antibody and macrocalcitonin). In recent years, the usefulness of the measurement of CT in washout fluids of FNA (FNA-calcitonin) in diagnosis of primary MTC nodule and lymph node metastases has been proposed. The objetive of this study was to assess the clinical utility of FNA-calcitonin in the identification of primary MTC and lymph node metastases. Data from FNA-cytology were compared to FNA-calcitonin in both MTC thyroid nodules (confirmed by histological study) and MTC lymph node metastases (confirmed by cytology and/or histology). FNA-calcitonin from nonmedullary thyroid nodules (confirmed by histology) and reactive hyperplasia lymph nodes (confirmed by cytology) were used as controls. Serum calcitonin values collected at the time of the FNA were also reviewed. The calcitonin was measured using an “in-house” immunofluorometric assay. Mean FNA-calcitonin measurements in 15 MTC thyroid nodules was 82,700 pg/mL (range: >1,600–2000,000) and significantly higher than that obtained in 28 nonmedullary thyroid nodules 1 pg/mL (range 1–8.8) (p < 0.01). In six out of 15 MTC patients, FNA-cytology had been classified as insufficient, benign, undetermined and suspicious of malignancy, but non-conclusive for MTC. The high levels of FNA-calcitonin found in these 6 patients (range: 2076–122,100 pg/mL) made preoperative planning, such as surgery extension and the evaluation of pheochromocytoma, possible. Regarding lymph nodes, the median FNA-calcitonin in 34 MTC metastatic cases was 135,491 pg/mL (range 558–2000,000) and 1.2 pg/mL (range 1–77) in 7 cases with reactive hyperplasia (p < 0.01). The relation between FNA-CT and sCT was also analyzed and a positive correlation in reactive lymph nodes (R2 = 0.35; p < 0.01), but not in metastatic lymph nodes (R2 = 0.002; p = 0.796), was observed. FNA-calcitonin is a valuable tool to identify thyroid nodules with MTC and metastatic lymph nodes.
Thyroid Cancer Friday Poster Clinical
Anaplastic thyroid cancer (ATC) is aggressive, with poor response to its limited therapies. Lenvatinib (LEN), an oral multikinase inhibitor of vascular endothelial growth factor (VEGF) receptor 1–3, fibroblast growth factor receptor 1–4, platelet-derived growth factor receptor alpha, and ret and kit proto-oncogenes, is approved for the treatment of radioiodine-refractory differentiated thyroid cancer (DTC), based on a phase 3 study (Schlumberger et al. NEJM 2015), and recently approved for advanced renal cell carcinoma in combination with everolimus after 1 prior VEGF-targeted therapy based on a phase 2 study. In a phase 2 study in patients (pts) with advanced thyroid cancer, LEN efficacy was promising in pts with ATC (n = 17; objective response rate [ORR] 24%; median progression-free survival [PFS] 7.4 mo; median overall survival [OS] 10.6 mo; Takahashi et al. JCO 2016). We report the design of a phase 2 trial of LEN for ATC, conducted in collaboration with the International Thyroid Oncology Group to further examine LEN activity in this population. Pts aged ≥18 years with an Eastern Cooperative Oncology Group performance status of ≤1, ATC diagnosis confirmed by central pathology review, and measurable disease per RECIST v1.1 are eligible. Pts with DTC showing a small focus of ATC and pts with ATC showing an incidental focus of other thyroid cancer are also eligible. Pts receive LEN 24mg/d until disease progression or development of unacceptable toxicity. The primary endpoint is ORR as assessed by investigator review. A binomial exact test will test the superiority of LEN based on ORR in this trial (estimated ≥27%) compared to historical ORR (10%) in ATC; LEN is superior to the historical control if P ≤ 0.025. Secondary endpoints include PFS rate at 12 wks, OS rate at 6 mo, median PFS, median OS, and safety. Exploratory endpoints include clinical benefit rate, disease control rate, duration of response, and correlation of biomarkers with efficacy outcomes. An interim analysis will be performed after 20 evaluable pts complete ≤2 tumor assessments or discontinue treatment due to death or disease. The study will be halted with ≤3 responders (ORR ≤15%); otherwise enrollment will continue to accrue 57 pts.N/AN/A
Thyroid Cancer Friday Poster Clinical
Recently, many studies reported the safety and feasibility of robot-assisted thyroidectomy, but most of these studies were performed in South Korea. Although there were several small series and case reports from the United States, most of these cases were for benign disease. The aim of our study is to report the safety and feasibility of robot-assisted thyroidectomy for thyroid cancer in the western population. Retrospective review of all patients who underwent robot-assisted thyroidectomy over the last 5 years for thyroid cancer, in two centers, one in France and one in USA. Those were compared to a control group who underwent open thyroidectomy at the same period. We analyzed demographic data, operative outcome and early oncologic outcome measures including; pathological margins, biochemical (thyroglobulin level) and radiological evidence for recurrence. Total of 108 robotic cases and 233 conventional cervical operations were included. 28.70% of patients who underwent central lymph node dissection and 9.26% had lateral neck dissection. The transaxillary approach was performed in 93.5% and the remaining underwent retroauricular approach. In the robotic cases, the mean age was 45.58 ± 10.58 years and BMI was 26.09 ± 6.47. The average nodule size was 2.05 ± 1.5 cm. The mean operative time was 161.1 ± 55.99 minutes with 3 patients required conversion to conventional cervical approach. Complications were reported in 8(7.4%) patients including 1 hematoma, 3 seroma and 5 patients developed transient vocal cord paralysis. Two (1.92%) patients had focal positive margins and two (1.85%) developed recurrence 24 and 16 months following initial surgery. In comparison to patients who underwent open approach, the robotic approach had significantly longer operative time (p < 0.001). On the other hand, there was no significant difference in the overall complication rate (p = 0.15), and surgical outcome (p > 0.5). Robot-assisted thyroid surgery is a safe and feasible approach for managing selected group of patients with thyroid cancer in the western population, and is associated with sound oncologic outcome comparable to the open approach.
Thyroid Cancer Friday Poster Clinical
Several studies have suggested that the stiffness of a thyroid nodule could be an indicator of malignancy. Ultrasonography can be used to identify a stiff nodule by using Acoustic Radiation Force Impulse Elastography technology. The Afirma gene-expression classifier (GEC) helps guide in the management of indeterminate thyroid nodules. We aim to evaluate the accuracy of elastography and Afirma GEC in predicting malignancies in patients presenting with indeterminate thyroid nodules. This is a retrospective review of all patients who underwent surgery for indeterminate thyroid nodules by a single surgeon over 1-year period. Analysis of ultrasound features including elastography, internal vascularity, echogenicity, irregular margins and calcifications. Color intensity was used to determine the stiffness. Clinical and pathological data including Afirma GEC testing were collected. A total of 93 thyroid nodules were examined; 64.9% presented with stiffness in elastography, 35.1% were soft on elastography. 75.6% of malignant thyroid nodules were stiff on elastography, compared to 24.4% were soft (p < 0.05). 50.8% of the stiff nodules were malignant. Stiffness on ultrasound elastography predicted malignancy in thyroid nodules (OR: 2.38, Sensitivity: 75.6%, PPV: 50.8%, NPV: 69.7%,) Interestingly, The presence of both stiffness and suspicious Afirma GEC testing was significantly associated with higher risk of malignancy in indeterminate thyroid nodules (OR = 3.25, p = 0.045, Sensitivity: 50%, Specificty: 76.5%, PPV: 57.9%, NPV: 70.3%)Our results indicate that the Afirma GEC in addition to elastography on sonographic assessment predict higher risk of malignancy in indeterminate thyroid nodules.
Thyroid Cancer Friday Poster Clinical
Although targeted therapy has been adopt to treat radioiodine-refractory differentiated thyroid cancer (RR-DTC) and other cancers, the most appropriate response criteria have not been determined. The aim of this study was to evaluate the role of 18F-FDG PET/CT in the monitoring of response to sorafenib treatment in RR-DTC patients, comparing Response Evaluation Criteria in Solid Tumors (RECIST) with the European Organization for Research and Treatment of Cancer (EORTC) criteria. This was a single-center retrospective analysis of 14 patients with RR-DTC treated with sorafenib in the period from December 2011 to December 2014. The percentage changes in the sum of tumor diameters and the sum of maximum standardized uptake values (∑SUVmax) before and at nearly 3 months after the initiation of sorafenib treatment were compared using Wilcoxon signed-rank sum test. Morphologic (RECIST 1.1) and metabolic (EORTC criteria) responses were statistically compared using the chi-square test (Fisher's exact test). The differences in progression-free survival (PFS) between response categories were evaluated. The Spearman rank correlation coefficient was estimated between PFS and either morphologic (RECIST 1.1) or metabolic response (EORTC criteria) categories. There was an agreement between the RECIST 1.1 and EORTC criteria in 10 of the 14 patients (χ2 = 2.345, P = 0.424). The remaining 4 patients with SD included 2 patients with PMR and 2 patients with PMD. Differences in PFS among different response categories according to either RECIST 1.1 (P = 0.003) or EORTC criteria (P = 0.003) were statistically significant. Correlation were found between PFS and either morphologic (r = 0.741; P = 0.002) or metabolic (r = 0.816; P = 0.0004) response criteria. Although RECIST 1.1 and EORTC criteria agree in 10/14 (71.4%) patients, PET-based metabolic response criteria seem to be more accurate in predicting therapeutic outcome and may be more suitable than morphologic response criteria for the evaluation of response to targeted therapy.
Thyroid Cancer Friday Poster Clinical
The indications for and impact of external beam radiotherapy (XRT) in the adjuvant treatment of thyroid cancer have not been well-defined. The current ATA guidelines state XRT “should be considered in patients over age 45 with grossly visible extrathyroidal extension at the time of surgery and a high likelihood of microscopic residual disease, and for those patients with gross residual tumor in whom further surgery or RAI would likely be ineffective”. Many studies show XRT improves locoregional recurrence rates. Routine serum thyroglobulin (Tg) screening is one of the clinical gold standards to detect recurrent or persistent differentiated thyroid cancer. The aim of this study is to examine the effect of XRT on Tg levels in patients with differentiated thyroid cancer. 83 medical records from patients with thyroid cancer and evaluated for XRT at Winship Cancer Institute of Emory University were reviewed from August 2001- August 2014. Exclusion criteria included: undifferentiated or medullary thyroid cancer, XRT was not performed at Winship, no follow up, or if consult did not include discussion about XRT. Suppressed serum Tg and antithyroglobulin levels were recorded before and after XRT end date or consult date. Patients with elevated antithyroglobulin labs were excluded. Patients were divided into two groups: patients who received XRT (n = 12) and patients who did not (n = 7). Whether a decrease in serum Tg occurred after XRT or consult was compared between the two groups using Pearson chi square test. A change in Tg <1 was deemed clinically insignificant and was excluded. The percent difference of Tg before and after XRT or consult was compared using Pearson chi square test. Tg levels decreased in 69.7% of XRT patients compared to 0% of patients who did not receive XRT (p = 0.005). The Tg levels in XRT patients decreased on average by 46.37% (± 10.89) compared to an average increase of 219.49% (±194.15) in non-XRT patients (p = 0.20). Thyroglobulin levels decreased in patients with differentiated thyroid cancer who received XRT compared to patients who did not, reflecting less cancer burden. This study is in accordance with previous studies showing XRT may be beneficial in preventing recurrent cancer.
Thyroid Cancer Friday Poster Clinical
Frequency of thyroid nodules and differentiated thyroid cancer (DTC) risk in Graves Disease (GD) is not clear yet. Previous studies reported an increased prevalence of thyroid cancer in GD patients. The goal of this study was to evaluate the prevalence of thyroid nodules and DTC in thyroidectomized patients with GD.
Graves disease patients who were evaluated in Ankara University Faculty of Medicine between 2005 and 2015 were included in this study. Demographical data, preoperative thyroid ultrasonography (USG), thyroid antibodies, thyroid scintigraphy and uptake, fine needle aspiration cytology (FNAC) and postoperative pathology results were assessed retrospectively. One hundred twenty one patients (31 male and 90 female) were included in this study. The median age at the time of diagnosis was 45 years (17–79). Preoperative thyroid USG revealed nodular goiter in 62 (74.4%) patients. Thyroid cancer was demonstrated in postoperative pathology specimens of 34 (28.1%) patients. DTC was observed in 41.6% (n = 24) of patients with nodular GD and 50% of these tumors were microcarcinomas (n = 12). Frequency of incidental thyroid cancer was 8.3% (n = 10) in whole group and all of them were found in patients without thyroid nodules. Nine patients with incidentally found DTC had papillary (8 microcarcinomas) and one had follicular thyroid cancer. Sensitivity and specificity of FNAC were 68% and 87 %, respectively in nodular GD patients.
We observed that thyroid cancer risk was increased in nodular GD. Besides, incidental thyroid cancer was also prevalent in toxic diffuse goiter cases. Our findings were concordant with previous studies and suggest that careful evaluation of all thyroid nodules in GD patients is essential.
Thyroid Cancer Friday Poster Clinical
Cervical lymph node (LN) metastases are a common finding in papillary thyroid carcinoma (PTC); nevertheless, the management of the lateral neck in this disease has been debated. Present study aimed to introduce metastatic ratio index (MRI) as an independent variable that influence the decision to carry out lateral LNs compartment surgery in addition to routinely performed central LNs dissection. Patients aged ≤18 years at surgery with unifocal PTC treated with total thyroidectomy combined with central and lateral LNs dissections (n = 509) were retrospectively analyzed. Total number of LNs dissected, number of positive LNs divided by the total amount of LNs (LN ratio), and characteristics of metastases in LNs were used to describe nodal disease. The metastatic ratio index (MRI) as a number of positive LNs divided by the difference between the total amount of LNs minus a number of positive LNs +1 was calculated. There were a median of eight nodes dissected in central compartment (1–35) with a median three LNs containing metastasis (0–21). For ipsi-lateral compartment a median of nine LNs (1–35) were revealed with a median number of metastatic LNs of one (0–16). Besides, for contra-lateral compartment a median of eight LNs (1–23) were detected with a median of zero for nodal metastases (0–5).
LN ratio correlated with total number of LNs dissected in central compartment (rho = -0.15, p < 0.001) but LN involvement is often detected in a somewhat arbitrary way – the recorded frequency of nodal metastases may rely heavily on the inquisitiveness and patience of the individual pathologist. The MRI associated (p < 0.0001) with central LNs involvement by tumour deposits (small, near total replacement, extra-nodal growth) and can be used to predict as ipsi- and contra-lateral LN metastases (p < 0.0001) as well. The MRI predicts lateral metastases better than LN ratio; it could be considered for decision-making for lateral LNs dissections in children and adolescents with PTC.
Thyroid Cancer Friday Poster Clinical
Serum Thyroglobulin (Tg) plays an important role in surveillance of differentiated Thyroid Carcinoma (DTC). In the initial follow up period, obtaining stimulated-Tg after recombinant human Thyrotropin (rhTSH) administration is a common practice. However, the value of the repeating rhTSH-stimulated Tg in subsequent years is not clear. Here we present a retrospective study evaluating the prognostic ability of rhTSH-stimulated Tg done in first year after surgery.
Patients with rhTSH-stimulated Tg test done 6 to 18 months after thyroidectomy and Radioactive Iodine (RAI) treatment who had already consented to be part of Thyroid Cancer Registry at Boston Medical Center, were included in this study. Subjects with detectable Tg antibody at the time of rhTSH-stimulated Tg testing were excluded. rhTSH- stimulated Tg level of 1 ng/mL or higher was considered significant. For each subject, the risk of persistence/recurrent disease based on 2016 American Thyroid Association (ATA) risk stratification as well as response to treatment (excellent, biochemical incomplete, structural incomplete, indeterminate) at final visit were recorded.
Average length of follow up was 7 years. Overall, 82% of all patients had a rhTSH-stimulated Tg <1 ng/ml within the first 18 months after diagnosis; among them 93% were found with excellent response to therapy at their final visit. In the ATA low-risk group, stimulated Tg was lower than 1 ng/mL in 91% of patients, however this rate was 70% and 56% in intermediate and high risk groups. 98% of low risk patients and about 75% in other groups achieved excellent response to treatment by the end of the study period.
For ATA low risk category patients (at diagnosis), a repeat rhTSH- stimulated Tg may not be necessary if the initial level is <1 ng/mL. However, for intermediate and high risk ATA categories, 20 to 25% of patients who had initially favorable rhTSH-stimulated Tg results will demonstrate biochemical or structural incomplete response during follow up, emphasizing the value of ongoing testing.
Thyroid Cancer Friday Poster Clinical
Video teaching modules have been shown to be effective tools in surgical education, complementing traditional post-graduate curricula. Unfortunately, there is a lack of validated modules described in the literature, specifically for teaching thyroidectomy. The primary objective of this study was to develop and validate a high definition video-based teaching module instructing thyroidectomy surgery to Otolaryngology – Head and Neck Surgery trainees. This prospective study included 7 intermediate to senior Otolaryngology – Head and Neck Surgery residents. Each consented participant first performed a hemi-thyroidectomy, serving as the initial assessment. After a washout period of at least 2 weeks, each participant was given the teaching module. The 15-minute module was developed using a three-camera system and detailed a step-by-step approach to the surgery. After exposure to the module, each trainee then performed the same procedure. Recordings of both procedures were de-identified and reviewed by an independent evaluator. Scoring was done using the Observational Clinical Human Reliability Assessment (OCHRA) system. A statistically significant decrease in error occurrence was found after exposure to the teaching module. In addition, the number of staff takeover events was less in the post-exposure group as compared to the pre-exposure group. This difference was found to be statistically significant. High-definition video teaching modules are a useful complement to traditional surgical training. Otolaryngology – Head and Neck Surgery resident trainees experienced a significant reduction in both errors committed and staff takeover events when performing a thyroidectomy after exposure to the teaching module.
Thyroid Cancer Friday Poster Clinical
The McGill Thyroid Nodule Score (MTNS+) uses 23 risk factors for thyroid cancer to attribute a malignancy risk for thyroid nodules. Currently, the MTNS+ overestimates the malignancy risk malignancy in patients with an initial benign result from ultrasound guided fine needle aspiration (USFNA). The aim of this study was to devise a modified scoring system, the MTNS Version 3 (MTNS V3), to better identify false negative benign USFNAs while avoiding unnecessary surgery. A retrospective analysis of 1189 included patients undergoing thyroidectomy at a tertiary care academic center was performed. MTNS+ results were calculated for all patients. A score of negative 3 points was attributed to benign USFNA results in order to produce an optimal sensitivity and specificity using the receiver operating characteristic (ROC) curves. Postoperative pathology results were compared to the MTNS V3 results. Malignancy rates for each MTNS V3 value were calculated. The malignancy rate was <5% for scores ≤1, 13% for scores 2–3, 28% for scores 4–6, 35% for scores 7–8, 42% for scores 9–10, 69% for scores 11–12, 77% for scores 13–15, 84% for scores 16–19, and >95% for scores ≥20. MTNS V3 scores 1–25 and malignancy rates correlated with an “r” coefficient of 0.962, 95% CI [0.912, 0.984]. A score ≤10 correlated with a 32% (220 of 679) risk of malignancy, whereas a score ≥11 implied an 80% (409 of 510) risk. The area under the ROC curve was 0.782 for the MTNS+ as compared to 0.788 for MTNS V3 (p = 0.024). In this study, the MTNS V3 allows for more accurate malignancy risk stratification in patients with an initial benign USFNA result.
Thyroid Cancer Friday Poster Clinical
Thyroid cancer is a rare tumor type representing 1% of all cancers, yet it is the most common endocrine malignancy worldwide with a small population of patients who develop radioiodine-refractory differentiated thyroid cancer (RR-DTC). The survival benefit and impact of treatment on quality of survival in this rare indication is not well understood and has limited quality of life (QOL) publications.
Thyroid Cancer Friday Poster Clinical
ATC is an aggressive cancer with poor prognosis. Cytotoxic chemotherapy (chemo) has low response rate (RR) and no modern chemos are approved for ATC. Lenvatinib (LEN) was studied prospectively in a small cohort of ATC pts and found to be promising. Dabrafenib (BRAF inhibitor) plus trametinib (MEK inhibitor) is currently being studied in BRAFm ATC. We studied the efficacy of these kinase inhibitors (KIs) in ATC in the non-clinical trial setting. This was an IRB-approved retrospective review of ATC pts treated with KIs outside a trial. RR evaluated by RECIST. All images were reviewed by a single radiologist. Progression-free (PFS) and overall survival (OS) were evaluated by Kaplan-Meier method. From our institutional database we identified 13 ATC pts between 4/2015–5/2016, who were started on KIs outside of clinical trial. Two of the 13 pts were excluded for the following: 1 pt received KI for only 3 days and the other was started on KI outside information about treatment/response unknown. This left 11 evaluable pts for OS, 8 for PFS, 7 for RR. 5 pts received LEN, 5 pts received dabrafenib+trametinib (D+T), and 1 pt received D alone. 6 pts failed at least 1 line of systemic therapy (excludes radiosensitizing chemo) prior to KI. 5 were treated with KIs as first line systemic therapy. Median age 67 yrs, 6/11 (55%) were men. Stage at diagnosis: 7/11 (63%) IVC, 3/11 (27%) IVB, 1/11 (9%) IVA. All tumors were genotyped and 6/11 (54%) were BRAFV600E mutated. RR: 3/7 (38%) PR (all on D+T), 4/7 (57%) SD with regression (-6% to −22%; 1 on D+T, 3 on LEN). Of the 3 pts who have no RR data: 2 pts on D + T have improved swallowing and visible tumor shrinkage. Median PFS: 113 days (95% CI 111–115); median OS: 180 days (95% CI 2.5–357.5). Survival data are immature, as only 2/11 pts have died and median follow up is only 53 days. Toxicities were as expected and manageable. Targeted therapy with D + T for BRAFm ATC and LEN for BRAFwt ATC showed clinical benefit, resulting in tumor regression. However, durability of responses and improvement of OS need further assessment. ATC pts should be treated in the context of clinical trials, however, when pts are unable to participate, treatment with D + T or LEN can be considered.
Thyroid Cancer Friday Poster Clinical
Management decisions are not straightforward when the Ultrasound Guided Fine Needle Aspiration (USFNA) demonstrates a Bethesda score of either category III or IV, and a diagnostic hemi-thyroidectomy or a repeat USFNA (r-USFNA) could be performed. The aim of this study is to assess the effectiveness of r-USFNA in the management of indeterminate thyroid nodules by evaluating the likelihood of obtaining a definite diagnosis. We reviewed the medical records of all patients with thyroid nodules between 2011 and 2015 at the Jewish General Hospital (Montreal, Canada). 351 patients who had undergone a surgical procedure (hemi or total thyroidectomy) and a diagnosis of B3 or B4 on the primary USFNA (p-USFNA) were included in the study. 96 of the included patients also had a repeat USFNA prior to the surgery. Demographic data, type of procedure, and McGill Thyroid Nodule Score (MTNS) were obtained from the medical records. Malignancy rates were calculated based on the final surgical histopathology report. Upon r-USFNA, an average 76% of patients did not change Bethesda categories, 7.4% downgraded to a benign category. The results showed that, on an average 17.3% of patients with p-USFNA of B3 and 20% of patients with p-USFNA of B4, upgraded to a malignant or suspicious for malignancy category, thus changing the clinical management to total thyroidectomy. Our data demonstrates that r-USFNA facilitates choosing the correct surgery of total thyroidectomy in about 20% of nodules that have upgraded from B3/B4 to a more definite malignant category. In our study, 7.4% of lesions downgraded from B3 to B2 after r-USFNA, changing their the clinical management to a more conservative one. r-USFNA in patients with indeterminate diagnoses (B3 or B4) increases categorization into more definite categories. Approximately 20% of patients are found to have malignant thyroid nodules and suspicious for malignancy thyroid nodules upon repeating the biopsy, hence leading to a total thyroidectomy instead of a diagnostic hemi-thyroidectomy. Futhermore, repeat USFNA results in a fewer number of hemi-thyroidectomy and completion thyroidectomy procedures.
Thyroid Cancer Friday Poster Clinical
Patient age, tumor subtype, extrathyroidal extension, and neck lymph node metastasis are known risk factors associatedwith increased recurrence of PTC (papillary thyroid carcinoma) and especially lateral neck lymph node metastasis is closely related to tumor recurrence and poor prognosis in patients with PTC. So we designed this study to evaluate the risk factors for lateral neck node metastasis in PTC preoperatively. A retrospective review of the medical record of the patients who were diagnosed with PTC and had total thyroidectomy with lateral neck dissection from 2000 to 2013. 75 patients enrolled to this study and we also reviewed and compared medical record of 75 patients who had total thyroidectomy without lateral neck dissection in that period. We investigate age, sex, pre-operative location of tumor, post-operative pathology including size, multifocality, capsular invasion, extrathyroidal extension, central neck lymph node metastasis, lymph node density of central neck node. In univariate analysis, we found stastical differences of sex of patients (male), tumor location (upper), size, extrathyroidal extension, central lymph node metastasis, central lymph node density (more than 50%) between two groups. Logistic regression analysis showed tumor location (p-value = 0.04, Odds ratio 4.10), central neck lymph node metastasis (p-value = 0.05, Odds ratio 3.39), central neck node density (p-value = 0.03, Odds ratio 4.89) had strong relation with lateral neck node metastasis. Also we had significant value of central nodal density (more than 5.2) using ROC curve that could be used to predict lateral neck nodal metastasis in PTC patients with high sensitivity and specificity. Although with pre-operative precise evaluation, We sometimes overlooked lateral neck lymph node metastasis in PTC. We could conclude that central neck node metastasis and node density, location of tumor could be the predictive factor of lateral neck node metastasis.
Especially in patients who showed high central nodal density, we should have more concern about lateral neck metastasis in follow up period.
Thyroid Cancer Friday Poster Clinical
The debate about whether Familial non-medullary thyroid cancer (FNMTC) has aggressive clinical features and a worse prognosis compared to sporadic non-medullary thyroid cancer remains controversial. This study aimed to determine the prevalence and surgical extension, and to evaluate the clinicopathologic features of FNMTC and sporadic thyroid cancer at a single institution. We conducted a retrospective review of 2,301 patients with differentiated thyroid cancer who underwent primary thyroidectomy from March 2007 to April 2016. In total, 283 FNMTC cases were identified. The clinicopathologic results were reviewed for comparison between familial and sporadic thyroid cancer. All 283 patients (12.3%) representing 213 families had a family history of thyroid cancer. Eighty two percent had 2 affected relatives, 18% had 3 or more affected relatives, and 53.7% for a sibling relationship; the proportion for a parent-child relationship was 46.3%. There was no significant difference in sex, age, tumor size, extrathyroid extension and lymph node metastasis between the FNMTC and sporadic groups. Patients with FNMTC were more likely to have multifocality (40.6% vs. 33.0%, p = 0.012) and benign nodules (43.8% vs. 36.6%, p = 0.020) compared to those with sporadic disease. A high number of affected patients had increased tumor multifocality (p = 0.009). Among the parent-child FNMTC cases, second-generation patients had a larger tumor size than the first generation patients (1.20
Thyroid Cancer Friday Poster Clinical
Hobnail and Tall cell variant of papillary thyroid carcinoma (PTC) are classified ATA intermediate risk. The clinical relevance of focal hobnail and tall cell change remains unclear. Patients treated for PTC at a university hospital were reviewed for hobnail features between 2011–2016 and for tall cell features between 2000 and 2016. Focal hobnail and focal tall cell change were defined as occupying <30% of the tumor volume; true variants as ≥30%. Control comparison was made using patients with classical PTC from 2011–2012. Recurrence rates were calculated for patients with ≥12 months of follow up. A total of 357 patients were included (80 classical PTC, 56 PTC with focal hobnail, 131 PTC with focal tall cell, 53 PTC with focal hobnail and focal tall cell, 6 hobnail variant PTC and 31 tall cell variant PTC). Those with true hobnail or tall cell PTC were significantly older than patients with focal changes as well as classical PTC (55.4 versus 45.2 years, p = 0.003). Vascular invasion was seen more frequently in patients with any hobnail or tall cell change (focal or true variants) (p = 0.002). True hobnail and tall cell variants were significantly larger compared to patients with focal changes or classical PTC (p = 0.001). Compared to true variants, patients with focal changes had a similarly high rate of lymph node metastasis (central compartment 35% versus 32%, lateral compartment 32% versus 41%) (p = 0.543). After a mean follow up of 42 months, recurrence was present in 33 (18.4%) patients with focal changes and 5 (18.5%) patients with a true variant compared to 7 (9.2%) patients with classical PTC (p = 0.096). Distant metastasis was not present in patients with classical PTC compared to 17 (7.1%) with focal changes and 7 (18.9%) of true variants (p = 0.001). Patients with focal hobnail or tall cell changes, defined as less than 30% of the tumor, resemble those with >30% change. Both have comparable rates of lymph node metastasis, vascular invasion, recurrence, and distant metastasis and are more aggressive than classical PTC. Consideration should be given to classify patients with focal changes of hobnail or tall cell variant PTC as ATA intermediate risk.
Thyroid Cancer Friday Poster Clinical
This study aimed to evaluate the feasibility and efficacy of solo-surgeon retroauricular thyroidectomy. For solosurgery, we used an Endoeye Flex Laparo-Thoraco Videoscope (Olympus America Inc., NJ). A Vitom Karl Storz holding system (Karl Storz GmbH & Co., Tullingen, Germany) composed of several bars connected by a ball-joint system was used for fixation of endoscope. A Snake retractor and a brain-spoon retractor was used on the SCM. Endoscopic thyroidectomy using the solo-surgeon technique was performed in 10 patients with papillary thyroid carcinoma. The mean patient age was 36.0 ± 11.1 years, and all patients were female. There was no conversion to conventional open thyroidectomy, nor was there any vocal-cord paralysis, inadvertently excised parathyroid glands, or hematoma formation. Additionally, there were no injuries to the great vessels, esophagus, trachea, or marginal mandibular nerve. When compared with a control group of 100 patients who underwent surgery via the conventional retroauricular approach between May 2013 and December 2015, the operating times were not significantly different between solo-surgery and conventional endoscopic surgery (127.5 ± 8.7 minutes vs. 128.3 ± 36.2 minutes; p = 0.781). The volume of drainage was also not significantly different between conventional retroauricular thyroidectomy and solo surgery (143.3 ± 53.8 mL vs. 149.6 ± 65.1 mL) (p = 0.541).
Solo-surgeon endoscopic retroauricular thyroidectomy has the following advantages: (1) Eliminating the need for an assistant during the major part of the surgery, which can be helpful in situations in which assistants are few in number, (2) Coordinating the endoscope and instruments, and widening the work space in order to keep instruments in their ideal positions, and (3) allowing the main operator to concentrate more intensely on the procedure by providing stable visualization of the endoscope and regulation of the surgical view. Solo-surgeon retroauricular thyroidectomy is safe and feasible when performed by a surgeon competent in endoscopic thyroidectomy.
Thyroid Cancer Friday Poster Clinical
Papillary thyroid carcinoma patients with high volume lymph node metastasis (hvLNM, >5 metastatic lymph nodes) have higher risk of persistent/recurrent disease. The aim of this study is to investigate the risk factor of hvLNM in cN0 papillary thyroid microcarcinoma (PTMC). The medical record of 1268 (998 female, 270 male) cN0 PTMC patients were reviewed. Clinical and pathological features were collected for analysis to identify the risk factors of hvLNM. Of all patients, 416 patients (32.8%) have lymph node metastasis and 43 (3.4%) have hvLNM. In univariate analysis, male patients (male 6.3% vs female 2.6%, P = 0.005), young age (<40 yrs 7.6%, 40–59 yrs 2.1%, >59 yrs 0, P < 0.001), tumor size >0.5 cm (>0.5 cm 4.0% vs ≤0.5 cm 1.36%, P = 0.027) were associated with hvLNM. In multivariate analysis, female patients was protective factor of hvLNM (OR 0.420, 95% CI 0.222–0.794, P = 0.008). Tumor size <0.5 cm was potential protective factor of hvLNM (OR 0.364, 95% CI 0.128–1.036, P = 0.058). Compared with young patients, middle age patients have lower risk of hvLNM (OR 0.270, 95% CI 0.144–0.508, P < 0.001). Lymph node metastasis is not rare in cN0 PTMC patients. However, the incidence of hvLNM is extremely low, especially in female, middle age and old patents, tumor size <0.5 cm.
Thyroid Cancer Friday Poster Clinical
Preoperative ultrasonography (US) is a widely used tool in screening patients with papillary thyroid carcinoma (PTC). However, the sensitivity of US in prediction of LNM was not satisfactory. The aim of this study is to evaluate the of US in prediction of lymph node metastasis (LNM) and high volume LNM (>5 metastatic lymph node, hvLNM) Clinical-pathological features and ultrasonography reports of 2073 PTC patients were extracted for analysis. Sensitivity and specificity of US were evaluated for detection of LNM, hvLNM. The US performed by experienced (Group A)/non-experienced (Group B) examiner were also evaluated. Of all patients, 936 had LNM and 254 had hvLNM. The sensitivity/specificity/negative predictive value/accuracy of US in prediction of LNM and hvLNM were 27.9%/93.1%/61.07/63.68% and 63.8%/90.3%/94.7%/87.0% respectively. 1251 preoperative US were performed by group A, 558 LNM and 144 hvLNM were confirmed. 822 preoperative US were performed by group B, 378 LNM and 110 hvLNM were confirmed. Age, sex, tumor size and incidence of LNM/hvLNM showed no difference between group A and B. The sensitivity and specificity of US showed no difference in detection of LNM/hvLNM between group A and B (Sensitivity Of LNM A: 27.8% vs B: 28.0%, P = 0.941, Specificity of LNM A:93.9% vs B: 91.9%, P = 0.188; Sensitivity Of hvLNM A: 64.6% vs B: 62.7%, P = 0.793, Specificity of hvLNM A:90.6% vs B: 89.7%, P = 0.571). The US had a better accuracy in prediction of hvLNM than LNM and the result was not examiner-dependent. In patients without suspected LNM, the prevalence of hvLNM is very low.
Thyroid Cancer Friday Poster Case Report
Membranous nephropathy (MN) is a subtype of nephrotic syndrome (NS) that can be either primary, or secondary to various causes. Around 10% of adult MN are associated with malignancies, most commonly being solid tumors in the digestive tracts and lungs. However, NS secondary to papillary thyroid carcinoma (PTC) was not reported before. The prognosis of malignancy associated NS is generally poor. A 30-year-old male of 110 kg was diagnosed with severe NS three months before asymptomatic thyroid cancer of 1.5 cm was found by ultrasound. Renal biopsy showed MN, with prominent interstitial mononuclear infiltration, which was atypical for primary MN. Treatment for metastatic cancer was initiated first, given this was most likely secondary MN. This included total thyroidectomy with lymph node dissection and TSH suppression therapy. Surgical pathology confirmed PTC with capsule invasion and 17/85 LN metastasis. A diagnostic whole body scan showed diffuse metastasis in both lungs. Two courses of delayed radioactive 131I were given, 4 months after the pre-operative contrast CT and stabilization of acute kidney injury (AKI). The therapeutic regimen reduced tumor load to a minimal level, as indicated by the reduction in tumor marker Tg. A post-therapy 131I scan showed a clear neck region and resolution of lung metastasis. Interestingly, a concurrent resolution of NS was observed after 131I therapy - 24h urine protein (24hUPro) correlated well with Tumor load Tg reduction. The required dose of L-thyroxine for TSH suppression was up to 400 μg daily, while it dropped to 225 μg after nephropathy has resolved. We presented a rare case showing clinical and pathological association between NS and metastatic PTC. The secondary NS was severe, demonstrated by the heavy proteinuria, edema and AKI. Multiple therapeutic regimens were required. 18 months after diagnosis, patient had a clear neck ultrasound, and suppressed Tg decreased from 227.6 to 2.87 ng/ml. Meanwhile NS significantly improved - 24 hUPro level dropped from 30.74 g to 0.56 g daily. NS can potentially be associated with occlude papillary thyroid carcinoma. Early identification and proper treatment can significantly improve malignancy associated NS and overall patient survival.
Thyroid Cancer Friday Poster Clinical
The presence of central lymph node (LN) metastasis is recognized as an independent indicator for recurrence in papillary thyroid carcinoma (PTC). The 2015 American Thyroid Association (ATA) guidelines took the number of metastatic LNs (mLNs) into consideration when stratifying risks, without mentioning the appropriate number of dissected LNs (dLNs). We aimed to investigate the minimal acceptable number of dissected central LNs and its prognostic impact on pathological N1a (pN1a) PTC patients. A total of 177 pN1a PTC patients with ≤5 mLNs were enrolled in this study, all of whom were clinical N0 or N1a underwent total or near total thyroidectomy with central neck dissection and subsequent radioiodine ablation. After a mean follow-up of 28 months, response to initial therapy was evaluated as excellent, indeterminate, biochemical incomplete or structural incomplete response (ER, IDR, BIR or SIR). ER ≤ n and ER > n denote the ER rates calculated in patients divided by the number of dLNs (n). The cumulative probability curves of ER according to the number of dLNs and mLNs were estimated using the Kaplan-Meier method. Univariate and multivariate analyses were further performed to explore the indicator for ER. As the increase in n value, ER ≤1, ER ≤5 and ER ≤10 rose from 25.0%, 68.0% to 75.5%. ER ≤ n was lower than ER > n (all P < 0.05) till n rose to 10 or more (all P > 0.05). At the same number of mLNs, patients with ≥10 dLNs presented higher cumulative probability of ER than those with <10 dLNs (P < 0.05). In multivariate analysis, ≥10 dLNs (OR = 2.666, P = 0.036) was an independent indicator for ER in addition to preablative thyroglobulin (OR = 0.951, P = 0.002). In pN1a PTC patients with ≤5 mLNs, the number of dissected central LNs has prognostic impact on response to initial therapy. Ten or more dLNs seem to carry incremental value in achieving better response.
Thyroid Cancer Friday Poster Clinical
Lymph node metastasis commonly occurs in papillary thyroid carcinoma (PTC). The object of this study is to investigate the relationship between the rate of involved lymph node (LR) and distant metastasis (DM) in PTC, and its potential value in predicting the risk of DM. PTC patients were divided into two groups as M0 (121 cases) and M1 (41 cases) according to the presence of distant metastases or not. T-text andχ2 test were used to evaluate the statistical differences of basic clinicopathological features between the two groups; Multivariate analysis was used to quantify LR as an independent factor of DM. The ROC curve was employed to evaluate the clinical value of LR and LNs for predicting DM and optimal cut-off point respectively. The cumulative risk of distant metastasis curves according to the LR and LNs status were constructed with the Kaplan–Meier method, and the log rank test was used to compare these curves. There were no statistical differences in age and multifocality among two groups (p > 0.05), while gender, extrathyroidal invasion and tumor size were significantly different. LR is an independent indicator for predicting DM (OR = 1.133, p = 0.000). An increase of LR was significantly associated with DM and patients with more than 15 involved LNs had the steepest increasing pattern in the cumulative risk of DM compared with those involved LN less than 15 (p = 0.002). LR may be an independent predictive marker for distant metastases in PTC, and might be more potential when LNs was combined as an adjuvant factor.
Thyroid Cancer Friday Poster Clinical
Central neck dissection (CND) at the time of total thyroidectomy (TT) remains controversial in PTC. This meta-analysis aimed at finding the possible indications and comparing the impacts between patients who underwent TT alone and TT with CND. We searched Pubmed, Web of Science and Medline, and reference list for selected observational. From the identified studied, we extracted the number of individuals with or without observational subjects and used fixed/random-effects models for the meta-analyses. Seventeen studies including 3631 patients with TT alone and 3014 patients with TT+CND were eligible for inclusion. Studies were at a moderate risk of bias. A combination of thyroidectomy and neck lymph node dissection resulted in a higher incidence of multifocal compared with thyroidectomy only (OR = 1.23, 95% CI 1.08–1.40, P = 0.002), a higher incidence of temporary/ permanent hypoparathyroidism (OR = 2.26, 95% CI 1.89–2.70, P < 0.00001/ OR = 2.50, 95% CI 1.76–3.56, P < 0.00001), and a higher incidence of temporary vocal cord palsy (OR = 1.68, 95% CI 1.23–2.28, P = 0.0010), but no significant difference was observed between the TT and TT+CND according to the analysis results (OR = 1.57, 95% CI 1.92–2.68, P = 0.10). It is important to evaluate PTC patients carefully in the light of existing clinic examinations due to a great rate of complications and has no significant difference in recurrence rate between TT+CND and TT alone, while avoiding clinic biases and other surgery complications can derail treatment process in PTC.
Thyroid Cancer Friday Poster Case Report
Metastatic disease to the thyroid gland was historically thought to be quite uncommon. However, in recent years metastatic malignancies have been diagnosed with greater frequency making up about 1.5– 3% of thyroid cancers. Some hypothesize that the extraordinary blood flow and the high iodine load in the gland make it difficult for cancers to thrive. It has been speculated that diseased thyroid glands with nodules, autoimmune disease, or underlying malignancies have reduced blood flow and lower iodine content allowing malignancies to prosper. We present a case of a 65 year old Vietnamese lady who presented with a mass located in her left thigh in February 2015. MRI of the femur at presentation showed a 2.5 · 4.9 · 2.7 cm lesion in the lower third of the lateral left thigh. Incisional biopsy performed in April 2015 revealed a poorly differentiated sarcoma. CT chest in April 2015 did not show any obvious metastatic disease. However, a density in the right lobe of the thyroid was noted. Thyroid ultrasound in May 2015 showed a 1.5 cm hypoechoic lesion in the right lobe of the thyroid gland. The patient was treated with preoperative radiation therapy for her sarcoma. In August 2015 the patient underwent surgical resection of the left thigh mass. Pathology report described a high grade poorly differentiated pleiomorphic sarcoma. PET scan performed in November 2015 showed an intensely positive FDG avid mass in the left thyroid lobe, which had not been seen on prior imaging. FNAof the left thyroid mass revealed high grade sarcoma. CT neck from December 2015 exhibited a 5.2 · 3.1 cm lesion in the left lobe of the thyroid extending into the isthmus. Total thyroidectomy with central neck dissection revealed high grade metastatic sarcoma measuring 5 cm in greatest diameter with extensive lymphovascular permeation and incidental papillary thyroid carcinoma measuring 1.5 cm. Metastatic disease to the thyroid gland is quite unusual. When present, the most common cancers to metastasize to the thyroid are renal cell carcinoma followed by lung cancer, colorectal cancer, and breast cancer. When metastatic malignancy in the thyroid is found, further evaluation should be done to rule out underlying pathological thyroid disease.
Thyroid Cancer Friday Poster Clinical
TERT promoter mutation has been suggested as a potential prognostic marker for thyroid cancer and its association with BRAF V600E mutation was demonstrated. However, the effect of their coexistence on clinical outcomes of papillary thyroid cancer (PTC) has not yet been established. Studies of the association of BRAF V600E and TERT promoter mutations with clinicopathological features or recurrence/persistence of PTC were included from PubMed and Embase databases. Eight eligible articles incorporating 2,866 patients with PTC were included and 164 (median 6.4%) of these patients had coexistent BRAF V600E and TERT promoter mutations. Coexistence of the two mutations were far more strongly associated with high-risk clinicopathological features than either mutation alone, including older age (vs. BRAF V600E, mean difference [MD], 13.58; 95% CI, 11.34–15.82; vs. TERT, MD, 10.67; 95% CI, 6.27–15.06), greater portion of male patients (vs. BRAF V600E, odds ratio [OR], 2.14; 95% CI, 1.48–3.09; for TERT, OR for male, 3.56; 95% CI, 1.69–7.49), advanced TNM stage (vs. BRAF V600E, OR, 5.74; 95% CI, 3.77–8.75; vs. TERT, OR, 5.29; 95% CI, 2.47–11.33), and with higher risks of extrathyroidal extension (vs. BRAF V600E, OR, 6.08; 95% CI, 3.68–10.05; vs. TERT, OR, 6.80; 95% CI, 2.89–16.05), lymph node metastasis (vs. BRAF V600E, OR 1.74; 95% CI, 1.14–2.65), and distant metastasis (vs. BRAF V600E, OR, 13.67; 95% CI, 5.99–31.17). Moreover, the coexistence showed the highest risk of recurrence/persistence even after adjustment for age and gender (no mutations vs. the coexistence, hazard ratio [HR], 7.55; 95% CI, 4.35–13.09; vs. BRAF V600E, HR, 1.18; 95% CI, 0.36–3.93; vs. TERT, HR, 2.18; 95% CI, 0.96–4.92). The coexistence of BRAF V600E and TERT promoter mutations had a synergistic effect on clinical outcomes in PTC, whereas each mutation alone had a modest effect. Therefore, molecular testing of BRAF V600E and TERT promoter mutations together is useful in assessing risk stratification of PTC.
Thyroid Cancer Friday Poster Clinical
One rationale for administering I-131 after total thyroidectomy (TT) is to identify iodine-avid metastases on post-therapy scan. Postoperative thyroglobulin (Tg) levels often can predict the likelihood of distant metastases helping individualize treatment approaches, particularly in patients with low-risk primary tumors. Anti Thyroglobulin antibodies (anti Tg-Abs) interfere with Tg preventing this use in clinical practice. It is not clear if the presence of Tg-Abs predicts metastatic disease on post-therapy scan. In the present study we compare the post therapy scans in pathological low risk patients with and without anti Tg-Abs. This is a retrospective study at The Ohio State University Medical Center performed with IRB-approval. We included all patients with low risk well-differentiated Thyroid Cancer (DTC) who underwent TT and RAI between 1/1/2006 to 9/1/2015 with well-differentiated intrathyroidal T1 or T2 DTC. Pts with N1a staging were included if there were ≤5 nodes and all measured <2 mm with no nodal invasion. Patients with high-risk pathology variants, extensive vascular invasion, or more extensive nodal disease were excluded. The included patients were divided into group A with positive anti Tg-Abs and group B with negative anti Tg- Abs. The groups were matched using propensity score matching with logistic regression model including age, gender, histology, N stage, and anti Tg-Abs assay.37 patients were included in each group. In group A: Median age was 40 years (18–67), 86% female and 76% PTC. Median tumor size was 2 cm (0.2–3.8), 32% had multifocal disease, 16% were N1a and 4% had vascular invasion. Parameters in group B were not statistically different except for the presence of Hashimoto's thyroiditis, which was more common in group A (p < 0.001). Post therapy scan results were compared by chi-square test with 86% negative post therapy scan frequency in group A and 92% in group B without evidence of a difference (p = 0.45). In patients with low risk well differentiated thyroid cancer, the presence of anti-Tg Abs did not increase the likelihood of metastatic disease on post-therapy scan in this study population.
Thyroid Cancer Friday Poster Clinical
Medullary thyroid carcinomas (MTC) and parathyroid lesions (PT) may mimic thyroid follicular cells-derived nodules, which cause diagnostic difficulty on imaging and fine-needle aspiration cytology (FNAC). In fact, FNAC accurately detects only ∼50% of MTC and ∼30% of PT cases. Therefore, additional approaches are needed to complement cytologic evaluation and improve preoperative detection of these lesions. ThyroSeq v2 analysis detects mutations in 14 genes and 42 types of gene fusions using targeted amplification based NGS approach and performed on Ion Proton (Thermo Fisher Scientific). In addition, it detects expression profiles specific to MTC and PT which were initially validated in a set of 21 MTC, 10 PT, and 120 benign and malignant thyroid follicular cell-derived tissues.
In this study, the results of ThyroSeq v2 testing were reviewed in 4765 consecutive FNA specimens with indeterminate cytology (Bethesda categories III-V). ThyroSeq v2 revealed molecular profiles of MTC in 21 (0.4%) cases; 18 of which (86%) also had mutations in the RET (n = 15), KRAS (n = 2), and BRAF (n = 1) genes. Five of these specimens had a cytology classified as Bethesda-III; 6 as Bethesda-IV; and 10 as Bethesda-V. Surgical follow up was available in 13 cases and MTC was confirmed in all of them. One MTC with an atypical BRAF L597V mutation was negative for RET germline mutations. ThyroSeq v2 demonstrated gene expression profile of PT lesion in 26 (0.6%) of cases; 25 of which (96%) had no mutations identified. Cytology was classified as Bethesda-III in 20 and Bethesda-IV in 6. Surgical follow up was available in 10 cases and PT lesion was confirmed in all of them; including one unusual case with HRAS G12S mutation finally diagnosed as atypical PT adenoma.
Our study demonstrates that approximately 1% of thyroid FNA samples with indeterminate cytology reveal molecular profiles of MTC or PT lesions. ThyroSeq v2 test can accurately detect these lesions in FNAC samples, helping to guide patient management.
Thyroid Cancer Friday Poster Clinical
Mutational profiling of thyroid nodules using fine-needle aspiration (FNA) samples is a useful diagnostic tool. Multiple driver mutations are rarely found in differentiated thyroid cancer and may be associated with more aggressive tumors. However, the impact of genetic markers on pre-operative cancer prognostication using FNA samples has not been well studied. We analyzed a series of 63 nodules with multiple driver mutations (MDM) identified by ThyroSeq v2 56-gene panel in FNA (n = 50) or surgically excised nodules (n = 10), either prospectively or blinded to the final pathology diagnosis. Mutations were grouped as high risk for cancer (HR) mutations (e.g., BRAF V600E, RAS, TERT, PIK3CA, fusions) and low risk for cancer (LR) mutations (PTEN, EIF1AX). Aggressive tumor features were evaluated using clinical records and morphologic findings.
Among 63 nodules with MDM, 50 had two and 13 more than two mutations. Thirty-five (55%) had BRAF plus one or more HR mutation(s), 18 (29%) RAS plus HR mutation(s), 3 (5%) had two other co-occurring HR mutations, and 7 (11%) had a HR mutation co-existing with LR mutation(s). The most common co-occurring mutation was TERT (n = 43). Among 56 cases with BRAF or RAS and other co-occurring HR mutations, 55 (98%) were cancers and one tumor carrying RAS+TERT was benign. Among the 55 cancers, 51 (93%) had aggressive features including extrathyroidal extension (55%), vascular invasion (53%), lymph node macrometastasis (47%), poorly differentiated/anaplastic carcinoma areas (14%), or distant metastasis (8%). FNA cytology in these nodules was malignant in 51%, AUS (Bethesda III) in 21%, FN (Bethesda IV) in 21%, and SUSP (Bethesda V) in 7%. Among 7 samples with co-occurring HR and LR mutations, 4 (57%) were cancers, and 1 (17%) had aggressive features.
Among nodules with MDM, co-occurrence of HR mutations, typically BRAF+TERT or RAS+TERT, is associated with very high probability of cancer with aggressive features. However, co-occurrence of HR with LR mutations, such as RAS+EIF1AX, correlates with lower cancer risk and rare aggressive features. Preoperative detection of multiple high-risk mutations may be important to optimize surgical management of these patients.
Thyroid Cancer Friday Poster Clinical
Papillary thyroid cancer(PTC) is the most common type of thyroid cancer with excellent prognosis in a large number of patients. There is a lack of evidence on the behavior of PTC during pregnancy for determining the timing of surgery. The aim of this study is to evaluate the natural consequences of small PTC in pregnant women. This study included 13 patients with PTC who underwent delayed thyroid surgery because they were diagnosed as PTC just before or early periods of pregnancy. We evaluated the changes of PTCs with serial neck ultrasonography (US) before surgical treatment and clinical outcomes of the patients after surgery. Median tumor size of PTCs measured at initial diagnostic US was 0.82 cm (IQR 0.65 – 1.14) and 8 of 13 patients (62%) had microPTC (equal or less than 1cm). Median tumor size of PTCs after median 9.5 months of follow-up was 0.9 cm (IQR 0.72 – 1.12). There was a significant change in tumor size during the follow-up periods in Wilcoxon signed rank test (p = 0.046). However, there was no significant change in tumor size in 8 patients with microPTC (p = 0.26). During the follow up periods, there was no newly appeared lesion on thyroid glands and lateral cervical lymph node in the study subjects. Surgical extent for all patients was not changed in delayed surgery of 11.8 months (IQR 8.5 – 12.6). There was minimal increase of tumor size in patients with PTC during pregnancy. However, these changes were not significant in patients with microPTC. Delayed thyroid surgery could be generally accepted in patients with small PTC during pregnancy.
Thyroid Cancer Friday Poster Clinical
Stage, age, calcitonin and CEA doubling time, and biochemical cure (BCC) have been shown to be predictors of survival (OS) in patients with medullary thyroid carcinoma (MTC). However, large single institution studies of surgical outcomes and prognostic factors in patients with MTC are rare. Retrospective review of all patients with newly diagnosed sporadic MTC at a tertiary care institution between 1992 and 2014 who underwent thyroidectomy with central +/- lateral compartment neck dissection. Serum calcitonin and CEA were checked approximately 3 months following surgery. Percent decrease calcitonin or CEA was defined as: (preoperative minus postoperative)/preoperative. BCC defined as calcitonin <10.144 patients presented with relatively advanced disease: 55% T3-T4; 58% N1b;17% M1; 79% calcitonin >500 pg/ml. Median preoperative calcitonin and CEA were 1,638 and 39 respectively. Median follow-up after surgery was 3.9 years. Median postoperative calcitonin and CEA were 11 and 2 respectively. Fifty percent of patients achieved BCC with surgery; 33% had postoperative radiation therapy. Twenty percent of patients failed locoregionally following surgery, while 33% had or ultimately developed distant metastases. 5- and 10-year OS for the entire group were 76% and 62%, while 5- and 10-year OS among patients who achieved BCC were 92% and 81% respectively. Age (p = 0.016), T-stage (p = 0.008), N-stage (p = 0.003), M-stage (p < 0.001), postoperative calcitonin (p = 0.002), percent decrease in calcitonin (p = 0.019), and percent decrease in CEA (p = 0.001) were associated with OS. Percent decrease in CEA was the strongest biochemical predictor of OS. 5-year OS was 100% if postoperative percent decrease in CEA was > = 99% compared with 62% if <80% decrease (p = 0.002). Greater percent decrease in calcitonin was associated with locoregional recurrence (p = 0.001) and distant metastases (p < 0.001), while greater percent decrease in CEA was associated with distant metastases (p = 0.001). In a cohort of surgical patients with advanced stage MTC, postoperative calcitonin and CEA were predictive of OS, especially percent decrease in CEA postoperatively. Postoperative percent decrease in CEA may be a novel and valuable predictor of overall survival.
Thyroid Cancer Friday Poster Clinical
Afirma ® Gene Expression Classifier (GEC) determines malignancy risk for Bethesda System of Reporting Thyroid Cytopathology (BSRTC) III/IV (indeterminate) thyroid nodules, and has been validated in a blinded, multicenter, prospective clinical trial. everal authors have purported to examine the diagnostic accuracy of GEC in observational studies. We use a customized Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS2) tool to evaluate the quality of these studies. We searched Medline and EMBASE from January 1, 2010 until March 15, 2016, for original, full-length studies that evaluated the diagnostic accuracy of GEC. We developed a customized QUADAS2 tool consisting of signaling questions that evaluated 4 domains of each study: patient population, index test, reference standard diagnosis, and flow and timing. For each study, these questions will used by a panel of reviewers to identify whether methodologic flaws exist that introduce bias into the study's findings and/or limit the applicability of the study's conclusions. Each of the reviewers will independently apply the tool to each included study, and disagreements will be discussed in conference. Once reviewers agree on answers for all questions, these selected answers will be presented in tables according to the QUADAS2 format. We have identified 11 studies that have purported to evaluate diagnostic accuracy of GEC. Four panelists have been recruited to evaluate these studies using the customized QUADAS2 tool. In studies evaluated to date, the reviewers have identified potential sources of bias, including lack of follow-up of unoperated, GEC-benign subjects who are subsequently excluded from the calculation of specificity and negative predictive value (NPV). In a blinded, multi-center, prospective study in which all subjects were assigned reference standard diagnoses and included in the analysis, GEC was demonstrated to have a high sensitivity and NPV. Subsequent studies have not fully evaluated the diagnostic accuracy of the test as they have suffered from bias introduced by disproportionate exclusion of GEC-benign subjects from the analyses, and therefore do not substantially add to current understanding of the performance of the test.
Thyroid Cancer Friday Poster Clinical
BRAF mutation is identified in approximately 50% of papillary thyroid carcinoma, and is potentially associated with adverse clinical outcome. Our objectives were to correlate the presence of BRAF mutation in cases of well differentiated thyroid carcinoma, with clinicopathological factors in a South African cohort. This study evaluated 48 patients treated for differentiated thyroid carcinoma at Groote Schuur Hospital in Cape Town between 2009 and 2015. Immunohistochemistry was used to detect BRAF V600E mutation using anti-BRAF V600E (VE1) mouse monoclonal primary antibody from Ventana Medical Systems, USA. The pathology reports and hospital records were analysed to identify markers of adverse clinical outcome. The pathology features used as markers of more aggressive disease were: anaplastic de-differentiation, tall cell variant, extrathyroidal extention, presence of metastases. The clinical features analysed were age and gender of the patient. From the 48 samples, 27 were identified as papillary thyroid carcinoma (PTC) and 21 as follicular thyroid carcinoma. The results of the BRAF status in PTC patients were examined in relation to the following clinicopathological features: presence of vascular and capsular invasion, presence of metastasis and gender. Fischer's test was used to determine any statistically significant associations. For our cohort BRAF status was positive in 3 males and 8 females, signifying no association between BRAF status and gender (p value = 0.4027). Eight of the BRAF positive PTC cases had a presence of metastasis (p value = 0.0414) and no BRAF positive PTC case presented with capsular or vascular invasion. There is a correlation of BRAF V600E mutation with metastasis, however no statistically significant association was seen for BRAF and other clinicopathological features.
Thyroid Cancer Friday Poster Clinical
Papillary thyroid cancer (PTC) is the most frequent type of thyroid cancer. There are several subtypes of papillary thyroid cancer. We campare the most frequent 2 variants of our PTC patients in terms of clinical and pathological charecteristics.
We included 442 patients (344 women and 98 men) followed for PTC in our endocrinology department. The average age of patients was 47.5 ± 12 years old and they were followed for an average of 53.8 (8–372) months. Classical PTC makes up 75.3% of cases, 18.6% of cases were follicular variant (FvPTC), 2.3% were oncocytic and 1.8% were tall-cell variant. When we compare the follicular and classical variant tumor diameter were statistically higher in follicular group (15.8 mm (14.4–17) versus 21.8 mm (18–25) (p = 0.03). There were no significant difference between other clinical and laboratory charecteristics. Extrathyroidal extension and lymph node were statistically higher in classical PTC according to FvPTC. There were no difference in vascular or capsular invasion or multifocality. There were no difference in risk level of cancer, remission or reccurence rate between two groups. Under 45 years old remission or reccurence also were not different between two groups. Although, lymh node metastasis and extrathyroid extension were lower in follicular variant PTC, longterm outcome were smillar according to classical PTC variant.
Thyroid Cancer Friday Poster Clinical
Papillary thyroid cancer (PTC) has a favorable course but has a recurrence rate of up to 30% after the initial operation treatment. We investigated the risk factors of PTC recurrence in patients who underwent thyroidectomy and estimated the risk by using the risk stratification system suggested in the 2015 American Thyroid Association (ATA) guidelines. We retrospectively reviewed the medical records of 2252 patients with PTC who underwent definitive surgery in a single institution between March 2007 and February 2015. Recurrence was defined as a structurally identifiable disease that occurs after initial surgery. Univariate and multivariate analyses were performed to identify factors associated with recurrence-free survival. A correlation analysis was performed to compare the relationships with the updated risk stratification system. The median length of follow-up was 46 months (range, 0–112 months). Of the 2252 patients, 28 (1.24%) had locoregional or distant recurrences. The univariate analysis revealed that PTC recurrence was associated with age, bilaterality, multifocality, tumor size, extrathyroidal extension, lateral neck node metastasis, whole body scan (WBS) findings after radioactive iodine (RAI) therapy, and stimulation thyroglobulin level (p < 0.05 each). Age (p = 0.001) and WBS findings after RAI (p = 0.007) remained independent predictive variables of recurrence in the multivariate analysis. The updated risk stratification system according to the 2015 ATA guidelines had no impact on recurrence. Age and WBS findings after RAI therapy are important predictive factors of postoperative recurrence of PTC. The risk factors identified in this study will be useful in choosing the appropriate intensity of treatment strategies and in the long-term surveillance of PTC patients.
Thyroid Cancer Friday Poster Clinical
To study application of Minilap in laparoscope thyroidectomy and central compartment neck dissection through bilateral breast approach. Totally 145 cases of papillary thyroid carcinoma patients perform the Laparoscope Thyroidectomy and Central Compartment Neck Dissection in Fujian Medical University Union Hospital were randomized to Minilap assisted Laparoscope group (ML group, n = 81) and conventional Laparoscope group (CL group, n = 64). The average age of the patients was 35.9 and 11 patients were male. All patients underwent Thyroidectomy and Central Compartment Neck Dissection through bilateral breast approach, the ML group additional used the MiniLap-assisted in operation. Seven kinds of skills for the utility Minilap in laparoscope thyroidectomy were demonstrated. The operative time, postoperative complications and cosmetic results were analyzed by t test and χ2 test. There were three states of Minilap and seven kinds of skills for the utility Minilap in laparoscope thyroidectomy. Operation time will be shortening by using these techniques. The operation time of thyroid gland in ML and CL Group was (42 ± 7) min and (31 ± 7) min (t = 9.082, P = 0.000), respectively. The operation time of central neck dissection was (33 ± 6) min and (26 ± 3) min (t = 9.050, P = 0.000), respectively. There were 4 cases occurs transient recurrent laryngeal nerve paralysis in CL group and no case occur in ML group (χ2 = 5.206, P = 0.036). There was no significant different in other postoperative complications and cosmetic results. Laparoscope thyroidectomy and central neck dissection using bilateral breast approach and MiniLap assisted technique is a safe and reliable approach, with high cosmetic effect. assisted of MiniLap devices can shorten the operation time while no significant increase trauma in patients, it will make laparoscope thyroid surgery easier to promote.
Thyroid Cancer Friday Poster Clinical
It is currently recommended that PET diagnosed thyroid incidentalomas undergo prompt evaluation due to a high risk of underlying malignancy. The aim of this study was to review physician management and outcomes for PET diagnosed thyroid incidentalomas in British Columbia (BC), Canada. All PET scans performed in BC, for non-head and neck indications, between 2011 and 2014 were reviewed, and patients with incidental thyroid findings were identified. Patient characteristics, investigations, and management were reviewed from patient records. Surveys were sent to the physician who ordered the PET scans for patients with limited records available.899 of 19322 PET scans (4.65%) identified focal or diffuse thyroid findings in 802 patients. We were able to obtain adequate data from chart review and mail out surveys on 726 patients. In those with diffuse findings (n = 286), 32.4% (n = 134) were included on the PET scan report impression and 4.86% (n = 28) underwent an ultrasound (US) or fine needle aspiration biopsy (FNAB). Of those cases investigated, 10.7% (n = 3) were found to have cancer. In patients with focal findings (n = 440), 85.7% (n = 377) were included on the PET scan report impression and 46.1% (n = 203) underwent an US or FNAB. Of those cases investigated, 21.2% (n = 43) were found to have cancer. Analysis of patient and PET scan report characteristics suggested that inclusion of the thyroid incidentaloma finding in the PET report impression, and recommending further workup within the PET report, are significant factors in predicting further evaluation (p-value <0.05). For focal findings, SUVmax and having undergone multiple PET scans with similar findings are additional factors associated with nodule work up (p-value <0.05). Patients with focal incidental thyroid findings diagnosed by PET scan are being under-investigated in BC. The most significant factors associated with undergoing further thyroid incidentaloma workup are actually PET scan report related. We are currently developing a reporting protocol that will improve the management of PET diagnosed thyroid incidentalomas in BC.
Thyroid Cancer Friday Poster Clinical
The Bethesda System for Reporting Thyroid Cytopathology (BSRTC) allows for standardization of terminology and provides treatment recommendations based upon the diagnostic category and its associated cancer risk. The influence of patient age and gender on BSRTC cancer risk estimation has received limited study. The aim of this study was to determine if patient age and/or gender can significantly alter the risk of thyroid malignancy in the BSRTC diagnostic categories. A retrospective pathology and case review of 291 sequential cases that underwent thyroid nodule fine needle aspiration biopsy (FNAB) and subsequent surgery at a single center was carried out. Cases were grouped according to age (older versus younger than 45 years) and gender. The cancer risk was calculated for each BSRTC category group. A p-value <0.05 was statistically significant. The study population was composed of 291 patients (227 females and 64 males). Histopathology diagnosed cancer in 113 cases (39%). The cancer risk was significantly increased in cases with a BSRTC diagnosis of Atypia of Undetermined Significance (AUS) in patients younger than 45 years of age (81.9% vs 17.8 %, p = 0.0322). Patient gender did not significantly influence BRSTC diagnostic category cancer risk. A BSRTC AUS diagnosis is associated with an increased cancer risk in younger patients, and thus age should be considered during thyroid nodule work-up and when planning the extent of surgical treatment.
Thyroid Cancer Friday Poster Clinical
Preservation of quality of life (QoL) is an important therapeutic goal in patients with thyroid disease. The purpose of this study was to assess the impact of thyroidectomy on QoL comparing to the general population while controlling the effect with propensity score matching. QoL was retrospectively investigated in the patient who underwent thyroid surgery with thyroid disease and the control who visited the health screening center. The generic Short Form 12 questionnaire (SF-12) was adoped to measure the QoL. Mental component score (MCS) and physical component scores (PCS) were expressed as numeric values in SF-12. The electronic database (SPSS ver. 22) was used for statistical analysis with 95% confidence intervals. QoL was retrospectively investigated in 105 patients with thyroid disease and 420 controls who visited the health screening center. Mean age of the patients and control were 49.18 ± 12.6 years and 49.9 ± 13.1 years. The radio of male to female was 15.0: 85.0%. On univariate analysis, two subtypes of physical component score in SF-12 are significantly different between patients and control group: Role Physical (SF4, 38.5% vs. 26.0%, P = 0.011) and Role Physical (SF5, 35.2% vs. 20.2%, P < 0.001) while three subtypes of mental component score in SF-12 were found in the following domains: Mental Health (SF11, 3.07 ± 1.49 vs. 2.61 ± 1.32, P = 0.002), Role Emotional (SF7, 33.7% vs. 20.7%, P = 0.005) and Social Functioning (SF12, 2.98 ± 1.56 vs. 2.62 ± 1.50, p = 0.03). Thyroidectomy reduces a QoL in comparison to a healthy population considering both physical and mental component. Psychiatric consultation or supportive care may be helpful for the patients with low value of mental scores.
Thyroid Cancer Friday Poster Clinical
The role of iodine in papillary thyroid cancer (PTC) risk has been suggested but not definitively established. The purpose of this study is to compare the iodine status of a PTC group and a healthy population cohort by means of median urinary iodine levels (MUI) and food frequency questionnaire (FFQ) scores. From March to December 2015, consecutive patients who received thyroidectomy at a single tertiary referral hospital were enrolled. Preoperative fasting urine was obtained on the morning of operation through which MUI and creatinine adjusted MUI were obtained; FFQ scores were calculated for the 14 most commonly consumed iodine rich food items in the Korean diet. In the same manner, MUI, creatinine adjusted MUI and FFQ scores were obtained from subjects of a community based health screening cohort with no known history of thyroid disease. The same sub-analysis was done between BRAF V600E positive and negative patients within the PTC group. There were a total of 210 patients in the PTC group and 90 normal subjects in the healthy control group. From the PTC group, the BRAF V600E mutational status was reported in 191 (91.0%) patients, among which 169 (88.5%) were positive and 22 (11.5%) negative. For the PTC group and the healthy control group, the MUI was 786.0μg/L and 112μg/L (p < 0.001), the creatinine adjusted MUI was 884.6μg/g creatinine and 182μg/g creatinine (p < 0.001), and the mean FFQ score was 66.2 ± 17.5 (range, 13–114) and 54.6 ± 21.5 (range, 16–134) (p < 0.001) respectively.
In the subgroup analysis of the BRAF V600E positive and negative group, the MUI was 884μg/L and 792.9μg/L (p = 0.841), the creatinine adjusted MUI was 953.5 μg/g creatinine and 948 μg/g creatinine (p = 0.841), and the mean FFQ score was 65.7 ± 17.2 (range, 13–114) and 66.8 ± 19.3 (range, 24–92) (p = 0.746) respectively. This study demonstrated a significant difference in iodine status between PTC patients and healthy control group, although not according to BRAF V600E mutational status within the PTC group. Such correlation suggests an active role of iodine in PTC occurrence. Therefore further research in order to elucidate the clinical implications is necessary.
Thyroid Cancer Friday Poster Case Report
There is an abundance of data published on the most common thyroid malignancies including papillary thyroid carcinoma, follicular thyroid carcinoma and medullary thyroid carcinoma; however, there is significantly less published regarding the uncommon thyroid malignancies that may be encountered in a clinician's practice. We present three cases of unusual thyroid malignancies including primary mucoepidermoid carcinoma of the thyroid, primary squamous cell carcinoma of the thyroid and carcinoma showing thymus-like differentiation of the thyroid (CASTLE). Case one presented as a recurrence in a prior surgical bed following total thyroidectomy in a 70 year old female approximately three months after her initial surgery. Fine needle aspiration demonstrated poorly differentiated carcinoma but was non-diagnostic. After resection final pathology demonstrated poorly differentiated mucoepidermoid carcinoma that was TTF-1 and Pax-8 positive but thyroglobulin negative with a small focus of metastatic papillary thyroid carcinoma in a regional lymph node. Case two presented as a 74 year old female with a one year history of dysphonia and episodes of aspiration pneumonia, found to have a unilateral vocal fold paralysis and right thyroid lobe mass. Fine needle aspiration demonstrated poorly differentiated carcinoma but was non-diagnostic. After resection final pathology demonstrated squamous cell carcinoma. Case three presented as a 43 year old male with a two year history of dysphonia and right neck mass, found to have a right vocal fold paralysis on exam. Fine needle aspiration demonstrated poorly differentiated thyroid carcinoma that was non-diagnostic. After resection final pathology demonstrated immunohistochemical staining consistent with CASTLE including staining positive for AE1/AE3, CD5, p63, BCL-2, CD117 and synaptophysin. Understanding the common clinical presenation, anatomic pathology evaluation and treatment is helpful in the identification and evaluation of unusal thyroid malignancies. Given the relative paucity of clinical data published for each of these primary thyroid pathologies, these case reports represent an important contribution to the current fund of knowledge available to clinicians.
Thyroid Cancer Friday Poster Case Report
Subacute thyroiditis has rarely been reported to coexist with thyroid carcinomas, occurring in less than 1% of cases. Hypoechoic changes seen in thyroiditis on ultrasound makes it difficult to differentiate nodular carcinomas from inflammatory lesions, complicating and delaying diagnosis. Repeat neck ultrasound after resolution of thyroiditis is needed in such cases to reveal underlying suspicious lesions. We present a case of a 31 year old Nepalese woman who presented with painful enlargement of the anterior neck. She first noticed neck swelling during pregnancy 12 months prior to presentation, at which time, however, no abnormality in thyroid function tests was apparent. Postpartum, she noted progressive neck swelling. In the week prior to admission she reported subjective fevers, odynophagia, dysphagia and dyspnea. Physical exam was remarkable for significant enlargement of the thyroid gland and severe neck tenderness. Initial work-up revealed TSH of 0.05 mIU/mL, free T4 of 1.5 ng/dL, and T3 of 2.9 pg/mL, while thyroid peroxidase antibody, thyroid stimulating IgG and thyrotropin receptor antibody were negative. Neck ultrasound displayed a 5.6 × 3.8 × 5.5 cm mostly solid partially cystic nodule in the isthmus without internal vascularity or calcifications, and a 6 mm hypoechoic solid nodule without internal vascularity or calcifications in the right lobe. She was treated for thyrotoxicosis with steroids and thyroid aspiration was performed with significant symptomatic improvement, albeit temporary. After discharge, symptoms of compression recurred and progressed eventually leading to thyroidectomy. Pathology showed multifocal microscopic papillary thyroid carcinoma involving the right and left lobes. Coexisting thyroiditis and papillary thyroid carcinoma is uncommon. Additionally the diagnosis can be difficult. Acute inflammatory changes seen in subacute thyroiditis can obscure sonographic evidence of underlying papillary thyroid cancer. Repeat thyroid ultrasound after resolution of thyroiditis is sometimes necessary to diagnose underlying thyroid malignancy.
Thyroid Cancer Friday Poster Case Report
The risk of papillary thyroid carcinoma (PTC) in Graves' disease is increased, with an overall incidence ranging from 7% to 33.7%. Thyroid nodules are found in up to 25% of patients with Graves' disease. The risk of malignancy in hyperfunctioning thyroid nodules is low with an estimated prevalence of 3.1%. We present a rare case of PTC within a hyperfunctioning thyroid nodule in a patient with Graves' disease. A 65 year-old female presented with weight loss, tremors, palpitations and shortness of breath. An asymmetric goiter was discovered on physical exam. Her labs were consistent with hyperthyroidism: TSH <0.005 uIU/mL (0.45–4.5), FT4 3.98 ng/dL (0.82–1.77), Total T3 385 ng/dL (71–180), TPO antibody 272I U/mL (0–34), TSI 309% (0–139) and thyroglobulin antibody <1I U/mL (0–0.9). A thyroid uptake and scan showed an increased uptake (66% at 24 hours) with possibility of a large hyperfunctioning nodule in the right hemithyroid and relative suppression of the left hemithyroid. The patient was diagnosed with Graves' disease. Treatment with Methimazole was initiated with significant improvement in symptoms. She underwent a thyroid ultrasound, which revealed multiple punctate calcifications within the hyperfunctioning right thyroid nodule. An FNA was performed and pathology was diagnostic for PTC (Bethesda class VI). The patient subsequently underwent a total thyroidectomy. Surgical pathology demonstrated a 1.3 cm classic PTC and diffuse follicular hyperplasia with lymphocytic thyroiditis consistent with Graves' disease. The risk of PTC in patients with Graves' disease is increased, however the risk of malignancy in hyperfunctioning thyroid nodules is low. Our case raises the question of whether occult thyroid carcinomas have been missed in patients with Graves' disease due to the assumption that hot nodules are usually benign. Thyroid ultrasounds should be performed in Graves' patients with suspected thyroid nodules, patients with cervical lymphadenopathy and patients with cold areas on thyroid uptake and scan. Thyroid FNA of cold nodules and hot nodules with suspicious characteristics on ultrasound, such as microcalcifications, irregular borders and vascularity should be performed to rule out thyroid carcinoma.
Thyroid Cancer Friday Poster Case Report
Median survival in ATC is 3.9 months, regardless of treatment. Small numbers ATC response to treatment exist in the literature due to the rarity of the condition and rapid progression of the disease. We report a single patient with ATC subjected to conventional therapy followed by Lenvatinib who has experienced 42 month disease free progression despite the presence of persistent surgically unresectable disease. A 67 Year old male presented in 12/12 with a rapidly expanding right thyroid and neck mass. Thyroidectomy and central compartment dissection confirmed ATC, 5.4 cm with positive nodes. (pT4N1M0). Pathology was independently confirmed. Right neck dissection revealed no additional metastatic nodes. PET CT revealed no tumor activity. The patient underwent 66GY EBRT in 13 fractions and chemotherapy with carboplat and taxol through 5/13. Periodic followup by PET, CT, PE, and US showed right pharyngeal activity with no identifiable disease that resolved by 12/13. Left level 6 PET activity was noted in 11/14 that led to left neck dissection with no disease identified, but persistent pet positivity in a lower left level 6 sonographically malignant node. Additional PET positive R mediastinal activity was seen in 8/15 and biopsy proven recurrence in the neck was confirmed 10/15. Repeat surgical attempt at resection deemed this unresectable disease. The patient declined clinical study referral and began Lenvatinib in 12/15. He experienced mild hand foot, stomatitis, and hypertensive response, all responding to standard management. PET in 5/16 shows regression of mediastinal activity and stable left neck activity. We report a single case of metastatic ATC with prolonged functional survival after use of a newer agent. Further evaluation of the agent in similar cases may be warrented. Despite the generally dismal prognosis of ATC, scattered reports of response to newer therapies exist. We report 42 month progression free survival of a single case subjected to conventional therapy followed by institution of a newer agent. At this time the patient continues to do well with good quality of life and remains functional. Additional study of novel agents may offer hope for improved outcomes in this disease.
Thyroid Cancer Friday Poster Case Report
Papillary Thyroid Cancer (PTC) is rarely associated with distant metastases. We report a highly unusual clinically presentation of PTC with cervical lymph node and uterine metastases. A 69 year old female presented with post menopausal bleeding (PMB). She was otherwise well with no significant medical history or regular medications. Her menopause was age 51 and she reported no family history of thyroid disease. An endometrial polyp was identified as the cause of her PMB and removed. In addition during her clinical examination a goitre was noted and radiology demonstrated a large 10 × 6 × 5 cm heterogeneous complex solid-cystic retrosternal mass arising in the left anterior triangle replacing the left thyroid gland with a normal appearing right thyroid gland. There were multiple subcentimetre bilateral cervical lymph nodes present. The mediastinum, abdomen and pelvis were otherwise normal. A bone scan was negative.
The endometrial biopsy showed strong TTF-1 expression, was Pax 8 positive and Thyroglobulin negative. Surprisingly the morphology demonstrated features of PTC with nuclear clearing, overlap and with a rare intranuclear inclusion. BRAF V600 Mutation was negative. She underwent a core biopsy of the mediastinal mass which was similar to the endometrial polyp morphologically and immunohistochemically, which favoured a primary papillary thyroid carcinoma. The mediastinal mass demonstrated a tubulo-papillary and tubular growth pattern. The nuclei showed cytoplasmic clearing and overlap. Intranuclear cytoplasmic inclusions were present. CK7 & TTF-1 positive, mCEA was negative.
She subsequently underwent a total thyroidectomy, sternotomy and left neck dissection. Surgical specimens demonstrated PTC, with focal `tall cell' features and lymphovascular invasion. Lymph node involvement was demonstrated at Level (2,3,4)[2/14 nodes] and Level (5,6)[1/22 nodes]. Thymus tissue was unremarkable. It was graded as pT3N1b. She is currently scheduled for a total hysterectomy and bilateral salpingo oophorectomy and radioactive iodine therapyThis is an extremely unusual presentation but overall the morphology and immunohistochemistry point towards a primary thyroid lesion metastatic to the uterus.
Thyroid Cancer Friday Poster Case Report
Hurthle cell carcinoma accounts for 3% of all thyroid malignancies. If distant metastases develop then the most common site is the lung, followed by bone, with other sites being much rarer. When liver metastases are present, they are almost always multiple or diffuse, and are usually accompanied by metastases at other sites. Here we present a rare case of Hurthle cell carcinoma of the thyroid, with a solitary liver metastasis. A 62 year old male underwent total thyroidectomy with final pathology demonstrating a 7.4 cm Hurthle cell carcinoma, with breached capsule and vascular space invasion (6 vessels). His postoperative thyroglobulin (Tg) level was at 40 ng/ml. He received 152 mCi I-131 with recombinant TSH stimulation. A post-treatment scan only showed persistent radioiodine activity in the right thyroid bed. Over the following 7 months, his Tg gradually increased to 318.1 ng/ml. A neck ultrasound, neck CT, chest CT, and brain MRI were unremarkable. A PET-CT at 4 months postop was unremarkable. A CT abdomen and pelvis at 8 months postop demonstrated a new solitary hypodense lesion in the posterior right lobe of the liver. This was FDG-avid on follow up PET-CT, and it was also confirmed with an abdominal MRI. Overall the lesion was consistent with a metastatic deposit. He underwent simultaneous laparoscopic core biopsy and microwave ablation of the liver mass. The liver biopsy confirmed carcinoma metastatic to the liver, compatible with thyroid gland origin. One month later, Tg dropped to 0.6 ng/ml. Abdominal MRI did not reveal residual or recurrent tumor. His Tg has slowly increased to 1.3 ng/ml at 9 month follow up after the ablation of the liver met without additional structural disease to date. We present a rare case of Hurthle cell carcinoma of the thyroid with a solitary liver metastasis. There has only been one similar case described in the literature. We recommend extensive cross-sectional imaging to identify structural disease in patients with very high Tg such as our patient, with surgical management if a solitary liver metastasis if identified. We present a rare case of Hurthle cell carcinoma of the thyroid with a solitary liver metastasis.
Thyroid Cancer Friday Poster Case Report
Association between thyroid cancer and familial adenomatous polyposis (FAP) is known but rare. We report a case of 11 cm of papillary thyroid cancer in a patient with a history of FAP.53 year old female with history of FAP s/p prophylactic colectomy presented with abdominal pain. Evaluation revealed benign ovarian tumor and endometrial cancer. Pre-operative evaluation revealed superior mediastinal mass causing rightward tracheal deviation on chest x-ray. CT scan revealed 11 cm substernal left thyroid mass compressing and shifting the trachea to the right. FNA of this mass revealed papillary thyroid cancer. Her family history is positive for multiple members with h/o colon cancer on the maternal side. She underwent total thyroidectomy without complications. Pathology showed papillary carcinoma, cribriform-morular variant. There was no lymphovascular invasion or extrathyroidal extension. Cribriform morular variant is a very rare subtype of papillary thyroid carcinoma that accounts for <1 in 500 cases of all papillary thyroid carcinoma. Typical patients are females in their second decade of life. They are usually bilateral and multifocal. About 90% exhibit characteristic histopathology of cribriform pattern with solid areas, and a spindle cell component associated with marked fibrosis and are B-Catenin positive. Cribriform-morular PTC is generally regarded as a low grade tumor with similar prognosis as classical PTC. The association between papillary thyroid carcinoma and FAP warrants diagnostic screening at regular intervals with annual neck exam and if abnormal findings on exam, ultrasonography and fine-needle aspiration biopsy should be considered. When thyroid carcinoma is found total thyroidectomy should be considered because of the tumor's high likelihood of being multifocal.
Thyroid Cancer Friday Poster Case Report
Due to the advances in medical technology, DNA-based screening of MEN2A now requires only a blood sample. However, recognizing the features of MEN2A can be the bigger challenge in this era of fragmented care. A 28-year-old lady with a history of Nodular Thyroid presented to our clinic after her sister was diagnosed with MEN2A. Interestingly, seven years earlier a Fine Needle Aspiration Biopsy (FNA) done at another institution revealed colloid and follicular cells. The patient had no pallor, palpitations, flushing or diarrhea. Delving into the family history we found that the patient's sister was diagnosed with Medullary Thyroid Cancer (MTC) and Bilateral Pheochromocytomas, prompting the diagnosis of MEN2A. Her mother had a Thyroidectomy in Poland in the 1980's for MTC and was lost to follow up.
Examination was unremarkable with a nodular thyroid, and no lymphadenopathy. Laboratory testing revealed an elevated Calcitonin of 53.3 pg/mL (< 5 pg/mL). Ionized calcium and Intact PTH were elevated too. RET oncogene test detected P.C634R mutation.
She underwent Total Thyroidectomy and Parathyroidectomy. Her mother had known Adrenal “Incidentalomas” which we diagnosed as Pheochromocytomas. MTC may occur sporadically, or as a part of inherited syndromes i.e. Familial MTC, MEN 2A and MEN 2B. Germ line mutations of RET proto-oncogene are used to screen for Hereditary MTC which allows for early prophylactic Thyroidectomies. Genotype-Phenotype correlation has been described between specific codon mutations. C634R mutation was associated with early onset of disease, increased penetrance, and more distant metastases. It is remarkable that the women we saw carried such an aggressive mutation undetected for so long.
Increasingly mobile families with several family members in different countries, crumbling relationships and having fragmented care with multiple providers are some of the barriers to recognizing the syndrome of MEN2A. In the era of sophisticated Electronic Medical Records which unfortunately do not communicate with one another, and busy outpatient practices, taking the time to get more information, communicating with other providers involved, and having a high degree of suspicion is of utmost importance.
Thyroid Hormone Action Friday Poster Clinical
Prior pre-clinical and clinical studies indicate that lowering serum free thyroxine was associated with extended survival in patients with terminal cancers. The objective of this study was (a) to substitute the less pro-oncogenic L-triiodothyronine [T3] for L-thyroxine [T4] as replacement therapy and monitor outcomes in hypothyroid metastatic sarcoma patients.(i) Patients:
All patients had Stage 4 soft tissue sarcoma [SSS] malignant disease deemed incurable by conventional means. Serum FT4 and TSH were serially monitored to enable adjustments to drug therapy. Patients were converted abruptly from L-T4 (50–88 mcg daily). After a week ‘washout’ period, exogenous L-T3 15–37.5 mcg/day was begun in two daily divided doses. In all patients FT4 levels had declined below the reference range to a nadir by 4 weeks. Survival is calculated from date of of L-T4 cessation. RESULTS M:F ratio 8:5, Median age 65 [range 31–70].
TUMOR TYPES: Liposarcoma −1, Leiomyosarcoma Uterus - 5, Synovial sarcoma - 2, Undifferentiated sarcoma - 2, Fibrosarcoma −1.
RESPONSE: 7 Patients CR, 5 had SD, 6 had PR.
Median follow up is 10 months [4–60 months], Median Survival is not yet reached. One patient [Synovial sarcoma] is disease-free at 60 months. In metastatic sarcoma survival may be prolonged in L-T3 supplemented patients.
Thyroid Hormone Action Friday Poster Clinical
Increasingly authorities are adopting stricter potency specifications for levothyroxine, 95–105% of the label claim over the whole shelf-life since small changes in levothyroxine dose can lead to significant clinical effects. A levothyroxine sodium product (brands: Euthyrox, Eutirox, Lévothyrox, Novothyrox) has recently been reformulated to meet these specifications. Two studies were performed to ensure bioequivalence to the currently marketed formulation and dosage form proportionality of the new formulation. Two pharmacokinetic trials were conducted. The bioequivalence study, a single-dose, two-period, two-sequence crossover study, compared the highest dosage strength of 200 μg at a total dose of 600 μg. The dosage form proportionality study, a three period, six-sequence crossover study, compared three tablet strengths (50 μg, 100 μg and 200 μg) of the new formulation at a total dose of 600 μg. Primary outcomes of both trials were AUC and Cmax of T4 in plasma. In the bioequivalence study, the geometric LS mean ratio of the baseline-corrected AUC0-72,adj was 99.3% (90% confidence interval (CI): 95.6–103.2) and of baseline-corrected Cmax,adj was 101.7% (90% CI: 98.8–104.6). Bioequivalence can therefore be established as the 90% CI lies within the predefined range of 90–111%. In the dosage form proportionality study, pairwise comparisons ranged from 99.3–104.8% and all 95% CI were within the pre-defined CI range of 80–125%. Therefore the three dose strengths were found to be dosage form proportional. The new formulation of levothyroxine that meets the most stringent potency specification guidelines is bioequivalent to the current formulation and shows dosage form proportionality. The new formulation will provide a more precise dose for each patient according to the medical need. Thus, control of thyroid hormone levels will be improved, leading to improved safety in the use of levothyroxine.
Thyroid Hormone Action Friday Poster Translational
VK0214 is a small molecule prodrug of a potent thyroid receptor beta (TRb) agonist. VK0214 was evaluated in a mouse model of X-linked adrenoleukodystrophy (X-ALD) to determine its effect on very long chain fatty acids (VLCFA) in blood and tissues.
X-ALD is a recessive X-linked genetic disorder characterized by adrenocortical insufficiency and deterioration of myelin insulating nerves and spinal cord. X-ALD results from mutations in the ABCD1 gene on Xq28, which is responsible for encoding adrenoleukodystrophy protein (ALDP). In healthy individuals ALDP functions to transport VLCFAs into peroxisomes for degradation. ABCD1 mutations lead to impaired ALDP function, resulting in VLCFA accumulation and myelin damage characteristic of X-ALD. Expression of the compensatory transporter ABCD2 has previously been shown to increase b-oxidation capacity and reduce VLCFA in various models. The thyroid hormone receptor-b is a key regulator of ABCD2 expression, thus providing a target for pharmacologic intervention and a potential approach X-ALD therapy. The objectives of this study were to determine the ability of VK0214, a small molecule prodrug of a potent TRb agonist, to reduce VLCFA levels vs. controls in an in-vivo model of X-ALD.
A previously-described ABCD1 knockout mouse model was utilized to study the effects of VK0214 on VLCFAs. Cohorts of 12 male hemizygotes, at least six weeks of age, received daily intraperitoneal injections of 3 mg/kg VK0214, 10 mg/kg VK0214, or vehicle for six weeks. Blood samples were evaluated from time points at weeks 0, 2, 4, and 6. VLCFAs of varying chain lengths were analyzed by LC-MS for plasma lysophosphatidyl choline (lyso-pc), and tissue samples were collected for evaluation of VLCFA and ABCD2 expression. Results of several cohorts will be presented. Preliminary data suggest VK0214 modulates VLCFA levels in a mouse model of X-ALD. Evaluations of dose-response and tissue-specific alterations in ABCD2 expression are ongoing. Preparations for studies in patients with X-ALD are underway.
Thyroid Hormone Action Friday Poster Case Report
Thyrotoxicosis by itself has been associated with hypercalcemia presumably because of increased bone turnover. Here we present a case of moderate hypercalcemia in a patient with thyrotoxicosis.18 year old male with no significant PMH presented to the hospital because of vomiting, palpitations, chest pain and shortness of breath. Symptoms were also pertinent for loss of weight, agitation and nervousness. Exam showed tachycardia, diffuse enlargement of the thyroid, tremors, brisk reflexes and warm and sweaty palms. Labs showed an undetectable TSH and elevated free t4 of >6.99 ng/dl and free t3 of >30 pg/ml. He was also found to have elevated corrected calcium of 12.6 mg/dl. Other labs showed an appropriately low PTH 9.6 pg/ml and slightly low vit D 25 OH 27 ng/ml. TSI Ab was also elevated. He was started on methimazole and propranolol and calcium declined after starting treatment. He was reevaluated 4 weeks after discharge at which time calcium levels had normalized. The most common cause of hypercalcemia in thyrotoxicosis is concurrent primary hyperparathyroidism. In 15%–20% of cases however, alterations of calcium metabolism are related to the thyrotoxicosis alone. Our patient had hypercalcemia associated with thyrotoxicosis alone as indicated by low PTH and resolution of hypercalcemia with treatment of thyrotoxicosis. Hypercalcemia in thyrotoxicosis is typically asymptomatic, with calcium levels rarely exceeding 12 mg/dl; in our case immobilization and dehydration were likely to also have played a part. The proposed mechanism of hypercalcemia is enhanced bone resorption, unrelated to the PTH levels. High circulating levels of interleukin (IL)-6 seen in hyperthyroidism stimulate bone osteoclastic activity and alter the osteoblast-osteoclast coupling. Acute treatment requires aggressive hydration and may include administration of calcitonin and bisphosphonates. The definitive treatment for hypercalcemia in thyrotoxicosis is correction of underlying thyroid disease. Hypercalcemia can be solely due to elevated thyroid hormone levels and does normalize with treatment of the underlying disease. However, hyperparathyroidism needs to be ruled out since it is a more frequent cause of hypercalcemia than thyrotoxicosis.
Thyroid Hormone Metabolism & Regulation Friday Poster Clinical
A recent study showed that supplementation with 4 g/d myoinositol (MYO) improved metabolic syndrome in postmenopausal women (PMW) (Climateric, 2012). Because there is literature on the direct relationship between insulinemia and serum TSH, we wished to ascertain, in euthyroid PMW (TSH <3 mU/L with normal FT4 and FT3, and negative thyroid antibodies), whether a 4 g/d MYO supplementation for 6 months changed serum insulin (μU/ml), TSH (mU/L), FT4 (pg/ml) and FT3 (pg/ml). Sixteen PMW were supplemented and sampled as said above. The post vs pretreatment (baseline) difference for each index was analyzed in absolute terms and as % change, in either case with the Wilcoxon test. Relationships between any two indices were analyzed with the Spearman test. Of the 16 initially PMW, 14 completed the study. Their age was 48.7 ± 1.5 years, and serum FSH 73.1 ± 10.9 mU/L, which remained unchanged after 6 months (73.4 ± 9.2). At baseline vs 6 months, serum levels were 7.6 ± 6.5 vs 4.9 ± 2.4 (insulin; −35.5%, P = 0.09), 1.52 ± 0.62 vs 1.37 ± 0.56 (TSH; −9.9%, P = 0.049), 14.3 ± 1.3 vs 14.7 ± 2.4 (FT4, +3.5%), 2.95 ± 0.24 vs 2.91 ± 0.4 (FT3, −1.3%). Percent change of insulin correlated with % change of TSH (Rho: −0.23, P = 0.37), % change of FT4 (Rho: 0.79, P = 0.002), and % change of FT3 (Rho: 0.82, P = 0.001). Percent change of TSH correlated inversely with % change of FT4 (Rho: −0.50, P = 0.054) and % change of FT3 (Rho: −0.64, P = 0.013). A 6-month supplementation with 4 g/d MYO decreases serum insulin and TSH, and increases serum FT4. This suggests that a MYO-induced improvement of insulin sensitivity of the thyroid increases secretion of T4 and subsequent decrease of serum TSH. Indeed, MYO treatment maintains the negative relationship (feed-back) between FT4 and TSH. Thus, MYO could protect from or delay the onset of mild thyroid failure. To add to the benefit, low insulin and low TSH are known to protect from thyroid oncogenesis.
Thyroid Hormone Metabolism & Regulation Friday Poster Clinical
Levothyroxine (LT4) and rifampin (RIF) are sometimes used together; however, no clinical studies have assessed the effects of these drugs on thyroid function or the need to adjust the LT4 dose.
We retrospectively reviewed 71 patients who started RIF during LT4 treatment. Clinically relevant cases that needed dose adjustment according to the American Thyroid Association (ATA)/American Association of Clinical Endocrinologists (AACE) guidelines were identified, and risk factors of increased LT4 dose were analyzed. Mean serum thyroid-stimulating hormone (TSH) level (2.58 mIU/mL, interquartile range [IQR] 0.21–7.44) after administering RIF was significantly higher than that before RIF (0.25 mIU/mL, IQR, 0.03–2.62; p < 0.001). An increased LT4 dose was required for 50% of patients in the TSH suppression group for thyroid cancer and 26% of patients in the replacement group for hypothyroidism. Risk factor analysis showed that remaining thyroid gland (hazard ratio [HR] 9.207, p = 0.002), the time interval between the start of RIF and TSH measurement (HR 1.043, p = 0.019), and baseline LT4 dose per body weight (HR 0.364, p = 0.011) were clinically relevant variables.
In patients receiving LT4, a serum thyroid function test should be performed after starting RIF treatment. For patients with no remnant thyroid gland, a lower LT4 dose, extra attention is needed when starting to administer RIF.
Thyroid Hormone Metabolism & Regulation Friday Poster Clinical
Consumption of kale has become increasingly popular. Kale is rich in thiocyanate, an inhibitor of the sodium-iodide symporter (NIS) present on thyroid follicular cells, potentially decreasing thyroidal iodine uptake and impairing thyroid hormone production. This study assessed urinary thiocyanate concentrations, serum thyroid function tests, and thyroid 123I uptakes before and after 1-week ingestion of kale juice.
Five adult subjects without known thyroid disorders were studied. Serum TSH and free T4; 24 hour urine thiocyanate, iodine, and creatinine concentrations; and an 123I thyroid uptake were carried out immediately before and following daily ingestion of two 15.2-ounce bottles of a commercially-available kale-containing juice for seven days (mean 5,098 μg/day thiocyanate). Thiocyanate was measured by mass spectrometry-liquid chromatography in urine and juice samples. Statistical analysis was performed using a two-tailed paired t-test with p < 0.05 as significant. Following 1 week of kale juice ingestion, there was a significant increase in urine thiocyanate/creatinine concentrations (mean ±SD: 36.7 ± 17.1 μg/mg creatinine) vs. baseline 22.6 ± 15.3 (p < 0.03). There was no change in serum TSH (p = 0.15) and free T4 levels (p = 0.21). Thyroid 123I uptakes at 6 hours were significantly decreased after 1 week of kale juice intake (mean −2.52 ± 1.99 [SD]%) (p < 0.05). There is a significant increase in urinary thiocyanate concentrations and a significant decrease in the 6 hour thyroid 123I uptake after 1 week of thiocyanate-rich kale juice ingestion. Over a more prolonged period of time, ingestion of excessive amounts of kale may potentially induce hypothyroidism.
Thyroid Hormone Metabolism & Regulation Friday Poster Translational
Thyroid hormone (TH) has important roles in regulating hepatic metabolism. We found that most hepatic genes activated by acute T3 treatment became desensitized to chronic T3, and that about 10% of up- or down-regulated genes did not return to basal levels of expression despite normalization of serum THs after T3 withdrawal (Ohba et al., Endocrinol 2016). To clarify the possible mechanism, we determined mRNA and protein expression levels of key regulators including TH receptors in livers from adult C57BL/6 mice treated with daily injections of liothyronine (20 μg/100 g BW) for 14 days followed by 10 days of withdrawal. We also analysed the metabolomics changes to understand the physiological relevance of desensitization and incomplete recovery of hepatic transcriptional regulation. T3 induced mild reductions in hepatic Thrb and Thra transcripts both acutely and chronically but not Mct8, Dio3, and Ncor1. In addition, T3 significantly decreased THRB but not THRA expression in a time-dependent manner. Decreased hepatic THRB expression was also observed in adult male Mct8-knockout mice, an in vivo model of chronic intrahepatic hyperthyroidism since birth. Interestingly, chronic T3 induced no significant reductions in THRB in kidneys from Mct8-knockout as well as T3-treated wild-type mice.
Previously, we identified increased long-chain acylcarnitines (LCACs) in liver after acute T3 treatment (Sinha et al., J Clin Invest 2012). In this study, increased LCACs were noted after T3 withdrawal but not chronic T3. In addition, T3 withdrawal decreased pACC/ACC protein expression. These findings were in agreement with our previous microarray analysis, which showed up-regulation in lipid biosynthetic process. Neither chronic T3 nor T3 withdrawal induced any major changes in amino acids and organic acids. In conclusion, our data contains two main findings. First, decreased THRB could play a key role in transcriptional desensitization during chronic T3 treatment. Second, metabolic abnormalities remained in liver even after serum TSH and THs have normalized after T3 withdrawal. Of note, increased lipogenesis after T3 withdrawal may contribute to excessive weight gain after therapy experienced by patients with hyperthyroidism.
Thyroid Imaging Friday Poster Clinical
Intraoperative tissue identification in thyroid and parathyroid surgery remains an intricate, time-consuming and costly challenge. To lower complication rates following thyroid surgery, technology development has focused on recurrent laryngeal nerve monitoring, while little has been done to minimize hypoparathyroidism, the most frequent complication in thyroid surgery. Avoiding hypocalcemia can be challenging in cases where the distinction between eccentric thyroid micronodules, parathyroid glands and lymph nodes is not obvious. We have developed a novel imaging probe which has been shown to provide appropriate microscopic information to differentiate the various tissues encountered intraoperatively in a phase 1 ex vivo study. Our objective was therefore to evaluate and assess the in vivo images provided by this probe, as well as its usability by surgeons. The probe uses optical coherence tomography (OCT), a non-irradiating imaging technique using near-infrared light, to obtain real-time high-resolution (∼10μm) morphological contrast images intra-operatively, without any tissue preparation. During surgery, a volumetric scanning yields three-dimensional images of the tissue of interest (adipose, muscle, lymph node, thyroid and parathyroid tissue) and is correlated to the surgeon's diagnostic prediction and the final pathology report. Twenty different specimens from 5 patients were imaged in vivo. Average tissue imaging time was 5.8 minutes/patient (1.5 minutes/specimen). The probe is easily manipulated by the surgeons and can be smoothly introduced into small spaces to allow for clear imaging (video available). Tissue-specific morphological patterns previously identified in our ex vivo study are seen in vivo and strongly correlate with the final histopathology. This is the first in vivo study of an imaging probe using OCT in thyroid and parathyroid surgery. This novel OCT probe allows for rapid high-resolution three-dimensional images in an intraoperative setting, providing quantitative and qualitative tissue information. The probe is simple to use with a small learning curve, providing the surgeons a low-cost and accurate tool in differentiating important structures.
Thyroid Nodules & Goiter Friday Poster Basic
Afirma gene expression classifier (GEC) has been used in evaluating thyroid nodules with indeterminate cytology. In our experience incidental thyroid malignancies appear more commonly in the lobe with GEC suspicious nodule. This study sought to evaluate the test performance of GEC in our institution. This retrospective cohort study was approved by Geisinger Health System IRB committee (number 2015-0530). The cytology, GEC and pathology results were analyzed in patients with GEC performed at Geisinger from 11/1/2013 – 10/30/2015. Statistical analysis was performed using Chi Square. A total of 153 GEC cases were reviewed, including 123 cases with atypia of undetermined significance/follicular lesion atypia of undetermined significance (AUS/FLUS), 28 with follicular neoplasm/suspicious for follicular neoplasm (FN/SFN), and 2 with benign cytology (sent in error). The GEC results included 85 benign, 59 suspicious and 9 non diagnostic. Among 123 AUS/FLUS nodules, GEC result included 70 benign, 45 suspicious and 8 non diagnostic. Among 28 FN/SFN nodules, 14 were benign, 13 suspicious and 1 non diagnostic. Only 14 of the 85 patients with benign GEC had surgery. All but one nodule (13/14) were confirmed to be benign. There were no incidental malignancies. Forty four patients (44/59, 74.6%) with suspicious GEC had surgery. Twenty three (23/44, 52.3%) patients had malignant pathology, including 13 cases with a cancerous nodule (13/44, 29.5%) and 10 cases with incidental microcarcinoma unrelated to the nodule. The GEC has 92.9% sensitivity and 29.5% specificity. Its negative predictive value was 92.9% and positive predictive value was 29.5%. Malignancy was found more commonly in the lobes with a GEC suspicious nodule, compared with the lobes with a benign GEC nodule (52.3% vs 7.14%, P < 0.01). More incidental microcarcinoma were discovered in the lobes with a GEC suspicious nodule (22.7% vs 0, P < 0.01) even after the nodule studied was excluded. Thyroid malignancy was discovered more often in thyroid lobes with a GEC suspicious nodule than in lobes with a GEC benign nodule. Additional research is required to determine whether the GEC suspicious profile portends an adverse microenvironment for thyroid cancer tumorigenesis.
Thyroid Nodules & Goiter Friday Poster Clinical
A recent manuscript announced a nomenclature revision for encapsulated follicular variant of papillary thyroid carcinoma (EFV-PTC), which is now termed noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). It is no longer considered a carcinoma. This change has gained wide attention, including a New York Times article, which suggested physicians have a moral obligation to inform patients with reclassified tumors that they no longer have a diagnosis of cancer. Here, we address the practical complexity and ethical challenges of disclosing a revised diagnosis based on retrospective pathology review. Pathologic specimens initially read as FV-PTC were reviewed by a single pathologist to determine if the reported diagnosis met the current consensus criteria for EFV-PTC/NIFTP. To evaluate if confirmation of NIFT-P diagnosis was consistent over time, 2 time periods were reviewed: an “early group” of 56 patients (diagnosed 1951–1987), and a “recent group” of 24 patients (diagnosed 2009–2015). After review, NIFTP diagnosis by current consensus criteria was confirmed in 4/56(7.1%) of the early group, and 19/24 (79%) of the recent group. All other specimens were found to be classic PTC (cPTC) with extensive follicular growth and intrathyroidal invasion or follicular thyroid carcinoma with subtle nuclear atypia and intrathyroidal invasion or metastasis. Respect for patient autonomy dictates physicians should disclose a revised diagnosis to equip patients with important information to make healthcare decisions. We found, however, that interpretation of pathologic features of EFV-PTC varied significantly over time. Therefore, it is critical that the initial diagnosis is confirmed before a new diagnosis is disclosed. This requires review of original specimens to prevent harming patients by inappropriately altering their follow-up, which may lead to a missed recurrence or metastasis of cPTC. Institutions must also address important questions before notifying patients of a new diagnosis: Who should speak with the patient? What if patients are not receiving care at the same institution? Should IRBs be consulted prior to chart review even when there is no intent to research?
Thyroid Nodules & Goiter Friday Poster Clinical
Thyroid Nodules & Goiter Friday Poster Clinical
Thyroid ultrasound is a widely accepted tool for evaluating thyroid nodules in children but the accuracy of specific ultrasound features in the pediatric population has not been well studied. Previous meta-analysis has suggested the presence of internal calcifications to be most predictive for cancer. We identified children aged <21 years who had evidence of thyroid nodules on thyroid ultrasound.
Two radiologists blinded to follow up reviewed the ultrasound imaging and quantified multiple ultrasound features, in addition they gave their overall impression of benign or malignant. The gold standard used for assessing accuracy of the thyroid ultrasound was either histopathology after surgery, or FNA cytology results plus follow-up (FNA and/or ultrasound) for at least one year, or stable follow-up ultrasound for at least one year.135 children (5:1 F:M) with nodules met inclusion criteria, 53% of patients had a single nodule, an additional 36% had 2 or 3 nodules. A total of 236 nodules were reviewed. 90 patients (117 nodules) had FNA performed with suspicious or malignant cytology noted in 42 (36%). 88 patients underwent thyroid surgery (118 nodules), malignant histopathology was noted in 56% of the nodules (53% of the patients). No single ultrasound feature predicted malignancy. Internal calcifications were highly specific (94%) but not very sensitive (62%) for malignancy and offered a 92% PPV and 70% NPV. The overall impression of the radiologist of malignancy had a sensitivity of 81% and a specificity of 83% with a PPV of 83% and NPV of 81% in this select population. This report confirms the much higher rate of malignancy in pediatric thyroid nodules in children compared to adults (36% of nodules). No single ultrasound characteristic could predict either benign or malignant disease but the presence of internal calcifications and the overall impression of the radiologist of malignancy were both strongly predictive of malignancy. Since this was a retrospective study where followup and further testing was determined based on clinical suspicion, whether these results are applicable to all children undergoing ultrasound for nodules will need to be determined.
Thyroid Nodules & Goiter Friday Poster Clinical
Most thyroid nodules are benign and their accurate identification can avoid unnecessary procedures. In adult patients, documentation of nodule autonomy is accepted as reassurance of benign histology and as justification to forego biopsy or thyroidectomy. In contrast, the negative predictive value of nodule autonomy in children is uncertain, and some guidelines recommend surgical resection as initial management. To study the presenting features and cancer risk of pediatric patients with autonomously functioning thyroid nodules, the medical records of 31 consecutive children diagnosed with autonomous nodules at a multidisciplinary pediatric thyroid center were retrospectively reviewed. All underwent 123I scintigraphy and ultrasonography. All children met full diagnostic criteria for autonomous nodules, defined by both autonomous 123I uptake into the nodule and the suppression of uptake in the normal thyroid parenchyma on scintigraphy performed during hypothyrotropinemia. The median age of presentation was 15 years (range 3 to 18) with a female:male ratio of 15:1. Fifty-eight percent of patients had solitary nodules and 42% had multiple nodules. The median size of each patient's largest autonomous nodule was 39 mm (range 18 to 67 mm). Most (68%) of the children in this series had diagnostic biopsies and/or operative pathology of their largest autonomous nodule, which showed benign cytology or histology in all cases. In this pediatric series, the cancer rate observed in biopsied or resected autonomous nodules was 0%. While larger studies are needed to confirm our findings, these results suggest that conservative management may be offered to selected children with autonomous nodules, deferring definitive therapies until adulthood when the risks of thyroidectomy and 131I ablation are lower.
Thyroid Nodules & Goiter Friday Poster Clinical
The incidence of thyroid nodular disease and thyroid cancer in Belarus is still among the highest reported. There are discussions about possible mechanisms linking 25(OH)D deficiency to greater risks of proliferative and neoplastic processes. Our study aimed to analyze serum 25-hydroxyvitamin D status and vitamin D receptor (VRD) polymorphism in thyroid nodular disease patients, living in Brest region of Belarus. Ultrasound screening in Brest region during winter-spring period revealed 320 individuals with thyroid nodular disease. Fine needle biopsy was done in all solid thyroid nodules under ultrasound control. Blood samples were collected and stored at −70 C until assayed. Serum TSH, fT4, TPOAb, TgAb and 25 (OH)D levels were analyzed. Genomic DNA was extracted from peripheral blood mononuclear cells. SNP genotyping in the VDR gene was performed. Individuals completed a questionnaire to provide information regarding their age by the date of accident, highest level of education, income level, cigarette-smoking status, and use of iodized salt, multivitamins, vitamin D consumption, sunlight exposure, followed by anthropometric measurements. Subjects provided a single-spot urine sample, from which urinary iodine concentration (UIC) was determined by the cerium/arsenite method. None of examined patients with thyroid nodules was getting vitamin D or iodine supplementations. 25-hydroxyvitamin D deficiency took place in 61,1% subjects with thyroid nodular disease. There were negative correlations between serum 25(OH)D, age, BMI and TSH (P < 0.01 each). Vitamin D receptor gene polymorphisms analysis did not show significant alterations. Population median UIC is the recommended method to assessed population iodine intake. Our results indicated that median UIC in Brest region was 85 μg/L (45,1–124,9 μg g/L). It appeared that population are not using preferably iodized salt despite the State programm of iodine prophylaxis. Our results suggest possible role of 25(OH)D deficiency and iodine insufficiency in thyroid nodular pathology progression in patients living in Brest region of Belarus. Sufficient sunlight exposure or vitamin D supplementation as well as iodized salt use might be useful as prevention procedures.
Thyroid Nodules & Goiter Friday Poster Clinical
Several sets of guidelines exist to determine which thyroid nodules should undergo fine needle aspiration biopsy (FNAB) based on sonographic features. The 2015 American Thyroid Association (ATA) Guidelines are the most recent. Others include those from The Society of Radiologists in Ultrasound (SRU), The American Association of Clinical Endocrinologists (AACE), and the Kim criteria.
The purpose of this study was to determine which thyroid nodule ultrasound characteristics provide the highest sensitivity and specificity for predicting thyroid cancer. This study also aimed to compare the sensitivity and specificity of the newest ATA guidelines with the three older guidelines at an urban endocrinology clinic from December 2011 to December 2015. We retrospectively reviewed the electronic medical records of all adult patients with thyroid nodules who underwent FNAB at our clinic from December 2011 to December 2015. Information collected from the charts included age, sex, gender, diagnosis, ultrasound characteristics (size, longer than wide morphology, presence or absence of microcalcifications, grade of vascularity, margins, echogenicity), cytology and surgical pathology results. We also reviewed the ultrasound images to corroborate all reported sonographic features.506 thyroid nodules from 363 patients between December 2011 and December 2015 were analyzed. There were no cases with prior diagnosis of thyroid malignancy. There were 22 nodules with surgically-proven thyroid carcinoma in 19 patients, which yielded a malignancy rate of 4.4%. 79% of the patients with papillary thyroid carcinoma were women. Diameter ≥1 cm had the highest sensitivity of 77.6% and hypoechogenicity had the highest specificity of 86.6%. The presence of irregular margins had the highest positive predictive value (6.8%; OR = 1.98). Sensitivities were 81.8%, 54.5% 36.3 and 81.8%, and specificities 27.8%, 45% 73.1% and 10.5%, for Kim, SRU, AACE and ATA guidelines, respectively. In our urban population, a diameter >1 cm is the most sensitive feature, followed by hypoechogenicity, the latter being the most specific sonographic feature.
The ATA guidelines 2015 were as sensitive as the Kim criteria, but had the lowest specificity.
Thyroid Nodules & Goiter Friday Poster Clinical
Fine needle aspiration with parathyroid hormone needle washout (FNA-PTH) has been increasingly utilized for preoperative differentiation of benign thyroid tissue from parathyroid tissue. FNA-PTH has not been described previously in the evaluation of suspicious central thyroid bed lesions after central neck dissection for thyroid cancer. This case describes utilization of FNA with thyroglobulin needle washout (FNA-Tg) and FNA-PTH to differentiate central bed lesions in patients with hyperparathyroidism and history of thyroid cancer. FNA-PTH and FNA-Tg samples were collected after radiographic and cytologic findings were inconclusive. Thyroglobulin levels in the needle washout were undetectable; whereas, the PTH levels in needle washout were elevated. This confirmed that the nodule in question was benign parathyroid tissue and not recurrent thyroid cancer, thereby preventing unnecessary repeat central neck dissection. This case demonstrates the utility of FNA-PTH in evaluation of recurrent thyroid bed lesions in patients with hyperparathyroidism and thyroid cancer.
Thyroid Nodules & Goiter Friday Poster Clinical
To investigate the different expression levels of DAPK, PTEN related miR-124/506/21/297 in organization and peripheral circulation of benign and malignant thyroid nodules (nodular goiter, thyroid adenoma, thyroid cancer), and to find new clinical molecular diagnostic marker. Apply qRT-PCR to detect miR-124/506/21/297 expression level in tissue and peripheral venous blood of 80 cases of benign and malignant thyroid nodules (30 cases of thyroid cancer, 28 cases of thyroid adenoma, 22 cases of nodular goiter). Using SPSS18.0 statistical software to compare miRNA expression level in organizations and peripheral venous blood of benign and malignant thyroid nodules (1) In tissue and peripheral circulation, the relative expression of miR-124, miR-506 increased gradually in thyroid cancer group, nodular goiter group, adenoma group and normal control group, each group was statistically significant difference (P < 0.05), but it was oppsite in miR-21/1297. (2) The sensitivity and specificity of miR-1124/506/21/297 is acceptable (AUC >0.5). Sensitivity and specificity of miR-124 in tissue and peripheral circulation were 78.8%, 69.2% and 74.1%, 62.4%; m124/506/21/297i were 76.3%, 63.5% and 74.5%, 69.8%. miR-21 were 77.2%, 78.3% and 61.4%, 78.3%; miR-1297 were 87.7%, 65.2% and 89.5%, 56.5%. (3) miR-124/506/21/297 expression level (rmiR-124 = 0.539, rmiR-506 = 0.604, rmiR-21 = 0.523, rmiR-1297 = 0.642) were positively correlated in tissue and peripheral circulation of benign and malignant thyroid nodules. (1) Peripheral blood is easily obtained, it can replace biopsy to screen and diagnose benign and malignant thyroid nodules, and help to avoid unnecessary surgery. (2) The expression level of miR-124/506/21/297 have no significant correlation with age, gender, nodule size. But it related to calcified nodules and lymph node enlargement. (3) The expression levels of miR-124/506/21/297 can be used as a potential reference identification of malignant thyroid nodules with lymph node metastases. (4) miR-124/506/21/297 can be used as clinical molecular diagnostic marker for benign and malignant thyroid nodules.
Thyroid Nodules & Goiter Friday Poster Clinical
Thyroid follicular lesions (FL) include follicular carcinoma (FC), follicular variant of papillary thyroid carcinoma (FVPTC), follicular adenoma (FA) and adenomatous nodules (ANs). Preoperative differentiation between benign and malignant thyroid FL is challenging. The objective of this study is to explore the value of conventional ultrasonography (CUS) and the latest referred risk stratification in the differential diagnosis of thyroid FL. The subjects of the study were selected from the medical database from January 2004 to April 2015 at Peking Union Medical College Hospital. Fifty-nine cases of FC confirmed by histopathology of surgical specimens with complete clinical and CUS data were enrolled in this study. Fifty-nine age- and gender-matched FVPTCs, FAs, and ANs were randomly selected from the same database during the same period. Clinical and CUS characters and 2015 ATA referred risk stratification were retrospectively analyzed. The sizes of nodules in the FC, FVPTC, FA and AN groups were 2.9 ± 1.5 cm, 1.4 ± 0.8 cm, 3.4 ± 1.5 cm, and 3.1 ± 1.3 cm respectively, and the differences were significant (P < 0.05). By comparing the CUS features, malignant FL were more likely to have irregular margins, a taller than wide shape, and absent or irregular halos; be solid; and exhibit hypoechogenicity and microcalcification (P < 0.05). Sensitive ultrasonic features for the diagnosis of malignancy were a solid mass, absent or irregular halos, and hypoechogenicity (sensitivity: 92.4%, 87.3%, and 86.4% respectively), while irregular margins, taller than wide shape, and microcalcification had high specificities (99.2%, 98.1%, and 91.5% respectively). High suspicion was assessed in 54.2% of malignant nodules and 7.6% of benign nodules (P < 0.001). 84.7% of FVPTCs were high suspicion compared to only 23.7% of FCs. Most FCs and benign FL were evaluated as intermediate and low suspicion (39.0% and 37.3% vs. 28.8% and 50.0% respectively). Thyroid FL with irregular margins, absent or irregular halos, a solid mass, hypoechogenicity, and microcalcification have a higher likelihood of malignancy. Risk stratification has good discrimination for high and very low suspicion nodules but is poor for nodules with intermediate and low suspicion.
Thyroid Nodules & Goiter Friday Poster Case Report
Colon cancer with metastasis to thyroid is extremely rare and a sign of poor prognosis. In the literature, about 50 estimated cases of colon cancer metastases to the thyroid have been reported in the last five decades. It is theorized the unfavorable environment of the thyroid gland with its high oxygen and iodine environment along with high vascularity structures impairs the ability of metastatic cells to settle and develop. We present a case of a patient with rectal adenocarcinoma who presented for work-up of an incidental thyroid mass found on imaging, and was found to have colon cancer metastases to the thyroid. A 53 year old Caucasian female in Southern California was referred to Endocrinology clinic in Kaiser Permanente in Fontana, California on January 2016 for an incidental thyroid mass finding. Her history consisted of stage IV rectal adenocarcinoma diagnosed in July 2015 and was undergoing palliative chemotherapy. She reported some heartburn symptoms and mild, “intermittent” thyromegaly, stating they fluctuated with her chemotherapy sessions. She did not show any clinical signs of hyperthyroidism aside from thyroid enlargement. Thyroid stimulating hormone (TSH) and Thyroid peroxidase antibody (TBO) antibody were within normal limits. Thyroid ultrasound showed hypoechoic masses measuring 2.6 × 0.9 × 1.75 cm (left) and 3.31 × 1.54 × 2.90 cm (right) that appeared to be contiguous across the isthmus. Fine needle aspiration (FNA) with pathology report returned as malignant, metastatic adenocarcinoma. Immunohistochemical stains CK20 and CDx2 were positive. Although metastases to the thyroid gland are uncommon, colorectal malignancy metastases to thyroid are rare. A literature search on colorectal cancer metastasis to thyroid was limited due to its rarity. It was noted in the literature review that the care of the patients involved multiple specialties. Because of the rarity of colon cancer metastases to the thyroid gland, a multidisciplinary approach with endocrinology, oncology, and surgery could be considered.
Thyroid Nodules & Goiter Friday Poster Case Report
Hemorrhage into multinodular goiter (MNG) is a rare and potentially life-threatening event. It may lead to respiratory compromise from acute laryngo-tracheal obstruction. A few cases; linked to trauma, neoplastic transformation, thrombolytic therapy or pregnancy; have been reported. We present a case of MNG with spontaneous life-threatening intra-thyroidal bleed precipitated by anticoagulation. 69-year-old black female with 5-year history of asymptomatic MNG was hospitalized for evaluation of leg edema. She had an enlarged nodular thyroid and left leg edema on examination. Thyroid function tests were normal. Computed tomography (CT) chest revealed sub segmental pulmonary embolism and MNG measuring 9 × 6 cm; calculated thyroid volume was 54 ml (normal volume - 8 to 10 ml); without tracheal compression or deviation. Several hours after initiation of therapeutic enoxaparin, she developed hypoxia (SpO2 of 70%) and stridor necessitating emergent intubation. Repeat CT neck showed a markedly enlarged left lobe, extending into the mediastinum, new rightward tracheal deviation and hyper density in left lower lobe measuring 5 × 6 × 2 cm, worrisome for hemorrhage. Repeat biochemical evaluation revealed hematocrit drop from 34% to 31% (Normal range 34.5% to 44 %), INR of 4.3, free thyroxine of 1.5 ng/dl (range 0.8 − 1.9ng/ml) and total tri iodothyronine of 2.07 pg/ml (range 1.8 to 4.4 pg/ml). Emergent trans-cervical total thyroidectomy was performed and a large clot was evacuated from the left lower lobe. The thyroid weighed 240 grams (reference range 15 − 25 grams); measured 18 × 8 × 4 cm and 6.4 × 3 × 2.5 cm for right and left thyroid lobes, respectively.(Normal range: 4 to 6 cm by 1.3 to 1.8 cm, isthmus 4 to 5 mm). Adenomatous nodules with cystic degeneration and hemorrhagic infarctions, were noted. Differential diagnosis of a rapidly enlarging neck mass includes both serious and benign etiologies; such as hemorrhage into a thyroid cyst or nodule, aggressive thyroid cancers, Reidels thyroiditis, reactive infectious lymphadenopathy, lymphoma and metastasis from cancer. In patients with MNG, rapidly enlarging neck mass in the context of anticoagulation therapy should prompt an emergent evaluation for intra-thyroidal hemorrhage.
Thyroid Nodules & Goiter Friday Poster Case Report
Total thyroidectomy is a common surgical procedure used to treat a variety of thyroid pathologies. Experienced endocrine surgeons perform this operation routinely without incident; however, extension of a goiter substernally can require better exposure than what is offered through a conventional cervical incision. XT is a 64-year-old woman who has had a goiter for approximately four years. One year ago she began to experience symptoms of hyperthyroidism including palpitations and tremors and was started on methimazole therapy. A CT scan was performed that showed substernal extension of a multinodular goiter to the level of her aortic arch. FNA of right sided dominant nodule demonstrated atypical cells of undetermined significance (ACUS). Given her hyperthyroidism that was inadequately managed medically and the cytology findings, the patient underwent total thyroidectomy. During the case adequate exposure of the inferior poles of the thyroid was difficult due to the extension of the gland beneath the sternum. An intraoperative decision was made to perform a sternal split. The manubrium was cut from the level of the sternal notch to the angle of Louis. An oscillating blade was used to make transverse incision between the rib spaces at this level. A self-retaining retractor was placed allowing for adequate exposure of the substernal portion of the gland, and the remaining portion of the gland was dissected off the trachea safely and the sternotomy was closed with a single sternal wire. Final pathology showed a 2.0 cm incidental focus of papillary thyroid carcinoma in a background of multinodular goiter. She recovered well postoperatively. This case illustrates a difficulty that can be encountered intraoperatively during a total thyroid resection for goiter. In patients with extension of the goiter far below the sternal notch or with posterior mediastinal extension, the need for sternotomy should be anticipated.
Saturday, September 24, 2016
Disorders of Thyroid Function Saturday Basic
Patients with mutations of the thyroid hormone receptor α (THRA) gene exhibit anemia. To understand the molecular basis of anemia in patients and identify novel molecular targets, we used the Thra1PV/+ mouse that shows erythropoietic disorders similar to patients. The Thra1PV/+ mouse expresses a similar mutated C-terminal sequence of TRα1 (denoted PV) as in patients with truncated termination of TRα1. The nuclear receptor corepressor 1 (NCOR1) mediates the dominant negative effects of mutated TRα1 to cause abnormalities. We crossed Thra1PV/+ mice with mice expressing a mutant Ncor1 allele (Thra1PV/+Ncor1 ΔID/ΔID mice). The mutated NCOR1 (NCOR1ΔID) cannot interact with the PV mutant to mediate its dominant negative actions. Abnormal erythropoietic parameters in Thra1PV/+ mice were significantly corrected in Thra1PV/+ Ncor1 ΔID/ΔID mice. The decreased number of erythrocytic progenitors in the bone marrow of Thra1PV/+ mice was markedly higher in Thra1 PV/+ Ncor1 ΔID/ΔID mice. Using an in vitro erythropoiesis system, we detected more matured erythrocytes in the lineage-negative bone marrow cells of Thra1PV/+ Ncor1 ΔID/ΔID mice than Thra1PV/+ mice. GATA1 and KLF1 are two hematopoietic transcription factors critical in erythroid cell differentiation. We identified TRα1 binding sites on the promoter of the Gata1 gene and elucidated that the expression of Gata1 was directly regulated by TRα1. The repressed Gata1 mRNA in the bone marrow of Thra1PV/+ mice was markedly de-repressed in Thra1 PV/+ Ncor1 ΔID/ΔID mice. KLF1, which is directly regulated by GATA1, was also similarly de-repressed in Thra1 PV/+ Ncor1 ΔID/ΔID mice. Importantly, similar de-repression of KLF1 downstream target genes in Thra1PV/+ mice, such as β-globin, bzrp, ahsp, bcl11a, and dematin, critical in erythropoiesis, was also detected in the bone marrow of Thra1 PV/+ Ncor1 ΔID/ΔID mice to revert erythroid defects. These findings provide, for the first time, direct in vivo evidence that NCOR1ΔID could ameliorate erythropoietic disorders caused by mutations of the THRA gene. These studies have identified a potential therapeutic target for erythropoietic disorders in patients caused by the mutated THRA gene.
Thyroid & Development Saturday Basic
For proper organ development, the balance between cell proliferation and differentiation is an important factor. If the balance tips in favor of proliferation, stem cells can over-accumulate, leading to cancer. If the balance tips toward differentiation, stem cells can disappear, leading to the deterioration of organs. Thus, it is important to understand how adult stem cells are formed and maintained in a well-balanced manner during vertebrate development.
The thyroid hormone (T3)-dependent frog metamorphosis resembles mammalian postembryonic development and offers a unique opportunity to study how adult stem cells are formed and how the balance between proliferation and differentiation are maintained as it is easy to manipulate the externally developing frog embryos. Microarray analysis of intestinal gene expression during metamorphosis was carried out and identified a number of novel candidate adult stem cell related genes. qPCR, in situ hybridization, and immunohistochemical analyses were utilized to analyze its role during intestinal stem cell development. Recently developed TALEN technology was adapted to knockout the stem cell related gene. In this study, we revealed epithelium specific induction of Mad, an antagonist of the c-Myc in the intestine during metamorphosis. Previous studies have shown that Mad inhibit transcription leading to cell differentiation while c-Myc induces proliferation. We further provided evidence that Mad expression is induced by T3, just prior to c-Myc expression and adult stem cell formation. High levels of Mad expression is localized to apoptotic cells while c-Myc expression is present in adult stem cells.
To investigate the role of Mad during adult stem cell formation, we used TALEN technology to knockout the endogenous Mad. Interestingly, we found that knocking out the endogenous Mad reduced the adult stem cell population. Our findings suggest that Mad/c-Myc balance is likely critical for cell fate determination during adult stem cell formation. These observations provided the first example for the involvement of Mad/c-Myc pathways in adult stem cell formation in vertebrate.
Thyroid Hormone Action Saturday Translational
Unaffected fetuses carried by mothers with resistance to TH due to mutations in the THRB gene (RTH-beta) have at birth low weight and suppressed TSH. We also showed that serum TSH in adult unaffected mice born to dams with RTH-beta is less suppressible by L-T3. The objective of this study was to determine if this also occurs in humans and to determine the mechanism using a mouse model of RTH-beta. Groups of adults without THRB gene mutations, aged 22–54 yrs, born to affected mothers and those born to affected fathers (controls), all from the same extended family with THRB R243Q, were given 200 μg TRH iv before and after 3 day treatment with 25 μg L-T3 twice daily. Serum was collected at baseline and 7 samples over 180 min after TRH. The same study was carried out in mice and tissues were obtained for studies in pituitary and brain. In humans, baseline serum TSH, FT4, FT3, rT3, TG, and PRL were not significantly different in individuals born to affected mothers compared to the controls. After L-T3 treatment, both groups had equal increase of serum T3 and decrease of TSH. Before L-T3 treatment, peak TSH response to TRH was similar in individuals born to affected mothers compared to the controls, 11.8 ± 1.7 vs 13.2 ± 1.7 mU/L, respectively. However, following L-T3 treatment, the corresponding TSH values were 6.8 ± 1.0 vs 1.6 ± 0.5 mU/L (P < 0.005). There were no differences in basal and stimulated PRL between the two groups before or after L-T3 treatment.
In mice, in addition to the similarly reduced TSH suppression by L-T3 in those born to affected dams as compared to those born to affected males, marked tissue differences were found in their pituitaries with significantly higher D3 and TSH-beta mRNAs (P < 0.01 and <0.05). D2, TRβ and TRα mRNAs were not significantly different between the 2 groups. Exposure to high TH level in utero resets the sensitivity of the thyrotrophs to L-T3, producing a phenotype of central resistance to TH, persistent into adulthood. Studies in a mouse model suggest that this epigenetic effect is due to increased T3 degradation by D3.
Autoimmunity Saturday Basic
Autoimmune thyroid diseases (AITD) arise from complex interactions between genetic, epigenetic and environmental factors. Interferon-alpha (IFNα), a cytokine secreted during viral infections, has recently emerged as a key cytokine that triggers AITD. Thyroglobulin (TG) is the most important thyroid-specific susceptibility gene for both Graves' disease and Hashimoto's thyroiditis. Our lab has previously identified a SNP in the human TG promoter (-1623 A/G) that is strongly associated with AITD. The risk (G) allele created an IRF-1 binding site causing upregulation of TG expression by IFNα (Stefan et al., 2011), however how the upregulation of TG by IFNα triggers AITD is still unknown. Here we sought to evaluate how IFNα triggers AITD by testing its effects on thyrocyte function and on TG processing. We found that human thyroid ML-1 cells and human thyroid primary cells exposed to 5000 U/ml of INFα for 48h showed high levels of UPR markers, such as BIP, CHOP, XBP-1, spliced (active) XBP1, ATF4 and pelf2α. IFNα upregulated TG mRNA but reduced TG protein levels, indicating degradation. We observed that chemical chaperones PBA and TUDCA did not prevent IFNα-induced TG degradation, neither did MG132, an ubiquitin proteasome inhibitor. UPR activation is known to be linked to autophagy. Indeed, INFα stimulated the expression of autophagy markers, such as LC3, ATG5 and Beclin1 in ML-1 cells. INFα also stimulated the expression and activity of lysosomal cathepsins B, D and L. Additionally, IFNα increased lysotracker staining in ML-1 cells. Moreover, chymostatin and CA-074Me (cathepsin B and L inhibitors) and pepstatin A (cathepsin D inhibitor) prevented IFNα-induced TG degradation, suggesting a specific role of these lysosomal proteases in the IFNα – induced degradation of TG protein. Cathepsins B, D, and L are involved in antigen processing but are also key enzymes in TG proteolysis making them major determinants of the TG peptide repertoire. Our data suggest that IFNα leads to TG degradation by inducing cathepsins B, D and L. Our data suggest a new model whereby IFNα triggers AITD by inducing degradation of TG into immunogenic peptides within lysosomes leading to activation of self-reactive T-cells.
Thyroid & Development Saturday Basic
Thyroid hormone insufficiency and iron deficiency (FeD) during fetal and neonatal life are both similarly deleterious to mammalian development suggesting a possible linkage between iron and thyroid hormone insufficiencies. Recent published data from our laboratory demonstrate a reduction in circulating and brain thyroid hormone levels in neonatal rats when dams are fed an iron deficient diet. We now report the effects of gestational and neonatal FeD, and the effects of neonatal iron repletion, on circulating and tissue thyroid hormone levels from birth through the first month of neonatal life. Gestational day 2 (G2) Sprague-Dawley rat dams were assigned to two groups. The Control group was fed a standard chow diet with 84 ppm iron while the FeD group was fed an iron deficient diet (6 ppm Fe). A separate FeD group was fed an iron replete diet starting on P14. All animals were maintained on the defined diets from G2 through weaning. Serum, brain, and thyroid tissue was harvested from neonatal male pups at postnatal day 0 (P0), P7, P14, and P30. Hemoglobin, iron, T4, T3, and rT3 levels were measured at all time points. Thyroid hormone levels were assayed by LC-MS/MS methods. Hemoglobin levels were reduced by 27% in FeD P0 pups and by 49% by P14 indicating a marked reduction in iron stores was achieved in the FeD group. We did not find significant reductions in serum T4 in FeD pups at P0, 41% reductions at P7, and 58% at P14. Dietary repletion of iron at P14 resulted in a normalization of T4 levels by P30. Similarly, serum T3 levels were reduced significantly in neonatal pups, however, reductions were more modest than T3 (36% reduction at P7 and 33% reduction at P14). No changes in hormone levels were observed at P0. rT3 levels were mostly unchanged at all time points. We are currently assessing thyroid hormone levels in brain and thyroid tissues at each time point. Our data demonstrate the importance of adequate iron stores in maintaining normal levels of circulating thyroid hormones during development. As the impact of inadequate thyroid hormone levels on development is well established, these data further support the inclusion of iron as a contributing factor in thyroid disease during development.
Autoimmunity Saturday Translational
Graves' disease (GD) is a common organ specific autoimmune disease, and 25% to 50% GD patients develop Graves' ophthalmopathy (GO). However, the exact mechanism remain elusive. Autoimmune diseases involve loss of tolerance to autoantigens, and autoreactive T cells play vital roles in the maintenance of this process. T cell receptor (TCR) repertoire analysis is the standard approach used to assess the clonal expansion status, for the amino acid sequence of a given TCR determines the specificity of individual T cell clones. This study is planned to identify potentially autoreactive lymphocyte clones in GD patients by TCR sequencing. Secondly, to establish parameters that distinguish the ‘GD’ or ‘GO’ immune repertoire for precision diagnosis. Last, to explore the change of immune system over the course of GD. We studied 15 Graves' disease patients (9 patients without Graves' ophthalmopathy and 6 with Graves' ophthalmopathy) diagnosed less than 2 months who were naive to treatment. We have for the first time used next generation sequencing to perform deep quantitative profiling of TCR repertoires for peripheral blood samples of GD patients (develops GO or not) from disease onset to remission at several time points. The diversity index of patients were significantly lower than health controls. In addition, compared with GD, GO patients had a significant decrease in diversity. The top 100 TCR families could be used to distinguish GD patients who develops GO or not. And they each had their own predominant clones, TRBV9-TRBJ1-6 in GO and TRBV29-TRBJ2-7 in GD, respectively. In addition, longitudinal study indicated that TCR repertoire kept stably from disease onset to remission. Interestingly, T cells subsets differentiation were closely linked with the course of GD. This work highlights that TCR repertoire could be a useful biomarker for diagnostic GD. In addition, GD remission is achieved through the “resetting” of immune balance rather than complete ablation of autoimmune clones.
Autoimmunity Saturday Clinical
There is little data on the effects of maternal thyroid antibodies during pregnancy on the odds of child having components of metabolic syndrome in adolescence. The objective of the current study was to investigate the relation between maternal TPO-Ab-positivity during pregnancy and child's components of metabolic syndrome in adolescence. Study population was based on prospective population-based cohort study, Northern Finland Birth Cohort 1986 with data on all expected deliveries within one year from the two northernmost provinces of Finland. Maternal serum samples were collected before 20th gestational week and analyzed for TPO-Ab. Data on child's metabolic syndrome and other metabolic disturbances were collected at age of 16 via clinical examination and blood sampling. The data included waist circumference, blood pressure, lipids and lipoproteins, and insulin resistance of children. Complete data on maternal TPO-Ab status and child's metabolic parameters were available for 3718-4176 mother-child pairs. Odds ratios (ORs) with 95% confidence intervals (95% CI) of metabolic syndrome and other metabolic disturbances among children of TPO-Ab positive mothers compared to those of TPO-Ab negative ones were estimated via logistic regression, adjusted for covariates. Children of TPO-Ab positive mothers had higher odds of having a waist circumference indicative of metabolic syndrome (OR 1.69; 95% CI 1.14–2.51) or having a metabolic syndrome (OR 2.63; 95% CI 1.23–5.60). They also had higher odds of being overweight/obese (OR 1.56; 95% CI 1.04–2.35). Other significant differences between children of TPO-Ab positive and negative mothers were not observed. Maternal TPO-Ab-positivity was associated with greater waist circumference and body mass index and more metabolic syndrome in adolescence.
Autoimmunity Saturday Clinical
We compare THAb rate and repertoire in GD patients with ophthalmopathy (TAO+) vs GD patients without (TAO−) (because not done previously), or HT patients.
We studied GD (n = 61; TAO+, n = 31; TAO−, n = 30) and HT (n = 41) patients without any associated nonthyroid autoimmune diseases (NTAID); none had received 131I, corticosteroids or other treatment for TAO, or was thyroidectomized. Of the HT patients (1 with overt and 9 with subclinical hypothyroidism), none was currently or previously under L-T4 therapy. We measured IgM and IgG THAb against T3, T4 or both T3 and T4 with a radioimmunoprecipitation method.
The rate of positivity for at least one of the 4 possible THAb (T3IgM, T3IgG, T4IgM, T4IgG) were 51.6%, 60% and 43.9%. The rates of at least one IgGTHAb, regardless of alone or combined with any IgMTHAb, were 32.2%, 46.7% and 31.7%. By comparison, the rates of TSHRAb, TPOAb and TgAb were the following in TAO+ GD, TAO− GD, and HT. TSHR-Ab rates were 67.7%, 70% and 2.4%. TPOAb rates were 77.4%, 70% and 90.2%, while TgAb rates were 41.9%, 50% and 56.1%.
There were differences in the THAb repertoire between GD and HT, with more variety in GD. Of the 15 types of THAb, 11 were detected in GD (TAO−, n = 9/15; TAO+, n = 7/15) but only 6 in HT. Differences in repertoire between TAO+ and TAO− GD patients emerged, particularly one double THAb pattern (T3IgG+T4IgG [0% vs 13%]), and the triple THAb patterns (T3-IgG+T4IgG+T3IgM [0 vs 10%] and T3IgG+T4IgG+T4IgM [0 vs 7%]). Other THAb patterns detected in TAO− GD solely were T3IgM+T4IgG (3.2%), T4IgM+T4IgG+T3IgG (6.7%), while detected only in TAO+ GD were T4IgM+T4IgG (3.2%) and T3IgM+T4IgM+T4IgG (3.2%). Detected only in HT were T3IgM+T4IgG (4.9%).
In conclusion, these rates of any THAb or IgGTHAb in GD are greater than reported by literature (56% vs 36% or 39% vs 32%; JEI, 2002), and so are rates in HT (44% vs 34% or 32% vs 20%). Development of TAO in GD seems to be associated with a more restricted repertoire, favoring single types of THAb over double and triple THAb. This, in turn, implies autoimmunization against distinct Tg iodinated tyrosines (T3-specific or T4-specific) in TAO− vs TAO+ GD. Study of THAb may help in understanding the pathogenesis of TAO itself.
Autoimmunity Saturday Translational
In the last years, Th17 lymphocytes and regulatory B lymphocytes (Breg) seem to play a promising role in understanding the pathogenesis of autoimmune disorders. In isolated Hashimoto's thyroiditis (HT), increased Th1 and Th17 activation has been described but little is known about Breg which allegedly suppress the pro-inflammatory response. Aim of this study was to compare Th17 and Breg subpopulation in healthy subjects and in patients affected by HT. A total of 19 patients (17 women and 2 men, mean age 48 ± 10 years) affected by HT and 18 age- and sex-matched healthy donors (16 women and 2 men, mean age 42 ± 12 years) were enrolled in this study. Effector Th17 lymphocytes were obtained from overnight stimulated PBMCs, then stained, fixed, permeabilized and stained intracellularly with anti-IL-17A. For Breg detection, freshly PBMCs were surface stained with anti-CD19, anti-CD24, anti-CD38, and anti-CD27. Cells were then acquired on a FACS ARIA II. Increased percentage (2.6% ± 1.6 versus 1.6% ± 0.9; p = 0.0337) of Th17 cells in HT patients as compared with healthy controls were observed. Instead, we found similar percentage of non stimulated CD24hiCD38hi Breg cells between isolated HT patients and healthy donors (2.4% ± 0.9 versus 2.0% ± 0.7; p = ns). Also, mature CD24intCD38int and memory CD24hiCD38neg B subsets, were similar in HT patients and healthy controls (30.8 vs. 25.1% and 49.5 vs. 56.0%, respectively; p = ns). Following CpG oligonucleotide stimulation (functional assay of B cells), small but not significant differences were seen in total CD19+ cells subset and total B lymphocytes producing IL-10 between HT patients and healthy donors (2.9% ± 1.9 and 1.9% ± 1.1; p = ns). However, a significant increase was recognized in the percentage of IL10-producing Breg cells in HT patients as compared to healthy controls (3.9% ± 1.8 and 2.4% ± 1.1; p = 0.0303). These preliminary findings confirmed activation of proinflammatory Th17 pathway but described for the first time an upregulation of IL-10 producing Breg cells in Hashimoto's thyroiditis which may oppose to Th17 activation.
Disorders of Thyroid Function Saturday Clinical
Immunotherapy-related destructive thyroiditis (irT) occurring with the newer immunotherapy (IO) agents is not yet well characterized. We sought to study its clinical presentation and natural course. This is a retrospective study of patients (pts) on IO referred for evaluation of irT between 11/2014 and 05/2016. We included only pts with normal baseline TFTs who developed thyrotoxicosis (hyperT) followed by a downtrend in free T4 (FT4) levels while receiving IO. Pts who had not develop hypothyroidism (hypoT) were censored at the time of their last follow up. At the time of irT dx, hyperT was defined as a low TSH (mIU/l) with a high/normal FT4 (mcg/dl). Peak FT4 was defined as the highest measured FT4 during hyperT. HypoT was defined as a low FT4 (regardless of TSH, if occurring after the hyperT phase) or a normal FT4 with high TSH.42 pts were identified: median age 60 yrs (21–81); 50% men. IO: nivolumab (13), ipilimumab + nivolumab (16), pembrolizumab (10), tremelimumab alone (1) or with durvalumab (2). At hyperT dx, median TSH = 0.03 (0.01–0.26) and FT4 = 2.59 (1.2 to >7.7), with peak FT4 of 3.76 (2.07 to >7.7). At hypoT dx, median TSH = 7.19 (0.05–168) and FT4 = 0.69 (0.22–0.96). Median time from IO start to hyperT dx was 4 wks (0–24). Median time from hyperT to hypoT dx was 6 wks (95% CI, 4.7–7.3). At the time of analysis, 31/42 pts had documented hypoT (28 started on LT4). 11/42 pts without hypoT had a median follow up time of 11 weeks (3–37). 13/32 tested pts were TPOAb+, 8/18 TgAb+ and 0/30 TSI+. Thyroid ultrasound was performed in 12 pts (8 showing thyroiditis). 9 pts had nuclear scintigraphy (2 RAI, 7 Tc99 scan), all revealing low uptake consistent with thyroiditis. 11/42 pts had hyperT symptoms;none had neck pain. All patients were treated conservatively at the time of hyperT dx. Patients diagnosed with destructive irT while receiving IO developed an early onset of hyperT typically followed by subsequent rapid hypoT. The majority were asymptomatic, not thyroid autoantibody positive, and most cases of irT were seen with the anti PD-1 drugs, alone or in combination. Conservative therapy during hyperT was sufficient. Our case series underscores the importance of routinely assessing TFTs before and during IO.
Thyroid Cancer Saturday Trainee Poster Contest Finalist Basic
The unique combination of reporter and therapy gene function of the sodium iodide symporter (NIS) displays an outstanding tool to target different cancer types allowing non-invasive imaging of functional NIS expression and therapeutic application of 131I. In a previous study tumor-selective accumulation and therapeutic efficacy of non-viral epidermal growth factor receptor (EGFR)-targeted NIS gene delivery vehicles were demonstrated in a subcutaneous hepatocellular cancer xenograft model. As a next step towards clinical application, we evaluated the EGFR-targeted therapy approach by applying EGFR-targeted polyplexes based on linear polyethylenimine (LPEI), polyethylene glycol (PEG), and the synthetic peptide GE11 as EGFR-specific ligand as systemic NIS gene delivery vehicles (LPEI-PEG-GE11/NIS) in a disseminated colon cancer liver metastasis model as clinically relevant tumor model. Human colon carcinoma cells LS174T were injected directly into the spleen of nude mice, which resulted in induction of multifocal liver metastases. EGFR-specific immunostaining of paraffin-embedded tumor sections revealed high levels of EGFR expression. Tumor specificity and transduction efficiency of LPEI-PEG-GE11/NIS were examined in this metastasis model by non-invasive imaging using 18F-tetrafluoroborate (TFB) as novel NIS PET (positron emission tomography) tracer. Mice that were injected intravenously (i.v.) with LPEI-PEG-GE11/NIS 48h before 18F-TFB application showed high tumoral levels of NIS-mediated radionuclide uptake in comparison to low levels detected in mice that received untargeted control vectors (LPEI-PEG-Cys/NIS). Three cycles of i.v. injection of LPEI-PEG-GE11/NIS followed by application of 55.5 MBq 131I 48h later resulted in a marked delay in tumor growth of mice compared to mice that received saline. This was associated with improved survival and reduced tumor perfusion determined by contrast-enhanced sonography. In conclusion, our preclinical data confirm the enormous potential of EGFR-targeted synthetic polymers for systemic NIS gene delivery in an advanced multifocal colon cancer liver metastasis model and open the exciting prospect of NIS-mediated radionuclide therapy in metastatic disease.
Thyroid Cancer Saturday Trainee Poster Contest Finalist Basic
The catalytic subunit of telomerase, human telomerase reverse transcriptase (hTERT), plays an essential role in telomere maintenance to oppose cellular senescence and is highly regulated. hTERT is upregulated in cancer, with over 90% of human malignancies showing telomerase expression. Of the multiple mechanisms of control altered in cancer, two of interest are alternative splicing of transcripts and promoter CpG methylation. In thyroid cancer it has been shown that a specific splicing pattern of hTERT, the increased percentage of the full length isoform present, correlates with more aggressive disease. However, the mechanistic basis of this switch in splicing pattern is unknown. While the methylation status of the promoter has not yet been explored in thyroid cancer, many studies have examined hTERT methylation in other cancers. A pattern emerges from the cancers studied in which the promoter region of hTERT at the TSS [−250 to +150] is hypomethylated, while further upstream of the TSS [−650 to −250] the promoter is hypermethylated, and it has been postulated that this pattern correlates with transcription factor binding availability. These binding factors could also play a direct or recruitment role in splicing of the transcript, and depend on methylation status of the binding site. To better understand these control mechanisms, the potential connection between promoter methylation and splicing of hTERT was examined. Seven thyroid cancer cell lines of PTC, ATC, and FTC origin (TPC1, BCPAP, C643, SW1736, FTC133, FTC236, and FTC238) were treated with DNA methylase inhibitor, 5-aza-2′-deoxycytidine (DAC). hTERT splicing isoforms were examined by nested RT-PCR, and promoter methylation was probed by Methylation Specific PCR (MSP) and bisulfite sequencing. Treating cells with DAC showed that perturbing CpG methylation is associated with changes in the splicing pattern of hTERT. Further studies are required to determine the exact mechanism of this pattern change. Cotranscriptional pre-mRNA processing of hTERT allows for the link between these two regulation strategies, and could offer additional insight into cellular control of active telomerase in thyroid cancer.
Thyroid Cancer Saturday Trainee Poster Contest Finalist Basic
Metastasis suppressors are proteins that inhibit tumor metastasis and secondary growth. Their loss can lead to metastatic progression. We recently identified Regulator of Calcineurin 1, isoform 4 (RCAN1-4) as a potential metastasis suppressor based on known metastasis suppression pathways and its overexpression in thyroid cancer cells inhibited cell motility. Here, we investigated the function of RCAN1-4 in vivo. Using human thyroid cancer cell lines FTC236 and HTh74, we developed RCAN1-4 knockdown stable cells (shRCAN1-4) using shRNA targeting RCAN1-4 and control stable cells (shCtrl) using scrambled shRNA. The cells also express firefly luciferase gene to enable in vivo imaging (IVIS). Loss of RCAN1-4 promoted cell invasion in both FTC236 and HTh74 cells in vitro. Subcutaneous xenografts demonstrated that shRCAN1-4 cells grew faster and had significantly larger tumor volumes compared with shCtrl cells in twelve weeks for both FTC236 (4417.3 vs 2012.2 mm3, p < 0.01) and HTh74 cells (2514.0 vs 172.4 mm3, p < 0.0001). Tail vein injection demonstrated that RCAN1-4 knockdown promotes metastases to the lungs and their subsequent growth. IVIS imaging showed that shRCAN1-4 cells had significantly stronger lung metastasis signals compared with shCtrl cells for both FTC236 and HTh74 cells (p < 0.0001). The metastases were confirmed by histological examination of the lungs. Microarray analysis was determined on RNA from the shRCAN1-4 and shCtrl cells. Nuclear Factor, Erythroid 2-Like 3 (NFE2L3) is the most highly upregulated gene in the HTh74 shRCAN1-4 cells and is also upregulated in the FTC236 shRCAN1-4 cells. NFE2L3 knockdown inhibited cell invasion in shRCAN1-4 cells while NFE2L3 overexpression independently increased cell invasion in both FTC236 and HTh74 cells. In human samples, NFE2L3 expression in the TCGA thyroid cancer samples is 7.52 times that of the normal tissues (p < 2e-16) and NFE2L3 overexpression was demonstrated in distant metastases samples from patients with thyroid cancer. We provided the first evidence that RCAN1-4 is a tumor growth and metastasis suppressor in vivo and that it functions, in part, through NFE2L3. RCAN1-4 may serve as a negative regulator of thyroid cancer metastatic progression.
Thyroid Cancer Saturday Trainee Poster Contest Finalist Basic
Thyroid Cancer Saturday Trainee Poster Contest Finalist Translational
Pancreatic ductal adenocarcinoma (PDAC) belongs to the cancers with most unfavourable prognosis. Despite promising results with a series of compounds in vitro and in xenograft models, the results of clinical trials are predominantly disappointing and new treatment options are urgently needed. In previous proof-of-principle studies using xenograft mouse models, the sodium iodide symporter (NIS) as well characterised theranostic gene allowed detailed molecular imaging of transgene expression and highly effective application of therapeutic radionuclides. As a next step towards clinical application, we here investigated tumour specificity and transduction efficiency of tumour-targeted polyplexes as systemic NIS gene delivery vehicles in an advanced genetically engineered mouse model (GEMM) of PDAC that closely reflects human disease. The GEMM employed in this study is induced by activation of constitutively active KrasG12D in combination with a deletion of p53. In order to target a NIS-expressing plasmid to high EGFR-expressing PDAC, we used tumour-targeted polyplexes based on linear polyethylenimine (LPEI), polyethylene glycol (PEG), and the synthetic peptide GE11 as an epidermal growth factor receptor (EGFR)-specific ligand (LPEI-PEG-GE11). In vitro iodide uptake studies with cell explants derived from murine EGFR-positive and EGFR-knockout PDAC lesions demonstrated high transduction efficiency and EGFR-specificity of LPEI-PEG-GE11/NIS. In vivo 123I γ-camera-imaging and three-dimensional high-resolution 124I-PET-imaging experiments showed significant tumour-specific accumulation of radioiodine. These results were further confirmed by NIS-specific qPCR analysis and immunohistochemistry. Administration of a therapeutic dose of 131I in LPEI-PEG-GE11/NIS-treated mice resulted in significantly delayed tumour growth compared to animals treated with non-coding LPEI-PEG-GE11/antisenseNIS + 131I or saline controls as determined by magnetic resonance imaging. In conclusion, our preclinical data in an advanced GEMM of PDAC clearly demonstrate the enormous potential of EGFR-targeted synthetic polymers for systemic NIS gene delivery allowing for targeted radionuclide therapy of non-thyroidal cancers.
Thyroid Hormone Action Saturday Poster Basic
Wound healing and tumour stroma formation are dynamic events that are associated with angiogenesis and require interactions of various different cell types, including fibroblasts, pericytes, endothelial cells (ECs) and mesenchymal stem cells (MSCs). We and others have shown that MSCs differentiate into fibroblast-/pericyte-like cells in the tumour milieu and secrete proangiogenic factors. Thyroid hormones act as non-classical proangiogenic modulators mediated by non-genomic mechanisms via cell surface receptor integrin αvβ3. The aim of this study is to evaluate the stimulatory activity of T3 and T4 on endothelial cell tube formation in concert with the assessment of angiogenic effects of MSCs.
Primary human umbilical vein endothelial cells (HUVECs) were seeded on Matrigel and tube formation was analysed microscopically after 12 h. Compared to untreated HUVECs, treatment with T3 stimulated tube formation, as evidenced by more intricate networks with larger numbers of junctions and meshes. Additional treatment with tetrac, a specific inhibitor of integrin αvβ3-mediated action of T3/T4, reduced tube formation to basal level. Similar, albeit weaker, effects were observed for T4. Further, primary human bone marrow-derived MSC-conditioned medium stimulated tube formation. After additional treatment with thyroid hormone, an even more pronounced angiogenic effect was observed compared to untreated control cells and tetrac-treated cells. In a further set of experiments, co-cultures of HUVECs and MSCs were analysed in this assay. MSCs were found to be integrated into developing tubular networks adjacent to HUVECs and to stabilise networks over time. At 12 h, no thyroid hormone effects were observed in co-cultures. However, after 24 h, T3 again stimulated angiogenesis.
Our data suggest that thyroid hormones, especially T3, stimulate angiogenesis in HUVECs in an integrin αvβ3-dependent manner, an effect that can be enhanced by both treatment with MSC-conditioned medium and co-cultures with MSCs. These studies improve our understanding of the critical role of thyroid hormone in the regulation of angiogenesis in the context of wound healing and tumour stroma formation.
Thyroid Hormone Action Saturday Trainee Poster Contest Finalist Basic
Thyroid hormone (TH) modulates gene expression via thyroid hormone receptors (TR) that regulate transcription by interacting with T3-responsive elements. In hypothyroidism the unliganded TR binds the nuclear receptor corepressor 1 (NCoR1), which regulates gene expression by recruiting a multiprotein complex including HDAC3. Binding of T3 to the TR induces the dismissal of the corepressor complex and allows the recruitment of coactivators. Previously, we showed that mice expressing an NCoR1 allele (NCoR1ΔID) that does not bind the TR were hypersensitive to T3 and derepressed positive T3-targets in the liver. To rule out any remaining function of NCoR1 we have now ablated all of NCoR1 (NCoR1KO) specifically in the liver of mice and analyzed the expression of T3-targets in euthyroid and hypothyroid conditions by qPCR. Also, we analyzed acetylation on H3K9 and H3K27 via ChIP. Ablation of NCoR1 in both euthyroid and hypothyroid conditions enhances the expression of T3-positive targets including Fasn, Me1, Scd1, and Thrsp. This is consistent with the increased acetylation of H3K27 and H3K9 that we observed in the vicinity of these genes in NCoR1KO mice. However, repression in hypothyroidism of these T3-positive genes still occurred in NCoR1KO mice. Thus, on these targets NCoR1 attenuates basal gene expression but alternate mechanisms mediate repression in hypothyroidism. NCoR1-independent repression was also observed on dio1, the most highly regulated T3-target in hypothyroidism. While H3K9 and H3K27 acetylation is dramatically reduced around TRbeta binding sites in dio1, this was not affected by the absence of NCoR1 in hypothyroidism. Thus, repression of dio1 in hypothyroidism is independent of NCoR1. To further explore the role of NCoR1 in hypothyroidism we bred hypothyroid Pax8KO mice with mice that express NCoR1ΔID. Remarkably, in the absence of all TH the presence of NCoR1ΔID had little effect on positive TR targets that were repressed in Pax8KO mice. Taken together our results indicate that NCoR1 mediates the set point of TH gene expression on a significant number of target genes potentially via histone deacetylation. In contrast, repression of T3-targets in hypothyroidism appears to be independent of NCoR1.
Thyroid Hormone Action Saturday Trainee Poster Contest Finalist Basic
Mutations in the TH receptor β gene (THRB) cause resistance to TH β (RTHβ). The clinical phenotypes include goiter, tachycardia, and elevated FT4 and FT3 with non-suppressed TSH. Here, we present the clinical phenotype and biochemical characteristics of a novel mutation, L341V-TRβ1, found in a 12-year-old Thai girl with RTHβ. Genomic DNA was sequenced for mutations in the exons of the THRB gene. To explore its pathogenic mechanism, the L341V mutation was modeled into a wild-type (WT) TRβ1 crystal structure (3GWS) using YASARA Structure and the L341V, L341A, L341I, L341F mutants were introduced in a FLAG-tagged TRβ1 construct. Binding affinity of in vitro translated L341V-TRβ1 was determined using competitive binding assays. Upon expression in JEG3 cells, transcriptional activity of WT and mutant TRβ1 were measured after 24 hours stimulation with 0-10,000 nM T3, using thyroid response element (TRE) luciferase reporter constructs (DR4, IR0 and ER6) and pMAXGFP as control. Our patient presented with diffuse goiter, tachycardia, palpitations and high serum FT4 [5.37 ng/dL (0.7–2.1)] and FT3 [14.31 pg/mL (2.7–5.2)] with non-suppressed TSH [3.29 μIU/mL (0.7–6.4)], indicative of RTHβ. A heterozygous missense mutation in THRB (c.1021C>G; p.L341V) was found. Structure modeling of this mutation showed changes in side chain orientation and distance to the inner ring iodine of T3, suggesting interference with substrate binding. Indeed, the dissociation constant (Kd) for the L341V-TRβ1 mutant was 4-fold higher than for WT-TRβ1 (4.0 vs. 1.0 nM, p = 0.033) and transcriptional activity was impaired, as indicated by higher EC50 than WT on all TREs tested (DR4: 19.0 vs. 0.23 nM, IR0: 29.6 vs. 0.92 nM, and ER6: 405.3 vs. 1.7 nM; p < 0.01). The EC50s for activation of the DR4-TRE by the mutants were: 0.2 nM for Leu (WT); 22 nM for Val (patient), P < 0.001; 20 nM for Ala, P < 0.001; 3.5 nM for Ile, p < 0.05; 1.1 nM for Phe, NS). Thus, in particular, substitution of Leu341 by smaller amino acids result in impaired TRβ1 function. We report a novel L341V-TRβ1 mutation as a cause of RTHβ. Functional studies confirmed the impaired binding and transcriptional activity, and illustrate the importance of L341 side chain length for TRβ1 function.
Thyroid Hormone Metabolism & Regulation Saturday Trainee Poster Contest Finalist Basic
Thyroid hormone (TH) synthesis is initiated within the precursor protein thyroglobulin (TG), a large (2746 residue) glycoprotein synthesized in thyrocytes and post-translationally iodinated on multiple monoiodotyrosine (MIT) and diiodotyrosine (DIT) residues. Chemical coupling of DIT-DIT, or MIT-DIT, within the TG protein, initiates formation of thyroxine (T4) and tri-iodothyronine (T3), respectively. TH synthesis is tightly regulated by Thyroid Stimulating Hormone (TSH) interaction with its receptor (TSH-R). Two common thyroid diseases —
Thyroid Cancer Saturday Trainee Poster Contest Finalist Translational
Screening-based detection of thyroid cancers has nearly quadrupled from 1993 to 2012 with no change in thyroid-related mortality, which may have led to an overtreatment of indolent cancer. Molecular markers of metastatic disease with high negative predictive values may serve to better stratify patient risk and, in turn, inform treatment protocols. Follicular thyroid carcinomas (FCs) represent 15% of well-differentiated thyroid cancers and yet, distinguishing non-metastatic vs. metastatic subtypes remains a challenge. This study therefore explores the potential for identifying RNA markers of metastatic follicular disease. Total RNA-seq was performed on 4 metastatic and 4 non-metastatic (indolent) primary formalin-fixed paraffin-embedded (FFPE) FCs, using an rRNA depletion library generation protocol. Reads were analyzed with Tophat2 and CLASS2, a novel transcript assembler specifically suited to FFPE samples. Cuffdiff2 and rMATS were used to identify differentially expressed genes and differential splicing events between metastatic and non-metastatic primary tumors, followed by gene set enrichment analysis.7 of the 8 samples had acceptable read mapping rates. We identified 140 known and novel differentially expressed genes. External validation of these genes using The Cancer Genome Atlas (TCGA) data in papillary thyroid cancer (PTC) and its follicular variant (FVPTC) showed a concordance of 80%. Distance-based analysis of genes revealed molecular similarities between FCs and FVPTCs compared to PTCs. Canonical RAS mutations, validated by pyrosequencing, were detected in 3 metastatic FCs and splice-site mutations of EIF1AX were detected in 2 non-metastatic cases. First, we demonstrated the feasibility of using RNA-seq to study FFPE thyroid material. Second, we discovered a series of biological changes uniquely characteristic of metastatic FCs compared to indolent cases. The finding that FCs and FVPTCs have molecular similarities also suggests a need to reassess the classification of FVPTC in the spectrum between FC and PTC.
Thyroid Cancer Saturday Trainee Poster Contest Finalist Translational
We have previously demonstrated that integrin-linked kinase (ILK) was involved in proliferation, migration, and epithelial-mesenchymal transition in papillary and anaplastic thyroid cancer cell lines, but its clinical significance is unknown. We thus examined ILK tissue expression patterns and correlated this with clinical factors and outcomes. Tissues were obtained from resected specimens of papillary (PTC, n = 51), follicular (FTC, n = 11), and anaplastic (ATC, n = 8) thyroid cancers. All tissues were stained using immunohistochemistry to assess for ILK expression. Expression was graded 0–3 in the primary tumor cells, the surrounding stroma, and normal adjacent tissue. The associations between ILK expression intensity scores and clinical and pathological features were investigated. Immunofluorescence was performed to assess for co-staining of ILK with cancer-associated fibroblast (CAF) marker alpha-smooth muscle actin (alpha-SMA). ILK was over-expressed in the stromal compartment of PTC and ATC versus paired normal adjacent tissue (P < 0.01) and the primary cancer cells (P < 0.05). There was no significant over-expression of ILK in FTC in any compartment. Stromal ILK expression, but not tumor or normal adjacent tissue expression, correlated with presence of lymph node metastasis (P < 0.01). Additionally, stromal ILK expression, but not tumor or normal tissue ILK expression, correlated with recurrence free survival (RFS) (median 38.7 months for score 3 vs. median not reached for scores 0–2, P < 0.01). This correlation in RFS persisted when stratified for nodal positivity (P < 0.01). ILK was expressed nearly exclusively in cells expressing alpha-SMA, consistent with CAF-specific ILK overexpression in the PTC and ATC stroma. ILK is over-expressed in the stroma of papillary and anaplastic, but not follicular, thyroid cancers. This over-expression, localized to the cancer-associated fibroblasts, is highest in those patients with more aggressive clinical and pathological features. Examining the mechanistic role of ILK in CAFs could lead to improved understanding of the microenvironment of aggressive thyroid malignancies, elucidating novel biomarkers or therapeutic targets.
Autoimmunity Saturday Trainee Poster Contest Finalist Case Report
The association between autoimmune thyroid disease and type 1 diabetes (T1D) is well-known. We report a case of a girl with Graves' disease and T1D who has remained euglycemic off insulin therapy 4.5 years after radioiodine ablation (RAI). A 14 year old girl presented with thyromegaly, mild proptosis, and thyrotoxicosis. Family history is significant for Graves' disease in a paternal aunt, rheumatoid arthritis and systemic lupus erythematosus in the paternal grandmother, and maternal cousins with T1D. Laboratory evaluation was notable for a suppressed TSH 0.01 uIU/mL and elevated T4 31 mcg/dL and T3 9 pcg/mL. Thyroperoxidase, thyroglobulin, and TSH receptor (TBII) antibodies were positive. I-123 scintigraphy scan showed increased uptake of 59% at 24 hours. Propylthiouracil (5 mg/kg/day) and propranolol were initiated. Due to failure to achieve euthyroidism, the patient was transitioned to Methimazole (0.7 mg/kg/day).
After 8 months of ATD, TSH remained suppressed; however, free T4 and T3 normalized. The patient developed polyuria and polydipsia, and a random blood glucose was >500 mg/dL. Hemoglobin A1c was 14.3% (normal <6%); there was no evidence of ketoacidosis. Insulin was initiated, and T1D was confirmed by positive pancreatic antibodies. One month after diagnosis of T1D, the patient developed arthritis of the knee and ankle. Rheumatoid factor, ANA, Lyme Ab, and ESR were negative. RAI with 18 mCi of I-131 was performed, and biochemical euthyroidism was attained in 2 months. Two weeks after RAI, prandial insulin was no longer required. Due to recurrent hypoglycemia, basal insulin was withdrawn. Evaluation for celiac disease and adrenal insufficiency was negative, and HbA1c normalized with euthyroidism. The patient remains euglycemic and off insulin (insulin level 3.2 mcIU/mL, c-peptide 0.6 ng/mL, HbA1c 5.3%); pancreatic antibodies remain positive. To our knowledge, this is the first report of prolonged remission of T1D after RAI. Hyperthyroidism is known to cause derangements in glucose metabolism. In this case, thyroid hormone levels were normal at the time of hyperglycemia. Further studies including HLA typing may provide insight into the mechanisms behind progression of T1D and other autoimmune diseases.
Disorders of Thyroid Function Saturday Trainee Poster Contest Finalist Case Report
Hyperthyroidism is commonly associated with supraventricular tachyarrhythmias, but ventricular arrhythmias are unusual. We present a case of a child who developed marked QT interval prolongation and sudden cardiac arrest while being treated for hyperthyroidism. A 6 year old boy presented due to progressive worsening of previously unrecognized fatigue, weight loss, and exercise intolerance. He was noted to have tachycardia, hypertension and increased work of breathing; exam was notable for mild proptosis, minimal thyroid enlargement, and a heart murmur. EKG showed bilateral ventricular enlargement and the QTc was 469 msec. Echocardiogram demonstrated dilated cardiomyopathy with reduced left ventricular systolic function (shortening fraction 18.9% [−7.2 SD]). An evaluation revealed Graves disease with marked hyperthyroidism (TSH <0.02 mcu/mL T4 > 24.9 mcg/dL T3 > 7.8 ng/mL). Treatment with methimazole, SSKI, and propranolol resulted in rapid improvement and suppression of thyroid hormone levels to mild hypothyroidism within 10 days.
Four days after starting antithyroid treatment, the QTc interval increased to 589 msec. The next day, he entered pulseless polymorphic ventricular tachycardia, requiring CPR and electrical cardioversion. A comprehensive evaluation found no clear etiology for prolonged QTc. Medications were sequentially withdrawn - including methimazole, as he was then hypothyroid. The QTc normalized over 10 days before hyperthyroidism recurred; methimazole was restarted at the previous dose and the QTc remained normal. Thyroid hormones modulate the expression and function of cardiac potassium and calcium channels, and QT prolongation is associated with both hypothyroidism and congestive heart failure (CHF). However, QT prolongation is not associated with treatment of hyperthyroidism. This patient's severe QT prolongation was transient and most intense as thyroid levels rapidly fell. We hypothesize that the rapid correction of severe hyperthyroidism in the setting of CHF and preexisting mildly prolonged QT may have further prolonged the QT interval. Therefore, it is reasonable to consider close monitoring for QT interval prolongation in children being treated for severe hyperthyroidism.
Thyroid Cancer Saturday Poster Case Report
Thyroid nodules typically grow slowly and cause no symptoms, but carry a greater risk of malignancy in children compared to adults. We present an unusual case of thyroid cancer found in a girl with a painful thyroid nodule. A 13 year old girl presented for evaluation of a tender thyroid lesion associated with odynophagia that evolved over several days in the absence of a febrile illness. Examination revealed a tender 3 cm left sided thyroid nodule and painful cervical lymphadenopathy. Ultrasound identified a 2.9 cm left lobe solid heterogeneous nodule with increased blood flow and vague margins. Laboratory studies demonstrated a normal TSH and Free T4, anti-thyroglobulin antibody >500 u/mL and anti-TPO Ab 166 units/mL; ESR was normal. She was diagnosed with Hashimoto's thyroiditis and presumed subacute thyroiditis.
Empiric steroid therapy was initiated and resulted in significant subjective clinical improvement, but symptoms worsened at the conclusion of therapy and so a trial of clindamycin was prescribed with similar subjective success. However, repeat ultrasound identified an increase in size of the thyroid nodule and fine needle aspiration (FNA) biopsy was recommended, but the family declined in favor of lobectomy. Lobectomy was achieved and intra-operative frozen sections confirmed the presence of papillary thyroid carcinoma (PTC), so a total thyroidectomy with central neck dissection was performed. Final pathology revealed classic variant papillary thyroid carcinoma isolated to the thyroid gland (T3N0M0). Thyroid carcinoma typically presents as an asymptomatic thyroid nodule. Subacute thyroiditis typically develops following a URI and causes painful thyroid swelling which may appear to represent a nodule on ultrasound. Our patient presented with symptoms suggestive of subacute thyroiditis but the lesion did not resolve with usual therapy. Surgery was ultimately pursued secondary to persistent symptoms ultimately leading to the diagnosis of PTC.
The presence of pain does not exclude the potential diagnosis of thyroid carcinoma. FNA biopsy should be completed for all thyroid lesions that do not follow an expectant course of medical management.
Thyroid Hormone Action Saturday Trainee Poster Contest Finalist Case Report
RTH is a rare genetic-disorder, usually inherited in autosomal dominant manner, and results in decreased end-organ responsiveness to thyroid-hormone. RTH is usually due to defects in thyroid-hormone receptors(TR), alpha and beta, which are located on chromosomes 17 and 3, respectively. TRs are present on end organs and thyroid-hormone action is mediated through these receptors. T3 binds to TRs and is responsible for brain/somatic development in infants, and metabolic activity in adults. About 85% cases of RTH are due to mutations in TR-beta. We present a case of RTH due to mutation in TR-beta gene resulting in cretinism. A 41 year-old female, nursing-home resident with history of hypothyroidism and mental-retardation was referred to Endocrinology for abnormal thyroid-function tests. She was mis-diagnosed as Graves' disease and had a total-thyroidectomy in early childhood possibly resulting in cretinism. When we first saw her, she was clinically hypothyroid on levothyroxine100mcg daily, TSH was 9.31 UIU/ml, free T4-2.1 ng/dl (0.7–1.6 ng/dl) and free T3-4.7 pg/ml(2.3–4.2 pg/ml). Genetic test for RTH showed heterozygous positive for one copy of p.arg338Trp mutation in exon 9 of the THR-b gene. We increased her levothyroxine dose and titrated it to 300mcg daily. Her TSH is 1.28 UIU/ml, freeT4-3.1 ng/dl, freeT3-6.2 pg/ml and she is clinically euthyroid. RTH has variable clinical presentation. Affected patients could be asymptomatic, present with goiter, symptoms of hypo/hyperthyroidism or abnormal routine laboratory tests, leading to further investigation resulting in diagnosis of RTH. It is characterized by non-suppressed TSH and high levels of serum Free-T4 and Free-T3. To compensate for RTH there is increased secretion of thyroid-hormone. Other causes of non-suppressed TSH with high thyroid-hormone levels like TSH-secreting pituitary adenoma should be ruled out. Most patients do not need treatment as they can adequately compensate for RTH by increased secretion of T4. Hypothyroid patients who had ablative/surgical treatments due to misdiagnosis should be treated with sufficient amount of T4 to maintain TSH in normal range. Correct diagnosis and knowledge of treatment goals is the key in management of RTH patients.
Disorders of Thyroid Function Saturday Poster Case Report
Lithium is a drug used to treat bipolar-disorder. It inhibits release of iodine from thyroid-gland and usually causes hypothyroidism as a side-effect. It has been used previously in a few case-reports for treatment of thyrotoxicosis when thionamides are contraindicated and patient is waiting for elective radioactive-iodine ablation (RAIA) or surgery. A 33-year old woman was admitted to ICU with acute heart-failure and fulminant ischemic-hepatitis secondary to cardiogenic-shock. Two weeks prior to this admission she was started on Methimazole 10 mg daily for thyrotoxicosis [TSH <0.006 UIU/ml, FreeT4-1.2 ng/dl (range-0.7–1.4), FreeT3-4.6 pg/ml (range-2.1–3.8)]. RAIU showed a hot-nodule in the right-lobe. Thyroid-ultrasound done previously showed a hypervascular dominant-nodule in right-lobe measuring 3.2 × 2 × 1.6 cm. She was started on dopamine drip for cardiogenic-shock. ECHO revealed EF <20% with global-hypokinesis. Laboratory-data showed ALT-3367U/L, AST-4921U/L, Creatinine-1.35 mg/dl, TSH- 0.047 UIU/ml, FreeT4-0.9 ng/dl and FreeT3-1.5 pg/ml. Beta-blockers contraindicated due to shock. There was no apparent cause for her heart-failure and with untreated hyperthyroidism her condition could not be stabilized. Over the period of 2-weeks she continued to be on dopamine-drip. Methimazole and Propylthiouracil were contraindicated secondary to fulminant-hepatitis. She was not stable for surgery and RAIA was not feasible while inpatient due to hospital-policies. Lithium was started as a last resort at 300 mg PO BID. She was weaned off dopamine drip. Thyroid-function tests were repeated in 1-week showing marked improvement with TSH-0.647 UIU/ml and FreeT4-0.7 ng/dl and Lithium-level-0.76 mmol/L(range-0.5–1.2). We recommended treatment with Lithium and definitive treatment with RAIA once she was discharged and to check Lithium levels weekly. It has been seen in previous case-reports that Lithium can be used to treat hyperthyroidism even at sub-therapeutic levels. Usually patients respond to a much lower dose that what is used for treating Bipolar-disorder. Lithium can be used to treat hyperthyroidism for short period of time when other treatment options are contraindicated or unavailable, although a close monitoring for lithium toxicity is needed.
Disorders of Thyroid Function Saturday Trainee Poster Contest Finalist Case Report
TSH secreting pituitary adenomas are a rare cause of thyrotoxicosis, with incidence of one case per million. Some patients do not have surgical cure, necessitating additional therapy such as somatostatin analogs for residual disease. 41 year old man with history of hypogonadism and gynecomastia was discovered on head MRI to have a 2.8 cm pituitary macroadenoma. Symptoms included chronic headache, loss of peripheral vision, weight loss, palpitations, tremors and heat intolerance. Pituitary hormone evaluation was notable for central hypogonadism, mildly elevated prolactin, and high free T4 with normal TSH. He underwent transsphenoidal resection with surgical pathology revealing focal positive staining for prolactin and FSH, and negative staining for LH, ACTH, GH and TSH.
Repeat head MRIs initially showed stable residual tumor. He had persistent hyperthyroid symptoms with progressive elevation of free T4 / T3 but normal TSH. Thyroid uptake and scan was normal. The possibility of a TSH secreting adenoma was entertained despite negative pathology stain for TSH. Pituitary glycoprotein alpha subunit was elevated. Around four years after surgery, head MRI showed interval mass enlargement. Complete resection was not possible due to bilateral cavernous sinus involvement and patient declined debulking surgery. He was started on octreotide injections with significant improvement of thyrotoxic symptoms, alpha subunit and thyroid function labs. Subsequent head MRI showed decreased mass size and less optic chiasm mass effect. This case demonstrates a TSH secreting pituitary adenoma with negative pathology staining. Supporting this diagnosis is elevated alpha subunit in the setting of pituitary mass, hyperthyroid symptoms, and elevated free T4 / T3 with inappropriately normal TSH. Additional confirmation was his clinical and biochemical response to octreotide therapy. While transsphenoidal resection is the definitive first-line therapy for TSHomas, one-third of post-resection patients have continued TSH hypersecretion. Somatostatin analogs can normalize circulating thyroid hormones in 95% of patients and reduce pituitary mass in 40%. Somatostatin analogs are effective therapies for residual TSHomas after surgery.
Disorders of Thyroid Function Saturday Trainee Poster Contest Finalist Case Report
Muscular symptoms occur in 30–80% of adults with hypothyroidism. The proposed mechanisms for altered muscle function include decreased energy metabolism, mitochondrial oxidative dysfunction, and impaired glycogenolysis. Usually, the clinical manifestations are mild to moderate. Rarely, patients present with rhabdomyolysis, a life-threatening condition associated with marked creatine kinase (CK) elevation (at least five times the upper limit of normal), electrolyte imbalances, and acute kidney injury. Six patients presented with fatigue, muscle weakness and myalgias. They were of different races, half were female, and the average age was 40 years. Reported duration of symptoms ranged from 6 days to 5 months. Biochemical evaluation was notable for hypothyroidism, with thyroid stimulating hormone (TSH) 14.13-280 uIU/mL (0.35–5.5 uIU/mL), and rhabdomyolysis, with CK 1284-8491 IU/L (20-210 IU/L). Acute kidney injury was noted in three patients.
Two patients had a prior diagnosis of hypothyroidism and poor levothyroxine (LT4) compliance. The other four had not been previously diagnosed. One had undergone radioactive iodine therapy for Graves' disease four months prior. The other three had elevated thyroid peroxidase antibodies, consistent with Hashimoto's. Precipitating factors included exertion, statin therapy, and marijuana use.
All patients received LT4. Two received a one-time dose of IV LT4. Maintenance LT4 doses were 0.5 to 2.7 mcg/kg/day. Five patients were hospitalized and given IV normal saline. CK decreased by at least 40% one week after treatment. Free T4 normalized in half within four weeks. One patient was lost to follow up. Improvement of symptoms was seen in four patients at 1 to 9 months. While muscular symptoms are common in hypothyroidism, rhabdomyolysis is rare and potentially life-threatening. Muscular symptoms may be present for months prior to presentation. Early diagnosis and treatment is essential in order to avoid associated morbidity and mortality. Over half of our patients did not carry a prior hypothyroidism diagnosis. This suggests that biochemical thyroid evaluation is an essential diagnostic component in cases of unexplained rhabdomyolysis. N/A
Disorders of Thyroid Function Saturday Trainee Poster Contest Finalist Case Report
Nivolumab is a monoclonal antibody against Programmed Cell Death-1 (PD-1) and has current FDA approval for the treatment of metastatic melanoma and advanced non-small cell lung carcinoma. With prolonged use, there may be associated thyroid adverse effects such as hypothyroidism, hyperthyroidism and thyroiditis. We report a case of asymptomatic thyroiditis followed by severe hypothyroidism associated with nivolumab use. A 71-year-old man with hypertension, hyperlipidemia, impaired fasting glucose, and remote history of prostate carcinoma treated with radical prostatectomy, was diagnosed with poorly differentiated metastatic lung adenocarcinoma. He was initially treated with carboplatin and taxol, but due to severe adverse effects, he was given nivolumb instead. After 2 months of therapy with nivolumab, he was found to have thyroiditis, with a TSH of 0.07 mU/L (0.35–5.5), free thyroxine index of 10.2 μg/dL (5.93–13.3) and total of T4 12.15 μg/dL (6.1–12.2). Thyroid stimulating immunoglobulins were negative, but he had positive thyroid peroxidase antibodies at 89 IU/mL (0–34). Physical exam was revealed a non-tender thyroid. Chart review also demonstrated 15 years of stable thyroid function tests. Four months after starting nivolumab, he developed severe hypothyroidism (TSH 84.2 mU/L, total T4 4.56 μg/dL and Free T4 0.3 ng/dL (0.6–1.2 ng/mL)) with the only complaint of fatigue and normal physical findings. He was subsequently started on levothyroxine. Treatment with nivolumab has been associated with the development of various autoimmune phenomenon. This case highlights an example manifested by very rapid progression to severe hypothyroidism, which initially began as thyroiditis after 2 months of therapy. As the number of patients being treated with nivolumab increases, clinicians need to be aware of the increasing potential for varying types of thyroid disease that can occur with prolonged treatment.
Thyroid Cancer Saturday Trainee Poster Contest Finalist Case Report
Differentiated thyroid cancer (DTC) carries an overall excellent prognosis with triple-prong treatment approach, including surgery, radioactive iodine (RAI) treatment and suppressive hormonal therapy. Many thyroid cancers dedifferentiate and lose their ability to take up RAI, rendering it an ineffective therapy in this subgroup of patients. Prognosis decreases dramatically in patients with metastatic RAI-refractory disease. Prior studies have suggested that use of tyrosine kinase inhibitors (KIs) can sensitize tumors to RAI. Here we describe a case report of a patient treated with targeted therapy to resensitize the tumor to RAI and allow for a therapeutic dose. We describe a 65-year-old female with follicular thyroid carcinoma who initially underwent a total thyroidectomy with bilateral neck dissection. Her pathology staged her at T4aN1aMX status. She underwent treatment with RAI twice with a cumulative dose of 199 mCi before she was deemed to be RAI refractory based on a negative diagnostic whole body scan (WBS) but a positive CT chest showing metastatic lung nodules. She had also underwent a second neck surgery for recurrent neck disease. Mutational profiling of cervical lymph nodes showed a RAS mutation. Given her progressive disease and KRAS mutation, she was started on a MEK162 inhibitor and was treated for 9 months. A postKI diagnostic WBS showed a meaningful increased uptake that allowed for treatment with 208 mCi of iodine-131. The patient's suppressed thyroglobulin (TG) level decreased from 2201 ng/mL (TSH of 0.67 mcunit/mL) pre-RAI treatment to 1143 ng/mL (TSH of 0.28 mcunit/mL) post-RAI treatment. Cross sectional imaging at 5 months post RAI treatment included a CT scan of the neck and chest which showed stabilization of cervical lymph nodes and pulmonary nodules that were previously progressing. Use of targeted KI therapy in iodine-refractory thyroid cancer patients may resensitize these tumors to iodine uptake and retention allowing for use of RAI therapy in a subset of patients. Clinically and radiographically meaningful responses may occur in appropriately selected patients. Long-term responses and survival need larger studies with longer-term follow-up.
Thyroid Cancer Saturday Trainee Poster Contest Finalist Case Report
Graves' disease (GD) is the most common cause of hyperthyroidism in adults. Hyperthyroidism due to autonomously functioning thyroid cancer or metastasis is extremely rare. We report a case of GD and papillary thyroid cancer (PTC) with recurrent hyperthyroidism after total thyroidectomy and radioactive iodine (RAI) ablation due to functional thyroid metastases.
66-year-old female was diagnosed with hyperthyroidism (TSH <0.005 uU/mL, Free T4 2.7 ng/dl (0.7–1.8), T3 316 ng/dl (94–170)) during evaluation of tachycardia and weight loss. She had a diffuse goiter without ophthalmopathy. She had elevated Thyrotropin- Receptor Antibodies (TRAb; TSI 151% (< 150), TBI 31.7 U/L (<1)), her RAI thyroid uptake was 28% and the scan was suggestive of GD. She was started on methimazole that was stopped after 3 weeks due to transaminitis and was found to have a 4.5-cm liver mass. Her thyroid ultrasound showed right lobe nodules measuring up to 4.3 cm, serum thyroglobulin (Tg) level of 619250 ng/mL (0.8–49) and incidental pulmonary masses on chest imaging. Fine needle aspiration biopsy of endobronchial lesion was suggestive of metastatic PTC. She underwent total thyroidectomy which showed 3.2 cm follicular variant of PTC and was treated with 100 mCi I-131 when her uptake in the large chest mass was 40%, her TSH was <0.005 uU/mL and T3 was 381 ng/dl. She briefly became euthyroid and then developed recurrent hyperthyroidism, rising Tg levels to 95,077 ng/ml and progression of metastatic pulmonary disease. She underwent repeat whole body scan while hyperthyroid and received another dose of 217 mCi of I-131. Her post-treatment scan showed uptake in the pulmonary and liver lesions and had normalization of Free T3 and T4 in a few weeks.
GD is associated with more aggressive thyroid cancer. Autonomously functioning thyroid cancer and metastases are proposed to be related to presence of stimulating TRAb in GD. In the absence of GD the autonomous functioning is thought to be related to bulky metastases. Hyperthyroidism in co-existing GD and metastatic thyroid cancer can be a diagnostic challenge and RAI uptake scan can be helpful in discerning the etiology. RAI ablation has a superior therapeutic response in functioning pulmonary metastases.
Thyroid Hormone Metabolism & Regulation Saturday Trainee Poster Contest Finalist Case Report
Allan-Herndon-Dudley (AHD) syndrome is a rare form of X-linked mental retardation and spasticity caused by defects in the thyroid transport protein monocarboxylate transporter 8 (MCT8). Boys with AHD have characteristic clinical findings and abnormal thyroid function tests, particularly high levels of total T3 (TT3). We present a case of a boy identified by newborn screening (NBS) with congenital central hypothyroidism found to have a previously undescribed mutation in the MCT8 gene. Our patient had 3 NBS tests with low-normal total T4 and non-elevated TSH, confirmed with serum testing. He was started on 37.5 mcg levothyroxine at 1.5 months of age. At follow-up at 5 months he was noted to be jittery and tachycardic with elevated free T4. Levothyroxine dose was decreased, yet at 7 months he had loss of motor skills, a diagnosis of spastic quadriplegia and absent weight gain despite frequent feedings. TT3 was markedly elevated at 401 ng/dl (normal range for age 87–200). With the findings of developmental delay, low T4 and high T3, there was strong suspicion for AHD and genetic analysis was requested. Direct sequencing of all coding exons of the MCT8 gene showed a novel mutation of one base pair deletion in exon 2 (c.754delG) resulting in a premature stop codon and a truncated protein lacking biological activity. The mother, maternal grandmother, aunt, and female cousin are carriers. A male cousin with severe global developmental delays was hemizygous for the mutation. Our patient was started on propylthiouricil to suppress T3 production, with levothyroxine supplementation to support adequate FT4 for cerebral development. Since starting the medication family reports improvements in alertness and interaction. This is the second reported case of AHD initially diagnosed as congenital central hypothyroidism, detected on NBS with low TT4 and non-elevated TSH. Although the MCT8 gene is included in many genetic panels for X-linked mental retardation, testing of T3 after NBS suggestive of central hypothyroidism would result in earlier detection of this rare disease. Early detection provides potential for therapeutic intervention and possible amelioration of thyroid hormone abnormalities.
Disorders of Thyroid Function Saturday Poster Clinical
Down Syndrome (DS) is associated with increased risks for thyroid disease. Historical studies are limited by small cohorts and inadequate diagnostic detail. This is a retrospective cohort study of the characteristics of thyroid hormone abnormalities (THA) in 565 patients seen at Oregon Health and Science University. Retrospective chart review of eligible patients in the Child Development and Rehabilitation Center's Down Syndrome Clinic (DSC) and patients with DS and THA diagnosis at OHSU's Pediatric Endocrinology Clinic (PEC). Data included age at last clinic visit, age at diagnosis with THA, and thyroid function tests at visit and diagnosis. Prevalence rates are from DSC cohort while diagnostic data and associations are from both clinics. 508 patients from DSC. 120 (34%) had a diagnosis of THA: 10 congenital hypothyroidism (CH), 52 subclinical hypothyroidism (SH), 31 overt hypothyroidism (OH), and 8 hyperthyroidism (HT); 19 had history of THA but no diagnostic information (unknown). 55 eligible patients in the PEC included 3 CH, 17 SH, 19 OH, 8 HT, and 8 unknown. Patients with SH were more likely than those with OH to be tested for anti-thyroid antibodies, but those with OH had twice the rate of positive anti-thyroid antibodies. Patients with OH required higher doses of levothyroxine at all ages. Logistic regression against multiple common DS comorbitities showed no identified associations. For any thyroid disease 50% of cases are diagnosed by age 3 years. For acquired hypothyroidism, 50% are diagnosed by 5 years. Using a Kaplan-Meier estimate, 25% of all DS patients have a diagnosis of hypothyroidism by age 7 years and 50% will be diagnosed by age 17.5 years. This is among the largest profiles of TH abnormalities in DS patients. We report a higher rate (1.5%) of hyperthyroidism than other cohorts. The Kaplan Meier estimate suggests that previous smaller pediatric studies may underestimate the prevalence in older children. There are no covariates that increase the likelihood of diagnosis of congenital hypothyroidism or any thyroid dysfunction. In cases of uncertainty in diagnosis, additional testing for anti-thyroid antibodies may predict disease severity and need for hormone replacement vs watchful waiting.
Autoimmunity Saturday Trainee Poster Contest Finalist Clinical
Thyroid hormones synthesis requires the continuous formation of hydrogen peroxide by thyroid peroxidase in order to maintain thyroid function and proliferation. Since hydrogen peroxide is a very reactive oxidant, antioxidant systems (AOS) are needed to protect the thyroid cell form reactive oxygen species (ROS). ROSs are generated in autoimmune thyroid disease (ATD) and in thyroid orbitopathy (TO), thus thyroid interstitial inflammation and retroocular fibroblast proliferation depend on the balance between oxidative stress (OS) and AOS. Which is why our objective was to assess OS in patients with ATD diagnosis with or without TO. Twelve patients with ATD and thyroid orbitopathy, were compared to 12 patients with ATD and no thyroid orbitopathy at the Centro de Investigaciones Endocrino-Metabólicas Dr. Félix Gómez, Venezuela. Clinical activity score (CAS) and ophthalmopathy severity index were assed. Thyroid profile, thyroid antibodies (AbTPO, AbTgB) MDA (malondialdehyde) and NO (nitric oxide) serum levels were quantified in all patients. T-Student and ANOVA tests were used for statistical analysis. Mean age was 38.75 ± 13.05 yo. All patients with thyroid orbitopathy had active CAS, and 33.3% (N = 4) had mild ophthalmopathy and 66,6% (N = 8) had moderate to severe ophthalmopathy. MDA levels were normal, but showed significant difference when compared among the ATD patients with TO and without TO, (0.82 mM and 1.09 mM, p = 0.007 respectively). NO serum levels although within normal range, were statistically different between the ATD group with TO and the group without TO (38.25 mM and 20.75 mM, p = 0.019 respectively). Thyroid hormones and TSH were within normal range. The exact mechanisms that lead to ATD and thyroid orbitopathy are not fully understood, but it is known that oxidative stress plays a major role. Oxidative profile in our group of patients, even though normal, indicated that NO is more elevated in patients with active TO and moderate to severe ophthalmopathy, leading to lower OS and to low grade inflammation. Seemingly, more free oxygen radicals generated in ATD with active TO unravel antioxidant response, but to draw firm conclusions, large randomized controlled studies are warranted.
Thyroid Imaging Saturday Poster Clinical
To evaluate the use of Thyroid Imaging Reporting and Data Base System (TIRADS) in the assessment of thyroid nodule risks of malignancy and its correlation with ultrasound-guided Fine Needle Aspiration (FNA) results. This study was approved by the Bioethics committee of the Hospital Universitario de Caracas. In this prospective study, a total of 117 patients were evaluated from January 2013 until December 2015 and categorized according to modified TIRADS by Russ et al. TIRADS category was then correlated to FNA histopathological findings according to Bethesda system in order to establish sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for this method. Of a total of 117 nodules, 4 where categorized as TIRADS 2 (100% benign, 0% undetermined, 0% suspicious, 0% malignant), 3 where categorized as TIRADS 3 (100% benign, 0% undetermined, 0% suspicious, 0% malignant), 48 as TIRADS 4A (56% benign, 45% undetermined, 4.8% suspicious, 0% malignant), 49 as TIRADS 4B (33.4% benign, 45.5% undetermined, 66.7% suspicious, 55.6% malignant) and 12 where categorized as TIRADS 5 (1.3% benign, 9.0% undetermined, 28.5% suspicious, 44.4% malignant). Sensitivity, specificity, PPV and NPV were 100%, 65.3%, 25.7%, 100% and 69%, respectively. TIRADS modified classification by Russ, has a high sensitivity specially to identify benign lesions, with a NPV of 100% and a relative high specificity to diagnose malignant and suspicious lesions, making it a useful and simple tool to evaluate nodular pathology in the decision making to perform FNA.
Disorders of Thyroid Function Saturday Trainee Poster Contest Finalist Clinical
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of abnormal liver function tests. It can progress to liver fibrosis, cirrhosis and hepatocellular carcinoma. Thyroid dysfunction, especially hypothyroidism, has been associated with cardiovascular disease, metabolic syndrome, and lipid metabolism dysregulation. We performed a systematic review and meta-analysis to find the association between hypothyroidism and NAFLD. We comprehensively searched the databases of MEDLINE and EMBASE from their dates of inception to May 2016. The inclusion criteria were articles related to thyroid gland, thyroid dysfunction, hypothyroidism, or hyperthyroidism and NAFLD or non-alcoholic steatohepatitis (NASH). Only studies that used either ultrasonography or liver biopsy for the assessment of NAFLD/NASH were included. Two authors independently assessed quality of the articles and extracted relevant data. Random-effects model was used for meta-analysis. From 25 full-text articles, nine studies were included in the meta-analysis of hypothyroidism. There was a significant increase in odds of NAFLD in patients with hypothyroidism with pooled odds ratio (OR) = 1.44 (95% CI: 1.14–1.80, p = 0.002). In subgroup analyses, subclinical hypothyroidism did not have significant association with NAFLD with pooled OR = 1.27 (95% CI: 0.76–2.10, p = 0.36); while overt hypothyroidism had significant association with NAFLD with pooled OR = 1.53 (95% CI: 1.10–2.12, p = 0.01). Overt hypothyroidism is significantly associated with non-alcoholic fatty liver disease. Thyroid hormone profiles could be a part of initial assessment in patients with NAFLD. Future studies should be performed to evaluate whether treatment of hypothyroidism in patients with NAFLD will improve disease outcome.
Disorders of Thyroid Function Saturday Trainee Poster Contest Finalist Clinical
Subclinical hypothyroidism (SCH) has been reported as an independent risk factor of non-alcoholic fatty liver disease (NAFLD), but whether treatment of SCH patients yields any benefits on NAFLD has not been studied. This post hoc analysis was conducted to evaluate the effect of L-thyroxine replacement therapy on prevalence of NAFLD and liver function in SCH patients. This analysis involved 363 SCH patients, 33 significant (TSH ≥10 mIU/L) and 330 mild SCH patients (TSH of 4.2 – 10 mIU/L). All the significant SCH patients received L-thyroxine supplement. Among the mild SCH patients, 181 were treated with L-thyroxine and 149 were not treated. After 15 months euthyroidism was reached in the intervened patients, the prevalence of NAFLD was reevaluated. Changes in liver enzymes also were analyzed. Subgroup analysis was performed to observe the effect of L-thyroxine on the prevalence of NAFLD in mild SCH patients having dyslipidemia. After treated with L-thyroxine, the prevalence of NAFLD in significant SCH patients halved from 48.5% to 24.2% (P = 0.041). In mild SCH patients, the prevalence of NAFLD and serum liver enzymes were not significantly affected by L-thyroxine supplement. Nonetheless, subgroup analysis exhibited benefits of L-thyroxine replacement therapy on NAFLD in mild SCH patients that having dyslipidemia. Patients received L-thyroxine treatment experienced significant decrease both in the prevalence of NAFLD (54.3% to 40.5%, P = 0.035) and the serum alanine aminotransferase (ALT) level (19.93 ± 10.60 to 18.07 ± 8.27 IU/L, P = 0.043) during the course of study. In contrast, the prevalence of NAFLD and liver function remained comparable stable throughout the study in patients that were not treated. Accordingly, there were significant reductions in body weight, BMI, as well as serum atherogenic cholesterols in patients treated with L-thyroxine, suggesting that improvement of NAFLD may be associated with the reductions of these factors. This study demonstrated a benefits of L-thyroxine replacement therapy on NAFLD in patients with SCH. For NAFLD patients that combined with SCH, treatment of SCH with appropriate supplement of thyroxine may be an effective means for controlling NAFLD.
Disorders of Thyroid Function Saturday Trainee Poster Contest Finalist Clinical
Limited data suggest that the prevalence of thyroid functional disease may differ across racial and ethnic groups in the general population. We sought to examine the characteristics of serum thyroid functional status among a large university-based cohort with a strong minority representation. Among adult patients who received care within the University of California, Los Angeles Healthcare System and underwent serum thyrotropin (TSH) testing over the period of 2000–2015, we conducted a cross-sectional analysis examining race, ethnicity, and other case-mix characteristics across categories of thyroid functional status defined as: hypothyroidism (serum TSH >5 mIU/L), euthyroidism (serum TSH 0.5–5 mIU/L) and hyperthyroidism (serum TSH <0.5 mIU/L). Among 54,306 patients who met eligibility criteria, 2476 (4.5%) were hyperthyroid, 49,391 (91.0%) were euthyroid, and 2,439 (4.5%) were hypothyroid. The mean ± SD age of the overall cohort was 52 ± 17 years, among whom 64% were female, 77% were White, 9%, were Black, 13% were Asian, and 2% were of other race. Patients of Hispanic ethnicity comprised 9% of the cohort. Across racial groups, hypothyroidism was most prevalent among White patients (4.7%) and those of other race (5.1%), whereas the prevalence of hyperthyroidism was highest among Black patients (5.7%). By ethnicity, Hispanics had a higher prevalence of hypothyroidism compared to non-Hispanics. The mean and standard deviation of TSH levels among White, Black, Asian, Hispanic, and non-Hispanic patients were 2.39 ± 4.63, 1.95 ± 5.53, 2.22 ± 3.91, 2.49 ± 5.73, and 2.31 ± 4.49, respectively. There appears to be variation in the distribution of thyroid functional disease across racial and ethnic groups. Further studies are needed to determine the clinical implications of these differences.
Thyroid Cancer Saturday Trainee Poster Contest Finalist Clinical
Follicular thyroid tumors pose a diagnostic problem because there is no established way to pre-operatively differentiate between follicular thyroid carcinoma (FTC) and adenoma (FTA). Our aim was to investigate whether cytological MIB-1 index can contribute to the distinction between these groups of tumors. All patients with FTC and atypical adenoma (AFTA) that were operated at Karolinska University Hospital in the period 2006–2015 were reviewed retrospectively. A control group of patients with FTA operated during the same period was randomly selected. MIB-1 proliferation indices determined by Ki-67 immunocytochemistry in the routine setting of cytology were analyzed together with clinical data. Kruskal-Wallis was used for comparisons between groups. A binary logistic regression model was used for analysis of factors predicting FTC and predictive power was determined with receiver operating characteristic (ROC) analyses. Patients with FTC (n = 41) had higher MIB-1 (median: 4.0%, P < 0.001) and larger tumor sizes (median: 4.0 cm, P < 0.001) compared with patients with FTA (n = 129; 1.0%; 2.8 cm) and AFTA (n = 11; 2.0%; 3.2 cm). Oxyphilic (Hürthe cell) differentiation was present in 39 FTA, 11 FTC and 5 AFTA. Multivariate analysis identified high MIB-1 index (odds ratio [OR]: 1.234, 95% confidence interval [CI]: 1.093–1.394, P = 0.001) and large tumor size (OR: 1.386, 95% CI: 1.099–1.747, P = 0.006) as independent risk factors of FTC, while age at surgery and gender were not associated with FTC. In a subgroup analysis of FTA with and without oxyphilic differentiation, oxyphilic FTA was associated with higher MIB-1 (OR: 1.430, 95% CI: 1.124–1.820, P = 0.004) and higher age at surgery (OR:1.036, 95% CI: 1.008–1.063, P = 0.010). Diagnostic accuracy for predicting FTC was higher for MIB-1 (Area under curve [AUC]: 0.747, 95% CI = 0.655–0.838, P < 0.001) than tumor size (AUC: 0.709, 95% CI: 0.624–0.795, P < 0.001). Accuracy for MIB-1 slightly improved when excluding all oxyphilic tumors (AUC: 0.779, 95% CI: 0.677–0.882, P < 0.001). MIB-1 index in follicular tumors may add diagnostic information preoperatively since a higher MIB-1 indicates an increased risk of carcinoma. Our results also suggest separate cut-off values for oxyphilic tumors.
Thyroid Cancer Saturday Trainee Poster Contest Finalist Clinical
The American Thyroid Association (ATA) revised the guidelines for management of thyroid nodules and differentiated thyroid cancer (DTC) in 2009 and again in 2015. Both guidelines have suggested more conservative recommendations about use and dosing of radioactive iodine (RAI). However, substantial practice variation exists for RAI administration, especially with low/intermediate risk disease. Limited data has been published examining trends in these practices in response to changing guidelines. The objective of this study was to evaluate trends of RAI administration for DTC at the University of Chicago Medical Center (UCMC) in light of changing ATA guidelines, using the 2009 guidelines as a reference point. A retrospective chart review was conducted at the UCMC to identify patients diagnosed with DTC between January 1, 2006 and November 30, 2014 who received initial surgical treatment at UCMC. Data was collected including demographics, pathology, AJCC staging, and use and dose of RAI. The subjects were divided into two cohorts: those diagnosed prior to the release of the 2009 ATA guidelines and those diagnosed after the guideline release (dividing date January 1, 2010). Data was analyzed in SAS using chi square, Fisher's Exact, and student's T testing. A total of 394 patients were identified. In the post-2010 cohort 49.5% (107/216) received RAI compared to 40.4% (72/178) in the pre-2010 cohort, though the difference did not reach statistical significance (p = 0.071). The dose of RAI administered also did not change, with an average dose of 86.9 mCi in the later cohort compared to 92.5 mCi in the pre-2010 cohort (p = 0.45). Among patients who were treated with RAI, tumor size tended to be about the same in the pre-2010 and post-2010 cohort with an average of 2.1 cm and 2.4cm, respectively (p = 0.33). There were no significant differences in the use of RAI by AJCC stage between the two cohorts. These results suggest that at this institution the use of post-operative RAI has not declined. Larger sample sizes are needed to identify statistically significant trends in RAI administration within specific populations, particularly for low/intermediate risk disease.
Thyroid Cancer Saturday Trainee Poster Contest Finalist Clinical
Fine needle aspiration (FNA) biopsy, the most frequent methodology for thyroid nodule evaluation, is fraught with indeterminate cytopathology in 15–30% of cases. Previously, surgery for definitive pathologic diagnosis was recommended, with the vast majority having benign surgical pathology. Afirma Gene Expression Classifier (GEC) offers potential preoperative reclassification of indeterminate to “benign” or “suspicious” with a NPV of 94%. This study reviews the role of the Afirma GEC since implementation at Scripps Clinic in La Jolla, California.60 month, single center retrospective review of 2,038 FNA cases performed at Scripps Clinic from 2011–2015, of which 59 indeterminate cases were analyzed by Thyroid Cytopathology Partners (TCP) and subsequently 29 TCP indeterminate cases by Afirma GEC. The study cohort was 56 cases, 3 excluded due to TCP nondiagnostic results. Mean age 52.5 (range 20–93 years) including 43 females (77%) and 13 males (23%) (male:female ratio of 1:3.3). 41 Scripps Clinic cases (73%) identified as atypia or follicular lesion of undetermined significance (AUS/FLUS) and 14 (25%) as suspicious for follicular neoplasm (SFN). TCP reclassified 24 (43%) indeterminate to benign, 4 of which had surgery for compressive symptoms with 100% benignity on surgical pathology. 3 cases (5.3%) reclassified as malignant with 100% papillary thyroid carcinoma (PTC) on surgical pathology. Afirma GEC performed on 29 cases (33.9%), 13 benign (45%) with no surgical intervention and 16 suspicious (55%), of which 9 underwent recommended surgery with 1 follicular carcinoma (11%) identified. The absence of microcalcifications was the only nodule characteristic with statistical significance between GEC benign and GEC suspicious groups (p = 0.03). Afirma GEC is a useful tool in preoperative classification of indeterminate nodules. At Scripps Clinic, since the inception of Afirma GEC, there was a 23% reduction in thyroid surgery performed on indeterminate nodules. Loss of patient follow up contributes to the challenge of comparison between the Scripps Clinic experience and previously reported GEC NPV. Overall, the review demonstrates that a conservative approach with the use of Afirma GEC can limit unnecessary surgery.
Thyroid Cancer Saturday Trainee Poster Contest Finalist Clinical
MEN2A is a rare disorder caused by mutations in the RET oncogene. Most commonly patients are affected by medullary thyroid cancer (MTC), and less often by pheochromocytoma (PHEO) and primary hyperparathyroidism (PHP). The prevalence of these features is related to the causative mutation. Reports on the clinical features of patients with the mutation D631Y are scarce and suggest that MTC is not the main feature. We aimed to describe the clinical features of a family with MEN2A caused by the D631Y mutation. We performed a detailed electronic chart review of the members of a recently discovered family with MEN2A (D631Y) and recorded their clinical information. The mean age at diagnosis of the MEN2A (D631Y) mutation in the 10 members of this family that have presented for evaluation was 43 years, with 60% been women. The index case was a 24 year old man, with history of recurrent anaplastic ependymoma who was incidentally found to have the D631Y mutation while undergoing genetic testing to guide his oncology treatment. All others were found by screening. At first assessment, 4 patients had evidence of PHEO with a mean tumor size of 3.2 cm, 3 out of 4 had symptoms (hypertension and/or palpitations) and all had positive biochemical findings with mean plasma metanephrines level of 3.1 nmol/L. All PHEO were unilateral. In addition, one patient was found to have a 2 cm adrenal mass with normal biochemical evaluation and was asymptomatic. All patients were evaluated for MTC with an US, carcinoembryonic antigen (CEA) and/or calcitonin levels. Only one patient was found to have micromedullary thyroid cancer (0.2 cm) at age 79. Her calcitonin level was 11 pg/mL and CEA 5.2 ng/mL. Tumor resection was complete and lymph nodes were negative. PHP was evaluated in 9 out of 10 patients, with normal calcium levels found in all. Patients with MEN2A caused by a D631Y mutation most commonly present with PHEO. Rarely, MTC is part of the syndrome and appears to have a late onset and be less aggressive. Our findings add to the body of evidence suggesting that the need and timing of prophylactic thyroidectomy should be discussed, as less aggressive management could be considered in families with low risk mutations.
Thyroid Imaging Saturday Trainee Poster Contest Finalist Clinical
Shear waves, used by shear wave elastography (SWE), are slow compared to ultrasound waves. It is thought that shear wave measurements may differ when performed axially and sagittally, because shear wave is easily affected by environmental factors such as neck shape, artery pulsation, and the cartilage. The approach to SWE in thyroid tissue has been recently established but there have been no reports about environment-induced artifacts. The aim of this study was to clarify the most suitable direction of the probe for measuring shear wave velocity (SWV) in the thyroid. The subjects were 197 cases (78 normal thyroid, 43 autoimmune thyroiditis (AIT), 62 benign nodule, 14 malignant tumor) in which SWV was measured between October 2012 and May 2013. We used an ACUSON S2000 ultrasound system (Siemens Healthcare, Erlangen, Germany), and measured SWV five times at the same location with both the axial and sagittal methods. The mean and the coefficient variation (CV) of the variability of the five measurements were compared between the two approaches. The medians of the mean of the five SWV measurements of each type of thyroid lesion by the axial and sagittal procedures, respectively, were as follows: normal thyroid, 2.42 (interquartile range (IQR): 1.58–2.47) and 1.47 (IQR: 1.52–1.73); AIT, 2.49 (IQR: 2.52–3.06) and 2.53 (IQR: 2.42–2.74); benign nodule, 1.94 (IQR: 1.82–2.23) and 1.79 (IQR: 1.68–2.00); and malignant tumor, 2.94 (IQR: 2.24–2.59) and 2.65 (IQR: 2.11–3.32). The median CVs of the axial and sagittal approaches were 0.054 and 0.077 for normal thyroid (p < 0.0001); 0.071 and 0.072 for AIT (p = 0.656); 0.076 and 0.073 for benign nodule (p = 0.441); and 0.088 and 0.060 for malignant tumor (p = 0.313), respectively. In normal thyroid, the CV of the sagittal measurement was smaller than that of the axial measurement. This result showed that the SWVs obtained using the sagittal approach were more stable. By contrast, in the other thyroid lesions there were no differences in the CVs of the SWV measurements between the two procedures. The reason was thought to be that the effect of nodule boundaries or tissue structures on shear waves was greater than that the differential effects of the two measurement procedures.
Thyroid Nodules & Goiter Saturday Trainee Poster Contest Finalist Clinical
While benign fine needle aspiration (FNA) results have a low false negative rate, some studies suggest a rate as high as 20% for nodules >4 cm. In addition, nodule size may be an independent risk for malignancy in indeterminate nodules. Our objective was to determine the accuracy of FNA and risk of malignancy in thyroid nodules >4 cm with Bethesda II (B-II) or Bethesda III (B-III) cytopathology.
This IRB-approved retrospective chart review included all FNAs of thyroid nodules >4 cm with B-II or B-III on initial cytology from 2010–2014 at the University of Washington. Outcomes included subsequent management (surgery, repeat FNA, or repeat US) and final diagnosis. Nodules with <2 years of follow up were excluded. Of 653 B-II nodules, 83 were >4 cm, with 40 excluded for <2 years of follow-up. For the remaining 43 nodules, 21 went to surgery (13 after initial FNA, 8 after follow up US) with 1 malignancy identified in the US group; 5 had repeat FNA all with benign cytology; and 17 had stable US imaging (<50% increase in volume) over an average follow up of 32 months. Of 108 B-III nodules, 33 were >4 cm, with 9 excluded for <2 years of follow-up. For the remaining 24 nodules, 16 went to surgery, with 5 malignancies identified; 5 had repeat FNA, 4 with benign cytology and 1 non-diagnostic but stable on US over 56 months; and 3 had stable US imaging over an average of 38 months. Overall, for B-II nodules >4 cm, 2.3% were malignant, and for B-III nodules >4 cm the malignancy rate was 20.8%. For B-II and B-III nodules treated with surgery, malignancy rates were 4.8% and 31.3%, respectively. Our study finds a low false negative rate for B-II nodules >4 cm. However, when analysis is limited to nodules treated with surgery, the rate is higher, comparable to previous studies. Unlike previous studies, our analysis is not limited to nodules with surgical pathology and includes all nodules evaluated by FNA. This is clinically relevant given that many B-II or B-III nodules >4 cm are monitored without surgery. Our study is limited by small sample size and cases with incomplete follow-up. Larger studies with long-term observation are needed to determine true risk of malignancy for thyroid nodules >4 cm.
Thyroid Nodules & Goiter Saturday Trainee Poster Contest Finalist Clinical
Current ATA guidelines recommend interval US monitoring and repeat FNA based on US pattern risk stratification instead of size criteria alone. There are two objectives of this study. The first is to evaluate if current radiology reporting of thyroid nodules adequately describes US features to allow for implementation of the current ATA guidelines. The second is to evaluate indications for repeat thyroid FNA and clinical outcomes of benign thyroid nodules based on changes in US features. A retrospective cohort study examined all nodules with benign cytopathology between 2007–2014 at a single university. A randomly identified sample was selected for preliminary data analysis of radiology reports to capture descriptive US features of the nodules. Of 1825 FNAs, 944 were benign and 251 (26.6%) were reviewed. Of the 251, 50 underwent repeat FNA. Nodules with repeat FNA had a significant increase in volume (30% vs 18%) compared to nodules without repeat FNA (p < 0.01). No comment was included in radiology reports on high risk US features on average 79.6% of the time. Of the 50 nodules that underwent a repeat FNA, 10% (n = 5) were non-diagnostic, 70% (n = 35) benign, and 20% (n = 10) indeterminate (AUS/FLUS). Of the 10 indeterminate nodules, 3 had benign pathology after resection, 2 had stable serial US monitoring over an average of 17 months, 3 had another repeat FNA with benign cytopathology, and 2 were lost to clinical follow up. In follow-up of the 50 nodules with repeat FNA, 40% (n = 20) had stable US over a median time of 15.5 months, 10% (n = 5) had sonographic change in either high risk features or size, 8% (n = 4) had another repeat FNA, 12% (n = 6) had surgery showing benign pathology, and 30% (n = 15) were lost to clinical follow up. Indications for repeat FNA included: 60% (n = 30) for increased size, 12% (n = 6) for change in high risk US features, and 28% (n = 14) for other reasons. This study illustrates the challenges in applying the new ATA guidelines for thyroid nodules due to a lack of standardized radiology reporting on high risk US features. However, this analysis supports the change in guidelines as no new malignancies were diagnosed by repeat FNA in nodules for change in size without change in suspicious US features.
Autoimmunity Saturday Poster Clinical
Autoimmune diseases tend to cluster in the same individual or in families. Four types of Multiple Autoimmune Syndromes (MAS) have been described: type-1 (at least 2 among chronic candidiasis, chronic hypoparathyroidism, disease Addison); type-2 [Addison's disease plus ATD and/or diabetes mellitus type 1]; type-3 (ATD plus other autoimmune diseases) and type 4 (association of diseases that do not fit in type-1,2 and −3). The natural history of autoimmune diseases is characterized by three stages: a) potential (presence of circulating autoantibodies) b) subclinical (presence of subclinical alteration of the target organ function) and c) clinical (appearance of symptoms and signs of the disease). The objectives of our study are: 1) to establish the prevalence of organ-specific autoantibodies [anti adrenal Ab (ACA), anti ovary Ab (StCA), anti pituitary Ab (APA), anti parietal gastric cells Ab (PCA), anti transglutaminase Ab (tTGAb), anti glutamic acid decarboxylase Ab (GADA), anti muscle nicotinic acetylcholine receptor Ab (Arab)] in patients with ATD; 2) to determine the stage of the disease (potential, subclinical or clinical) in patients with positive organ-specific autoantibodies 3) to characterize HLA class II aplotype in a subgroup of subjects.
538, out of the planned 2000, patients [477 F / 51 M; 51.7 ± 15 (m ± SD) years] with ATD (488 with chronic autoimmune thyroiditis and 538 with Graves disease) have been prospectively enrolled. ACA, StCA, APA and PCA were measured by indirect immunofluorescence assay, tTGAb and GADA by an enzyme immunoassay and Arab by a radioimmunoassay.
ACA were positive in 5/392 patients (1.3%), StCA in 2/3408 (0.6%) APA in 4/394 (1%), PCA in 492/389 (12.6%), GADA in 28/483 (5.8%), tTGAb in 7/392 (1.8%) and Arab in 4/316 (1.3%). The prevalence of MAS was: 1.5% type-2, 7.8% type-3A, 14.7% type-3B,3.6% type-3C, 2.1%-3D type and 5.4% type-4; no case of type-1 was recorded. HLADR3 and DR4, as expected, were the most common haplotypes.
The association between ATD and chronic atrophic gastritis was the most frequent and the potential stage of the disease was the most common allowing to set an appropriate follow-up for early detection and timely treatment of the autoimmune diseases.
Autoimmunity Saturday Poster Case Report
In recent years, significant progress has been made in cancer immunotherapy by the development of drugs acting as modulators of immune checkpoint proteins, such as the programmed death-1 (PD-1) inhibitors. Cancer cells bind to the PD-1 receptors in the T-lymphocytes hence evading immure destruction. However, immune checkpoint blockade can lead to the breaking of immune self-tolerance, thereby inducing a autoimmune side effects. As with all new medications, side effects start coming to light with increased use and time of follow up. A 76 year old female with history of hypothyroidism on a stable dose of levothyroxine (LT4) 88 mcg/day or 1 mcg/Kg was diagnosed with melanoma of the nail bed with metastasis to the axilla for which she underwent surgery. Had disease progression with metastasis to the vertebral bodies, lungs, and liver and received 4 cycles with the PD-1 inhibitor ipilimumab without alteration of the thyroid function. Imaging studies showed progression of disease and a new focus of brain metastasis. A second PD-1 inhibitor, pembrolizumab, was administered achieving disease regression. Received a total of 7 cycles in 5 months before the TSH increased to 14.5 mIU/mL and LT4 was increased to 100 mcg/day. Before cycle 10, the TSH rose to 13.95 and LT4 was increased to 112 mcg/day. She went on to receive 5 more cycles in 9 months before she required a lastPembrolizumab, one of the newest immunotherapy drugs for cancer, has higher rates of thyroid side effects as compared to older drugs, with one RCT (2) showing hypothyroidism in 10.1% and hyperthyroidism in 6.5% at 2 weeks.
Case series (1) with exposure to PD-1 inhibitors have reported an initial thyrotoxic phase (6–8 weeks) that resolves spontaneously and progresses to hypothyroidism. Few patients had no documentation of a previous hyperthyroid phase and none had previous documentation of hypothyroidism like our patient. We must recognize these novel immunotherapies have the potential to cause immunotoxic effects on the thyroid gland, including worsening of pre-existing well-controlled hypothyroidism. Anticipation is key to diagnose and control these complications.
Autoimmunity Saturday Poster Case Report
Hashimoto encephalopathy (HE) is a rare form of acquired autoimmune encephalopathy, characterized by elevated anti-thyroid antibodies in the absence of a central nervous system infection, tumor or stroke.
Report of two patients diagnosed with HE at a tertiary hospital.
Case 1: A 61 year old female with a previous diagnosis of primary hypothyroidism was admitted to Emergency Unit with acute confusion, agitation, aggressiveness and slurred speech. Laboratory: TPOAb1496I U/mL, TSH80 uUI/mL and FT40.02 ng/dL, cerebrospinal fluid (CSF) revealed protein 117 mg/dL. Cranial MRI: white matter signal change. Normal electroencephalogram (EEG). Pulsetherapy with methylprednisolone was instituted due to HE diagnosis. Patient developed progressive neurological improvement and was discharged with oral prednisone.
Case 2: A 47 year old female presented with progressive neurocognitive disorder, seizures and psychiatric symptoms. Cranial MRI: hyperintensity in hippocampus, basal and midbrain temporal region. Normal EEG. Laboratory: hypothyroidism, CSF with increased protein, TPOAb1246 IU/mL. Due to HE hypothesis, plasmapheresis and steroid therapy were introduced. There was remission of the initial clinical presentation and she was discharged with oral prednisone.
Although the pathogenesis of HE remains unclear, it has been demonstrated brain vasculitis and lymphocyte infiltration. Autoimmunity is a possible mechanism of HE since autoantibodies to thyroid antigens are present and has response to immunosuppressive medications, however there is no relationship between thyroid function and disease`s outcome.
Clinically, the vasculitic subtype is characterized by intermittent acute to subacute onset of symptoms, including stroke-like episodes, seizures and confusion, and the indolent progressive subtype which is characterized by gradually worsening cognitive and neuropsychiatric performance.
The diagnosis of HE is one of exclusion with good response to steroid therapy. Laboratory, neuroimaging, and neurophysiologic investigations are usually nonspecific.
HE is an underdiagnosed treatable condition that once detected and treated early has a good prognosis.
Disorders of Thyroid Function Saturday Poster Clinical
The extent to which levothyroxine dose adjustments increase utilization of healthcare resources has not previously been described in the literature.
The objective of this study was to measure the effect of levothyroxine dose adjustments on direct and indirect healthcare costs. A secondary goal was to identify patient characteristics associated with levothyroxine dose adjustments. A retrospective medical chart review was conducted among hypothyroid patients treated by selected healthcare providers, with 227 study subjects chosen from each of the following two groups: No Dose Adjustment (NDA) and Dose Adjustment (DA). We analyzed the cost of healthcare products and services (direct costs) and lost productivity (indirect costs) associated with each group over a 24-month period. Statistical significance was based upon t-tests to compare the two groups. Costs were calculated per subject and then averaged across subjects within groups. Among the 454 patients in the study, overall mean resource utilization was significantly higher per patient in the DA Group than in the NDA Group ($5,824 vs. $3,166; P < .05). Mean costs were greatest among the 58 patients in the DA Group requiring ≥3 dose adjustments, and significantly greater than in the NDA Group ($8,220 vs. $3,166; P < .05). The mean cost of lost productivity was significantly higher among patients in the one dose adjustment group (n = 122) than in the NDA Group ($1,381 vs. $984; P < .05). Among the 58 patients in the DA Group requiring ≥3 dose adjustments, mean direct medical costs were significantly higher than in the NDA Group ($6,387 vs. $2,182; P < .05). Patients requiring dose adjustments had more GI disorders that might adversely affect levothyroxine performance, including GERD, lactose intolerance, and IBS. Patients with these conditions who required ≥3 dose adjustments (n = 25) incurred mean total costs that were significantly higher than for 83 similar patients requiring no dose adjustment ($7,670 vs. $2,624; P < .05)Patients experiencing levothyroxine dose adjustments incurred greater costs, both direct and indirect, than those not requiring dose adjustments. These costs were highest among patients with concomitant GI disease.
Disorders of Thyroid Function Saturday Poster Clinical
An evaluation of the efficacy of switching patients from levothyroxine tablets to levothyroxine softgel capsules had not previously been conducted.
The main objectives were to quantify the percentage of patients who achieve TSH levels within the range of 0.40–4.2 mlU/L, the median number of dose changes experienced, and the percentage of patients with improved hypothyroid symptom control after switching from levothyroxine tablets to levothyroxine softgel capsules. Other objectives included describing patient characteristics, including any relevant comorbidities, among the study cohort. A retrospective medical chart review was conducted among 99 randomly-selected providers' patients who were switched from a tablet to a softgel formulation of levothyroxine. Data was collected for six months pre and post switch. Statistical significance was determined by a paired t-test or Chi-Square Goodness of Fit test. Of the 82 patients with a documented reason for switching, there was an increase in the number of patients within the prescribed TSH range post switch (53% vs. 57%; P > 0.05). Among all patients, there was a significant decrease in the mean number of dose changes experienced (1.61 ± 0.96 vs. 0.73 ± 0.96; P < .0001); 52.5% had no dose change, and 85% had <1 dose changes. Improved hypothyroid symptom control was reported among 62% of patients post switch (61of 99; P < .0001).
Among the 25 patients who switched medication for efficacy reasons, there was a significant decrease in dose changes post switch (1.60 ± 0.92 vs. 0.44 ± 0.71; P < .0001); 68% had no dose change and 88% had <1 dose change post switch. Improved hypothyroid symptom control was reported among 64% of these patients (16 of 25; P < .0024).
Consistent with prior studies, there was a high prevalence of GI conditions and treatments that are known to interfere with levothyroxine tablet therapy: GERD (16.7%), celiac disease (9.1%), GI surgery (4.5%) and IBS (4.5%). Switching patients between levothyroxine formulations resulted in a small increase in the percentage of patients achieving their target TSH range. However, there was a significant reduction in the number of dose changes experienced and a significant improvement in hypothyroid symptom control.
Disorders of Thyroid Function Saturday Poster Clinical
Antithyroidal drug (ATD) therapy is considered as choice of treatment for Graves' disease; however, the treatment response varied among the patients. Although several studies reported risk factors for relapse after initial treatment, there were few studies for the responsiveness during early treatment period. Using serial levels of free thyroxine of 99 subjects who were diagnosed as Graves' disease for the first time, we estimated responsiveness to ATD of each patient. Drug responsiveness was defined as the correlation coefficients between decreasing rates of free thyroxine level per month and exposed dose of ATD during the same period. After the subjects were classified into two groups by responsiveness, ‘Poor’ and ‘Good’ responder group, clinical factors and anti-TSH receptor antibody (TRAb) titer were compaired. The mean age of subjects was 44.0 ± 13.5 years old and male patients were 40 (40%). The median level of titers of TRAb at diagnosis was 12.6 IU/L (1.6 ∼ 520), and the mean value of free thyroxine was 3.8 ± 1.7 ng/dL. The mean value of correlation coefficients between decreasing rate of free thyroxine and ATD dose was −0.72 in ‘Good’ responder and −0.21 in ‘Poor’ responder group. ‘Good’ responder group showed higher level of TRAb titer and free thyroxine level at diagnosis, while age and sex were not different between two groups. In the logistic regression analyses, higher level of serum thyroxine and TRAb titer showed significant association with ‘Good’ response, while age and sex were not significant factor for prediction of reponsiveness. In patients with new onset Graves' disease, higher level of free thyroxine and TRAb titer were associated with good responsiveness to ATD.
Disorders of Thyroid Function Saturday Poster Clinical
South Korea is generally known as an area with high iodine intake which might induce thyroid dysfunction. However, there are no data regarding exact iodine intake status and its relationship with a specific thyroid disease in this area. We evaluate the association of urinary iodine concentration which is an easily obtainable indicator of iodine intake status and thyroid dysfunction in tertiary referral hospital in South Korea.
The medical records of 1285 patients who measured spot urine iodine and creatinine concentration, thyroid function, thyroid autoantibody between December 2012 and March 2016 were retrospectively reviewed. History of thyroid cancer (n = 591), amiodarone user (n = 2), patients who performed iodine contrast computed tomography (n = 12), radioiodine thyroid uptake scan (n = 1) were excluded. The enrolled patients (n = 699) were divided into euthyroid (n = 401) and thyroid dysfunctional group (n = 298), and the latter was divided into autoimmune thyroid diseases (Graves' disease or Hashimoto's thyroiditis) (n = 202) and non-autoimmune thyroid dysfunction group (n = 96).
Median urine iodine concentration (UIC) and adjusted by Cr (UI/Cr) were higher in thyroid dysfunctional group (393.30 μg/L and 380.44 μg/gCr, respectively) than euthyroid group (312.0 μg/L and 267.29 μg/gCr, respectively) (p = 0.026 and 0.005, respectively) and were higher in non-autoimmune thyroid dysfunction group (585.30 μg/L and 578.30 μg/gCr, respectively) than AITD group (322.8 μg/L and 325.09 μg/gCr, respectively) (p = 0.002 and 0.00, respectively). The proportion of extremely high (exceeding 75th percentile) UI/Cr patients was higher in non-autoimmune thyroid dysfunction group than AITD group (OR = 1.9; 95%CI, 1.11–3.28). Among the hypothyroidism (n = 119), there was more chance of extremely high UI/Cr patients in non-autoimmune thyroid dysfunctional group (OR = 2.53; 1.14–5.62), especially in female (OR = 2.91; 1.15–7.35) and over 60 years old (OR = 7.25; 1.44–35.71) patients.
The median level of UIC and UI/Cr in South Korea seems to be excessive according to WHO criteria. In excessive iodine intake area like South Korea, extremely high iodine intake is associated with non-autoimmune hypothyroidism, especially in female and the elderly subjects.
Disorders of Thyroid Function Saturday Poster Clinical
The aims of this retrospective cohort study were to assess the prevalence of liver biochemical test (LT) abnormalities among patients with untreated thyrotoxicosis and investigate differences in the prevalence and incidence of these abnormalities stratified by severity of thyrotoxicosis. Patients with thyrotoxicosis (defined as serum TSH <0.3 mIU/L or ICD-9 code for thyrotoxicosis, and an elevated serum T3 and/or T4 concentration within 3 months) with available incident LT results within 6 months of thyrotoxicosis in the UCLA electronic medical record database between 2002–2016 were included. Exclusion criteria included use of medications such as statins that could potentially cause liver enzyme elevations and preexisting known liver disease, including hepatitis, fatty liver, and cirrhosis. Patients were divided into two groups based on the initial TSH values at diagnosis. Chi-squared tests and Cox regression analyses were conducted to investigate differences in the prevalence and incidence of serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma-glutamyl transpeptidase and bilirubin concentrations between the two groups. The cohort included 1,515 subjects (mean ± SD: 51.0 ± 19.0 years; 23% men; 60% Caucasian, 14% Asian, 9% Black; 77% non-Hispanic) with a new diagnosis of thyrotoxicosis. The prevalence of LT abnormalities within 6 months of thyrotoxicosis was 39%. There was a higher prevalence of any one LT abnormality in those with an initial serum TSH below the detection limit of 0.02 mIU/L (n = 811), compared to those with TSH above the detection limit (n = 697) (44.6% vs. 32.6%, P < 0.0001). There were increased risks of developing an incident LT abnormality among those with an initial serum TSH <0.02 mIU/L (HR 1.41, 95% CI 1.18–1.67, P = 0.0001) and in Blacks (HR 1.65, 95% CI 1.26–2.15, P = 0.0002). In this single-center retrospective cohort study, patients with a new diagnosis of thyrotoxicosis have a 39% prevalence of liver biochemical abnormalities. The underlying reasons for differences in the patterns of these abnormalities based on the severity of initial thyrotoxicosis should be further investigated.
Disorders of Thyroid Function Saturday Poster Clinical
The association between thyroid dysfunction and the risk of cognitive decline validated in several studies. We investigated the association between serum thyrotropin levels and cognitive decline in elderly subjects. We conducted a population-based prospective study as a part of the Korean Health and Genome Study. Excluding the subjects with known thyroid disease, dementia, cerebrovascular disease, and head injury at baseline, 501 healthy participants (mean age, 69.2 ± 2.9 years; men:women = 255:246) whose scores of the baseline mini-mental state examination (MMSE) and dementia screening questionnaire were ≥23 and ≤7, respectively were included in the present study. They completed MMSE and their family members completed the dementia screening questionnaire (DSQ) at the baseline and 6-year-follow-up evaluations. At the baseline evaluation, mean MMSE score was 26.5 ± 2.0 and median DSQ score was 2(3). During 6-year of study period, the MMSE score decreased by 1.1 ± 2.8 and the DSQ score increased by 1.2 ± 4.1. The change of MMSE score was correlated with age, education period, the baseline MMSE score, and the baseline serum thyrotropin level. The change of DSQ score was correlated only with the baseline DSQ score. Lower baseline serum thyrotropin level was associated with cognitive decline measured with MMSE (r = −0.103, p = 0.021). This association between the decrease of MMSE score and baseline thyrotropin level was maintained after adjusting with conventional risk factors of cognitive decline, including age, education period, the baseline score of depression scale, and the baseline MMSE score (B = −0.315, p = 0.041). Lower serum thyrotropin level was independently associated with cognitive decline measured with MMSE in elderly subjects. However, cognitive decline measured by DSQ was not associated with baseline serum thyrotropin level.
Disorders of Thyroid Function Saturday Poster Clinical
Maternal hypothyroidism can lead to congenital hypothyroidism. Some providers check thyroid function tests (TFTs) on infants of mothers with thyroid disease because they consider them a higher risk population, in addition to mandated newborn screening for congenital hypothyroidism performed on all newborns. There are no specific guidelines for obtaining routine serum thyroid function tests on these newborns. This study was conducted to assess the timing and utility of obtaining serum TFTs on healthy infants with a maternal history of thyroid disease. Clinical Looking Glass search was utilized to find thyroid function tests obtained on infants in the newborn nursery at the Children's Hospital at Montefiore from January 2009 to June 2014. Preterm infants, infants who went to the neonatal ICU and those who had TFTs checked for non-maternal reasons were excluded. A retrospective chart review assessed maternal history and infant disease status at subsequent visits. Newborn screen results were confirmed via documentation or communication with the New York State Newborn Screen Program. A total of 734 infants were identified, and 559 meet inclusion criteria. Final diagnosis was known for 355 infants. Seven had congenital hypothyroidism requiring levothyroxine supplementation. Three of these 7 patients had normal newborn screens with no evidence of congenital hypothyroidism. Levothyroxine was started on day of life 4, 72, and 201 on these patients. TSH levels prior to treatment were 6.58 to 28.4 uU/mL. Free T4 levels were normal. A total of 490 TFTs and 20 endocrine clinic visits were done to identify 7 patients ultimately treated for thyroid disease. Of these 7 infants, 3 had normal newborn screens and 2 were started on medication after 2 months of life. For these infants TSH were levels below 10 IU/L, which could be considered subclinical. Based on these results, given the expense of testing compared to the relatively poor yield with high false positive rate, we recommend no routine testing in the newborn nursery for infants of mothers with hypothyroidism. However, given the fact that there were 3 cases missed by newborn screen, providers could consider TFTs at 10–14 days.
Disorders of Thyroid Function Saturday Poster Case Report
Interference with immunoassay measurements of thyroid hormones by various substances including heterophile antibodies may have serious implications in patient care. Here we report a patient with very high TSH and normal Free T4 who was clinically euthyroid and had high rheumatoid factor titers interfering with TSH measurement. 61 year old male with type 2 diabetes mellitus, hypertension and coronary artery disease, was admitted to MICU for respiratory failure after 2 weeks of outpatient antibiotics for pneumonia. Admission TSH was >100 mIU/mL (0.73–4.6 mcIU/mL), with same value on repeat testing. Free T4 was 1.3 (0.58–1.64 ng/dL) and Free T3 was low 1.75 (2.75–4.03 pg/mL). Thyroid antibodies were negative. He had no prior history of thyroid disorder, neck surgery, neck radiation, amiodarone use, or recent iodinated contrast. He had normal thyroid function tests 4 months before admission: TSH 0.92 (0.4–4.5 mIU/L and Free T4 of 1.3 (0.8–1.8 ng/dL) at Quest. Physical exam was significant for respiratory distress and tachycardia. Thyroid was mildly enlarged with no palpable nodules; DTR's were2+. Based on initial lab results, he was started on levothyroxine 25 mcg daily, but given discrepant clinical findings and lab values, we suspected presence of heterophile antibodies, and serum was sent to Quest with request for TSH with anti-HAMA (human antimouse antibody) treatment. TSH at Quest was 0.12 (0.4–4.5 mIU/L), with unchanged values before and after HAMA treatment. Serial sample dilutions of TSH revealed a non-linear pattern, suggesting assay interference. Rheumatoid factor (RF) titers were elevated at 2048 IU/ml (<8IU/mL). A specimen was sent to USC Endocrine Service Laboratory for Macro TSH evaluation using PEG precipitation, but this test was not performed because TSH was normal by that assay: TSH 0.55 mIU/L (0.3–4), with Free T4 of 0.89 (0.8–2 ng/dL). Based on normal TSH results at two outside labs and clinical euthyroid status, levothyroxine was stopped. We present a case of falsely elevated TSH due to assay interference by heterophile antibodies related to high RF titers. It is essential for clinicians to be aware of this possibility, as over treatment with thyroid hormone can lead to severe consequences.
Disorders of Thyroid Function Saturday Poster Case Report
Thyrotoxic periodic paralysis (TPP), a disorder most commonly seen in Asian men, is characterized by abrupt onset of hypokalemia and paralysis. Hypokalemia in TPP is thought to be secondary to intracellular shift of potassium induced by the thyroid hormone sensitization of Na+/K+–ATPase rather than depletion of total body potassium. We present a case of TPP diagnosed in a young asian male. Pt is a 27 y/o Asian male with no significant PMH, presented to the Emergency room with chief complaint of - “not feeling his legs” and unable to move them immediately after waking up in the morning. No recent h/o URTI/ diarrhea/ fever/ chills/ dysuria/ constipation. Pt was tachycardic and slightly dyspneic on admission. Physical exam showed significant motor weakness of the lower greater than upper extremities, (Power 0/5 B/L LEs, 1 - 2/ 5 B/L UEs), diminished deep tendon reflexes. Labs on admission showed K+ of 1.7, TSH - undetectable, Free T4 - 16, Free T3 - 272. His basic metabolic panel and CBC were with in normal limits.
Pt initially was treated with IV potassium Supplementation and was started on Propylthiouracil, Propranolol after he was found to have abnormal TFT's. As the serum potassium returned to normal range pt improved with return of muscle strength back to baseline. Pt underwent Total Thyroidectomy per his choice for defenitive treatment. Post Op Cytology reports were positive for Small focus of papillary carcinoma - follicular variant in Rt thyoid lobe. Thyrotoxic periodic paralysis is most common in Asian populations, male sex in 2nd to 4th decade. TPP has been increasingly reported more recently in the USA. TPP is commonly misdiagnosed in western countries because of its similarities to familial periodic paralysis. It is important for physicians to distinguish TPP from familial hypokalemic periodic paralysis. Treatment of TPP includes slow repletion of potassium and prevention of intracellular shift of potassium by using nonselective beta-blockade and correcting the underlying hyperthyroid state. Low carbohydrate diet and avoiding insulin is very important step in management to prevent recurrence of hypokalemia.
Disorders of Thyroid Function Saturday Poster Case Report
Graves' disease is an autoimmune disorder characterized by the syndrome comprising of hyperthyroidism, diffuse goiter, and occasionally orbitopathy and dermatopathy. In Graves' disease, the involvement of thyroid is most commonly diffuse, involving both the lobes of thyroid. However, a few cases of unilateral involvement of thyroid have been reported without clear explanation of the etiology. We present a rare case of unilateral Graves' disease that can sometime present a diagnostic challenge in clinical practice. A 49-year-old woman who presented to our endocrinology clinic after an incidental finding of an asymmetric enlargement in the thyroid gland on MRI neck done after a car accident. She has a family history of hypothyroidism in 2 sisters. Evaluating thyroid function tests (TFTs) revealed undetectable thyroid stimulating hormone with elevated free T4 2.5 (nl, 0.9–1.7) and T3 219 (nl, 80–200). Thyroid stimulating immunoglobulin was normal but thyroid peroxidase antibody was elevated at 134 (nl, <9). Anti-thyroglobulin and thyrotropin receptor antibodies were negative. She reported symptoms of tremor and heat intolerance which spontaneously improved within a few weeks. Six months later, repeat TFTs revealed normalization in FT4 and T3 but TSH remained suppressed at 0.07 (nl, 0.45–4.5). Thyroid uptake and scan showed increased uptake in right lobe only. Thyroid ultrasound revealed asymmetric thyroid with the right lobe double the size of the left lobe. The right lobe texture was very heterogeneous and mildly vascular. The left lobe texture was homogenous. No discrete nodules were identified in both lobes. DEXA scan was normal. Watchful approach was opted for the management. High suspicion and clinician's awareness about occasional unilateral involvement of gland is important to make an accurate diagnosisUnilateral Graves' disease is a rare entity and can present a diagnostic challenge as it can be confused with a toxic nodule on thyroid scan
Disorders of Thyroid Function Saturday Poster Case Report
Graves' disease (GD) is an autoimmune disorder in which autoimmunity is sustained by the different autoantibodies. Various commonly tested antibodies include thyroid stimulating immunoglobulin (TSI); thyroid peroxidase (TPO) antibodies and rarely thyrotropin receptor antibodies (TRAb) for establishing the diagnosis. Classically, GD patients present with weight loss in addition to other typical symptoms. We present a case in which weight gain was initial manifestation of GD which resulted in delay of GD diagnosis. A 58 yo AA male initially presented to outside endocrinology clinic in 2015 for evaluation of thyroid stimulating hormone (TSH) level of <0.01 (0.4–4.0 mIU/ml) and elevated FT4 of 2.37 (0.7–1.5 ng/dL) and total T3 of 222 (57–144 ng/dL) suggesting hyperthyroidism. His symptoms were significant for chronic constipation, insomnia and weight gain. TSI level was normal at 35% (0–139%) and TPO level was elevated at 320 (0–34IU/mL). Thyroid scintigraphy and radioiodine uptake showed borderline elevation of 24-hr iodine uptake at 31% (10–30%). Thyroid ultrasound showed diffuse gland heterogeneity without any discrete nodule. Given absence of classic GD symptoms and normal TSI level, wait and watch approach was opted. Six months later patient presented to local hospital complaining of chest congestion and sore throat. Cardiac work up was negative however biochemical hyperthyroidism persisted at which point he was referred to our clinic for further evaluation. Patient continued to report weight gain and constipation. Nuclear imaging studies showed homogenous increase of iodine uptake at 40%. We found that his TRAb level was elevated at 2.52 (0–1.75 IU/L). Given unequivocal diagnosis of GD, we started methimazole therapy. This case highlights an uncommon clinical presentation of GD in middle-age male and the importance of positive TRAb level which could help to establish diagnosis GD in hyperthyroid patients in whom levels of other autoimmune markers are equivocal. GD as a syndrome may present with unusual symptoms, high suspicion and sometime testing for TRAb antibodies may be necessary to make the diagnosis.
Disorders of Thyroid Function Saturday Poster Case Report
Struma ovarii is a variant of dermoid tumors of the ovary which is relatively very rare and usually benign. It accounts for <1% of ovarian tumors. The diagnosis of struma ovarii is often delayed until the development of symptoms related to ovarian torsion, hyperthyroidism and ascites. We herein report a case of struma ovarii diagnosed by I-123 whole body scan in a patient with persistent hyperthyroidism. A 61 year old woman was referred to our institution for a second opinion regarding persistent hyperthyroidism since 2009. She did not have any work up or treatment until 2011, when 123-I thyroid uptake was reported 1.2%. Ultimately she was prescribed methimazole (MTZ) for her persistent thyrotoxicosis. Evaluation in 2015 (while off MTZ for 2 weeks) showed negative TPO and TSI antibodies and low 123-I thyroid uptake at 4.6%. I-123 whole body scan performed at another institution showed a large area of intensely focal activity in the mid-line pelvis which was interpreted as physiologic urinary activity and the study was reported negative. Work up in our institution (while off MTZ for 4 weeks) showed: thyroglobulin 8612 ng/ml, normal 24- hour urine iodine (105 mcg/L), TSH 0.02 mU/L with elevated FT4: 1.76 ng/dL and FT3: 6.4 pg/mL. I-123 whole body scan with SPECT/CT revealed normal scintigraphy findings of thyroid gland with depressed 24 hour I-123 thyroid uptake at 2% and intensely focal radioiodine uptake in a large 4.9 cm heterogeneous left pelvic mass, most consistent with left adnexal struma ovarii. MTZ was re-started and she was referred for surgical resection. This case illustrates the misinterpretation of first I-123 whole body scan of left adnexal struma ovarii as a physiologic urinary 123-I excretion with accumulation in the bladder, and presents the advantage of fusion SPECT/CT imaging in addition to planar 123-I whole body scan for diagnosis of unusual cases of extra-thyroidal thyrotoxicosis which occurs only in about 5% of cases of struma ovarii. Surgical resection is the primary therapy and in the case of malignancy (5–10%), patients should also undergo total thyroidectomy followed by radioactive iodine therapy. Struma ovarii should be considered in persistent thyrotoxicosis and low thyroid uptake.
Disorders of Thyroid Function Saturday Poster Case Report
Marine-Lenhart Syndrome (MLS) is a rare presentation of hyperthyroidism with co-occurrence of Graves' disease and hyperfunctioning nodules. A literature review revealed that most reported cases followed a history of prior euthyroid status or chronic Graves' disease. A 61-year-old lady presented to clinic for management of new onset hyperthyroidism. She had a 33-year history of hypothyroidism from Hashimoto's that was well controlled on levothyroxine. Symptoms included palpitations, heat intolerance and anxiety that persisted 6 months after cessation of levothyroxine. Physical exam revealed thyromegaly and a bilateral resting tremor. Labs showed suppressed TSH <0.015 (0.465–4.68 mIU/L), normal free T4 1.48 (0.78–2.19 ng/dL), elevated total T3 1.75 (0.97–1.69 ng/ml), elevated TSI 151 (< 140%) and elevated TPO 490 (< 9 IU/ml). Nuclear medicine thyroid uptake and scan revealed elevated uptakes at 4 and 24 hours of 21.7% and 48.7% respectively. Images revealed focal increased uptake in the left superior and left mid thyroid and the right mid thyroid lobes, but also with bilateral diffuse increased uptake that was not suppressed despite the focal areas of intense uptake. Neck ultrasound showed right mid 1.17 × 0.7 × 0.9 cm, left mid 1.0 × 1.2 × 1.0 cm and left superior 1.2 × 0.9 × 0.8 cm solid thyroid nodules that corresponded to the areas of focal increased uptake on nuclear medicine imaging. The patient initially declined treatment with radioiodine ablation treatment or thyroidectomy and is currently on methimazole until she finalizes a decision for long-term treatment. The patient's clinical presentation, biochemistry and imaging were consistent with MLS. Hashimoto's has been well reported to occasionally progress to Graves' disease. However, it is rarely noted to progress to MLS. A diagnosis of MLS should be considered in patients with Hashimoto's who develop persistent hyperthyroidism after levothyroxine cessation.
Disorders of Thyroid Function Saturday Poster Case Report
Ultra sound of thyroid gland showed enlarged right thyroid lobe with unremarkable blood flow. NM-thyroid scan showed no tracer uptake in thyroid gland suggesting thyroiditis. Thyroid stimulating immunoglobulin and thyroid peroxidase antibody levels were normal. A diagnosis of amiodarone induced thryroiditis was made and she was started on prednisone.
Amiodarone induced thyrotoxicosis is seen in 3% of patients taking maintanance dose of amiodarone. Amiodarone may cause type 1/type 2 thyrotoxicosis. So, it is important to monitor thyroid function tests in regulatr intervals per guideline.
Disorders of Thyroid Function Saturday Poster Case Report
Thyroiditis and thyroid swelling are uncommon and rare adverse effects of fine needle aspiration (FNA), with a previously reported incidence of 1% of patients who underwent FNA. The mechanism for thyroiditis is suspected to be leakage of cystic material triggering an inflammatory response and release of performed hormone resulting in thyroiditis. 56-year-old female with a past history of multinodular goiter presented with neck pain accompanied by fever, fatigue, and enlargement of thyroid gland. One-week prior she underwent FNA of a cystic right thyroid nodule with a 25-gauge needle. On examination she had sinus tachycardia at 110 bpm. Thyroid was very tender to palpation and diffusely enlarged. Her TSH was <0.02 (0.3–4.7 mcIU/mL), Free T4 1.9 (0.8–1.6 ng/dL) Free T3 452 (222–383 pg/dL) TPO Ab <5.0 (<20 IU/mL), Thyroglobulin Ab <0.9 (<4.0 IU/mL), Thyroid Stimulating Immunoglob <89 (<140%). Ultrasound of thyroid gland revealed a multinodular goiter with heterogeneous echotexture and diffuse hypoechogenicity. Iodine 123 uptake scan showed decreased uptake level at 1.9%. The patient developed hypothyroidism two weeks later. Three weeks after that the patient became euthyroid, which was consistent with thyroiditis evolution. Repeat ultrasound six months later demonstrated multinodular goiter with a 30% volume reduction in the overall size of the right lobe and a 50% volume reduction of the left lobe. Thyroiditis after thyroid FNA is rare and presents with a painful neck mass, with associated inflammatory changes on ultrasound. The potential release of thyroglobulin, thyroid hormone stores, and cytokines can trigger a series of symptoms that can be associated with pain, tenderness, and symptoms of thyrotoxicosis. Nodule characteristics may be risk factors for developing thyroiditis after FNA. It predominantly affects individuals with a higher cystic component to the nodule that was aspirated. Post-FNA thyroiditis is a rare clinical scenario with the presentation of thyroiditis with a painful neck mass. As the incidence of thyroid nodule discovery and evaluation is increasing, clinicians should be aware of the acute but rare complication of post FNA thyroid swelling and thyroiditis.
Iodine Uptake & Metabolism Saturday Poster Clinical
TERT promoter mutation has been reported to be associated with aggressive clinicopathological features and high recurrence. The object was to evaluate the prevalence of TERT promoter mutation in distant metastatic DTC (DM-DTC) and analyze TERT mutation with radioactive iodine (RAI) uptake status and RAI therapy response. Retrospectively evaluated TERT promoter and BRAF V600E mutation in primary tumor of 65 DM-DTC patients. And analyze their RAI uptake status and therapy response. RAI uptake status was identified as: 1) RAI-avid and 2) non-RAI-avid. According to the response to RAI therapy, patients were classified as: 1) disease control group and 2) refractory group. The overall prevalence of TERT promoter mutations was 20% (13/65), of which C228T mutation was more prevalent (11/13, 84.62%), while C250T mutation was rare (2/13, 15.38%). TERT mutation was associated with older mean age at diagnosis (t = 4.898, p < 0.001), larger mean tumor diameter (t = 2.438, p = 0.030), and more likelihood of both BRAF mutation coexistence (x 2 = 5.132, p = 0.023) and refractory to RAI (x 2 = 13.929, p < 0.001). A rising sTg was noticed in 92.31% (12/13) of TERT mutation group, regardless of BRAF mutation. And BRAF mutation alone accounts for 55.55% of patients with sTg increase. Conversely, in cases with both mutation negative, 76.47% presented with decreased sTg, and increased sTg only accounted for 14.71%. Almost half (31/65) of DM-DTC patients was identified as RAI refractory group. TERT mutation closely correlated with refractory to RAI, of which 12 of 13 were classified as RAI resistance with a high specificity of 97.06% and a positive predictive value (PPV) of 92.31%. In addition, both TERT (OR: 11.833, p = 0.042) and BRAF mutation (OR: 16.100, p < 0.001) was confirmed as independent predictors of refractory to RAI by logistic regression analyses. TERT promoter mutation associates with non-RAI-avidity in DM-DTC, and it could be a predictive marker to early identify RAI resistance with a high positive predictive value.
Thyroid & Development Saturday Poster Basic
Data indicate diverse origins of tissue resident fibroblasts, even within a single tissue. For example, depending on anatomic site, skin fibroblasts arise from the neural crest, the lateral plate mesoderm, or the dermomytome. Thyroid fibroblasts express a ganglioside profile distinct from dermal fibroblasts, but it is unclear if they retain thyroid specific gene expression. We longitudinally assessed thyroid specific gene expression (PAX8 and TTF1), as well as gene markers of thyrocyte (thyroglobulin [TG], TSH-R), C-cell (calcitonin [CT], calcitonin gene related peptide [CGRP]), fibroblast (vimentin, α-MSA), and epithelial (E-cadherin) lineage, in serial passages of primary human thyroid tissue cultured from 11 subjects by RT-PCR. Tissue obtained at thyroid surgery was collagenase digested, and cultured on tissue culture plastic in 10% FCS/DMEM. Passages (P) were typically ∼14 days. Cell aliquots were processed for total RNA at each passage from 2 to 6, while remaining cells were re-plated and expanded. Results were analyzed as fold-increase compared to expression in confluent HeLa cells. On average, samples expressed 7380 ± 4666-fold more PAX8 and 3241 ± 514-fold more TTF1 at P2 than HeLa cells, consistent with a thyroidal origin. However, both PAX8 and TTF1 expression persisted through P6, declining to 2892 ± 895-fold and increasing to 4859 ± 1447-fold, for PAX8 and TTF1, respectively. Progressive loss of thyrocytes reduced thyroglobulin expression from 466 ± 275±-fold at P2 to 8.66 ± 2.2-fold by P6. However, expression of TSH-R declined minimally from 73.86 ± 33-fold at P2 to 21 ± 3.7-fold at P6, consistent with a thyroid specific fibroblast phenotype. CT expression was never elevated, suggesting an absence of thyroid C-cells, but CGRP expression increased from P2 to P6. E-cadherin expression, a marker of epithelial cells, declined throughout the culture period, while expression of vimentin and α-MSA persisted, confirming the presence of fibroblasts. The combined persistent expression of PAX8 and TTF1, a hall mark of thyroid tissue, confirms retention of tissue specific genes in primary thyroid fibroblasts.
Thyroid & Development Saturday Poster Clinical
Thyroid hormone and iron deficiencies during pregnancy and early postnatal life are both associated with impaired motor and cognitive development. Despite these potential negative outcomes for infants, associations of iron status and thyroidal function have not been established in the pregnant US population. For this study our research question was: In the US, is there an association between iron status and thyroidal function in pregnant women?Using NHANES 2007–2008 data we assessed thyroid function by free thyroxine (fT4), thyroid stimulating hormone (TSH) and iodine levels and iron status by measured ferritin, transferrin receptor, hemoglobin and calculated total body iron in pregnant and non-pregnant women between the ages of 18–45. Women with current or past thyroid disease were eliminated from the study. Supporting the tested hypothesis we found a positive intermediate correlation (Pearson's correlation coefficient +0.425) between free T4 and total body iron stores in pregnant but not non-pregnant women. Similarly, total body iron stores were strongly negatively correlated with TSH levels (Pearson's correlation coefficient −0.745) in pregnant women. Free T4 levels also correlated with hemoglobin levels (Pearson's correlation coefficient +0.252). Correlational findings were unchanged by linear regression modeling. Together these findings support an association between total body iron stores and thyroid status in pregnant women. These novel findings suggest that reduced levels of circulating fT4 in pregnant women with low iron stores may negatively impact growth of a developing fetus, revealing the importance of monitoring iron together with thyroidal status during pregnancy.
Thyroid & Development Saturday Poster Clinical
Recurrent laryngeal nerve (RLN) palsy is the most common and serious complication of thyroid surgery. The use of energy-based devices (EBDs) has replaced handtying methods in many institutions. However, EBD use proximal to the RLN presents risks related to lateral thermal spread and associated nerve damage. THUNDERBEAT OPEN FINE JAW (TB OFJ) is one of the most widely used EBDs. This study aimed to test the safety of TB OFJ during thyroidectomy. Three piglets weighing 30–40 kg experienced thyroidectomy while continuous electrophysiologic monitoring (continuous intraoperative neuromonitoring) occurred, using an electromyography endotracheal tube and NIM 3.0 response system. Total 5 RLNs were evaluated during thyroid surgery. TB OFJ was applied at various distances from the RLN, and we assessed the safety of the protocols. Adverse electromyography events did not occur at any distances from the RLN.
No decrease of Amplitude and increase of latency were noted even if TB OFJ was 0 mm from the RLN.TB OFJ can be used safely at any distance from the RLN.
This is the first report assessing the safety of TB OFJ, and findings indicate that TB OFJ can be used safely during thyroid surgery.
Thyroid Cancer Saturday Poster Basic
Decreased expression of the microtubule-associated protein 1 light chain 3B (LC3B), a well-characterized regulator of autophagy, has been shown to be associated with metastatic progression in patients with thyroid cancer. We hypothesized that LC3B could play a role in the regulation of thyroid cancer cells response to radiation. Expression of LC3B was examined by real-time PCR and Western blot in FTC133, FTC236 and FTC238 cells. Stable LC3B-deficient cells were created by transfection with lentiviral particles containing LC3B specific shRNA. Thyroid cancer cell viability, proliferation, migration and apoptosis were analyzed in LC3B-expressing and LC3B-deficient cells after exposure to γ-radiation (6 Gy). Immunostaining with anti-LC3B was performed on tissue samples from 10 patients with anaplastic (ATCs) and 10 patients with papillary thyroid cancers (PTCs). LC3B expression was decreased in cell lines that derived from metastatic lesions (by 70% in FTC236 and by 90% in FTC238) as compared to FTC133 cells. Transfection with lentiviral particles inhibited LC3B mRNA level by 80% in FTC133 cells. LC3B silencing had no effect on cell cycle, did not inhibit thyroid cancer cells migration, and did not induce apoptosis. Glucose deprivation led to phosphorylation of AMP-dependent protein kinase (AMPK) in LC3B-expressing and LC3B-deficient cells. Induction of LC3BII and loss of p62 protein were detected in LC3B-expressing but not in LC3B-deficient cells. γ-radiation induced gH2AX and caspase 3 cleavage in LC3B-expressing and LC3B-deficient cells. However, recovery of thyroid cancer cells after irradiation was more efficient in LC3B-deficient cells. Colony forming assay showed that survival fraction after γ-radiation was higher in LC3B-deficient cells compared to LC3B-expressing cells (p = 0.01). Granular cytoplasmic staining with anti-LC3B was detected in 5/10 (50%) differentiated PTCs, but in 0/10 (0%) ATCs. LC3B is involved in thyroid cancer cell resistance to metabolic and oxidative stressors. Decreased LC3B expression in undifferentiated thyroid cancer suggests that defective autophagy can contribute to thyroid cancer cell resistance to therapy.
Thyroid Cancer Saturday Poster Basic
Thyroglobulin (Tg) is routinely used to identify recurrent thyroid cancer following thyroidectomy. Its use as a reliable pre-operative serum marker remains controversial, since an elevated Tg level can be attributed to conditions other than thyroid cancer. The purpose of this study is to evaluate the specificity of pre-operative thyroglobulin in differentiating between benign and malignant pathology while accounting for the size of the thyroid nodule. This study is a retrospective chart review of 525 patients that underwent thyroid surgery at a McGill University Teaching Hospital (2014–2015). Of the 327 patients with documented pre-operative thyroglobulin (Tg) levels, 295 also had recorded thyroid nodule size as measured by ultrasound. Pre-operative Tg levels were stratified according to nodule size and malignant pathology. Patients with irretrievable data, anti-Tg serum titre greater than 20 IU/L, or final pathology containing medullary carcinoma, poorly differentiated thyroid carcinoma, or lymphoma were excluded from the study. The mean pre-operative Tg values for benign and malignant nodules were 262.7 ug/L and 159.4 ug/L (p = 0.1874), respectively. Tg levels >150 ug/L were associated with a malignancy rate of 78%. When considering a Tg level of 150 ug/L as the threshold as a significantly elevated pre-operative Tg, the specificity for malignancy when divided by size was: 92.9% (0–1.99 cm), 75% (2–2.99 cm), 87.1% (3–3.99 cm), 57.1% (4–4.99 cm), 60% (5–5.99 cm), 27.3% (>6 cm). This study suggests that a pre-operative Tg level >150 ug/L can be a specific marker for identifying malignancy in thyroid nodules less than 4 cm. The smaller the nodule, the greater the specificity for malignancy. It may therefore have a role in the pre-operative setting in assessing whether a patient with a small thyroid nodule requires surgery.
Thyroid Cancer Saturday Poster Basic
The use of intraoperative frozen section has been greatly reduced since the introduction of a highly accurate diagnostic modality in the form of fine needle aspiration biopsy (FNAB). However, the utility of frozen section as an adjunctive diagnostic method in indeterminate nodules without the benefit of molecular studies has yet to be clearly elucidated. This is particularly of interest in developing countries where molecular testing of indeterminate nodules has yet to be established. This study aims to determine the usefulness of intraoperative frozen section in the diagnosis of thyroid nodules where fine needle aspiration biopsies have indeterminate cytologic features. A retrospective review of all patients who had intraoperative thyroid frozen section with preoperative indeterminate fine needle aspiration biopsy results from January 2013 to December 2015 was performed. The indeterminate nodules of the current Bethesda System for Reporting Thyroid Cytopathology includes 1) atypia of undetermined significance/ follicular lesion of undetermined significance 2) follicular neoplasm/ suspicious for follicular neoplasm and 3) suspicious for malignant cells. Final histopathology serves as the gold standard of comparison. Out of the seventy (n = 70) indeterminate FNAB results that underwent frozen section, twenty-seven (38%) still had indeterminate readings on frozen section. More concerning though are the benign readings on frozen section (n = 18) that were actually malignant (22%) on final histopathology. Still, frozen section was able to correlate if a nodule was malignant in 35% of the cases. Intraoperative frozen section should still be used with discretion in the thyroid gland, as a good percentage of cases will still have indeterminate readings.
Thyroid Cancer Saturday Poster Basic
Patients with progressive distant metastases from thyroid cancer have a poor prognosis and available treatments result only in non-durable partial remissions. Targets for thyroid cancer therapy are based largely on genomic and functional data derived from primary tumors; however, most patients are treated for progressive distant metastases years after the primary diagnosis and little information is available regarding these tissues. To address this we performed a targeted genomic analysis of rare surgically resected distant metastases of thyroid cancer, and when available matched primary tumor tissues to identify potential markers or regulators of disease progression. Samples from patients with distant metastases (n = 19) were analyzed by targeted deep sequencing of 682 genes known to be involved in regulation of cancer using a custom next generation sequencing platform. We identified genomic differences between the normal tissue, primary tumors, and metastatic samples. Functional mutations in genes encoding components of the MAPK pathway (BRAF & RAS) were common in the metastatic samples. BRAFV600E and RAS mutations were not identified in samples with variants in genes involved in the DNA damage response, ATM and ERCC4. The mutations identified in these genes are predicted to be involved in DNA repair and frequently co-occurred.
Our cohort identifies variants in the FATC domain of the ATM gene and in the ERCC4 gene, both involved in the DNA damage response, that are present in progressive distant metastasis tissue. Further, these are enriched in distant metastases of thyroid cancers that do not have BRAFV600E or RAS mutations in the analyzed samples.
Thyroid Cancer Saturday Poster Basic
Hispanics are an increasing minority in the United States. Hispanics in El Paso, Texas constitute approximately 85% of the population. Well differentiated thyroid cancer is a common malignancy and a rapidly rising incidence in the United States. While well differentiated thyroid cancer generally has a favorable outcome, there is limited research regarding thyroid cancer particularly in the Hispanic population, particularly regarding the stage at diagnosis and outcomes in the Hispanic population. Some studies suggest that Hispanics have a higher risk of thyroid cancer than non-Hispanic and there is also limited evidence that Hispanics may present with more advanced disease than other racial groups.
The objective of this study is to describe the presentation of well-differentiated thyroid cancer in a Hispanic population and to determine if these patients present with an advanced stage of disease more frequently than is typically reported in the literature.134 patients managed for well-differentiated thyroid cancer at University Medical Center identified from an institutional database from January 2005- February 2016. In the adjusted association, there was about 8.5% increase in tumor size for non – Hispanics, as compared to Mexicans. Similarly for Hispanics, there was about 10.4% increase in tumor sizes, as compared to Mexican participants. However, this association was not statistically significant.
For patients with similar age at diagnosis, gender, insurance status, type of cancer and best AJCC stage: there was about 13.8% and 11.2% reduction in tumor size for non-Hispanics and Hispanic patients respectively, as compared to Mexican patients. However, this association was also not statistically significant. There is no statistical significance to observe any difference in the AJCC stage or size of tumor at presentation of well-differentiated thyroid cancer between non-Hispanics, Hispanics, and Mexicans in our patient population.
Thyroid Cancer Saturday Poster Basic
Thyroid Cancer Saturday Poster Translational
Peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) is a transcriptional coactivator which involves in metabolic control of cells. In some cancer types, PGC1α is induced and activated to meet the increased metabolic demands for invasion and metastasis. Paradoxically, an association between lower levels of PGC1α and poor clinical outcomes is also observed in certain cancers. We set out to study the PGC1α expression in thyroid carcinoma. We investigated the PGC1α expression in thyroid carcinoma tissues by immunohistochemistry. The biological role of PGC1α in thyroid cancer cells was determined by the genetic knockdown. Abundant nuclear expression of PGC1α was observed in normal thyroid tissues and benign thyroid lesions. PGC1α expression was decreased in poorly differentiated thyroid cancers and some papillary thyroid cancers. Lower PGC1α expression in papillary cancer was associated with larger tumor size, extrathyroidal extension, lymphovascular invasion, lymph node metastasis, BRAF V600E mutation, and advanced TNM stage. PGC1α suppression decreased mitochondrial biogenesis and oxidative phosphorylation with enhanced glycolysis. Decreased PGC1α expression is associated with an aggressive phenotype of thyroid cancer and glycolytic metabolism.
Thyroid Cancer Saturday Poster Translational
In the last years, particular attention was dedicated to non-invasive follicular variants of papillary thyroid carcinoma (EFVPTC) recently reclassified as “Non-invasive follicular thyroid neoplasms with papillary-like nuclear features” or NIFT-P. These tumors have an extremely low recurrence rate, likely less than 1% within the first 15 years representing a group of thyroid tumors with an overall good prognosis. By a biological point of view NIFT-P tumors could represents the precursor of invasive or infiltrative follicular variant papillary carcinomas (IFVPTCs) particularly those harboring the RAS and BRAF (other than V600E) mutations. In this study we investigate the expression profile of NIFT-P customizing a nCounter code set including 75 genes selected on the basis of their observed differential expression between Adenoma (FA) and IFVPTC. Five housekeeping genes were also included in the code set for normalization purposes. Total RNA was purified from 19 FAs, 25 NIFT-P and 18 IFVPTCs. In order to group the samples with related gene expression profiles, a cluster analyses were performed on the nCounter data by using the Pearson correlation. We found two clusters of samples with a correlation of r = 0.23 and r = 0.28 respectively. The left-hand cluster comprises 28 samples among which 16 FAs, 10 NIFT-Ps and 2 IFVPTCs. The right-hand cluster includes a total of 33 samples that are 16 IFVPTCs, 14 NIFT-Ps and 3 FAs. These data indicate that the new diagnostic entity (NIFT-P) could be further sub-divided on the basis of gene expression profile in two groups: a) one similar to those found in benign follicular tumors, and the other b) similar to those of follicular variants of PTC.
Thyroid Cancer Saturday Poster Translational
Thyroid cancer is the fastest increasing cancer in the US. While surveillance bias and increased radiation exposure have been hypothesized to play a role, data suggest that other environmental factors are likely responsible. Human exposure to flame retardant chemicals (FRs) also is increasing, raising concerns about potential health impacts. Indeed, animal studies indicate that FRs disrupt endocrine function and are carcinogenic. We are conducting a case-control study investigating FR exposure and papillary thyroid cancer (PTC) occurrence and severity. We have recruited 61 participants with PTC and 61 matched controls. Participants provided blood samples, from which we measured exposure biomarkers. Because levels of FRs in house dust are strongly correlated with personal exposure, we also visited participants' homes and collected dust samples. Several classes of FRs were measured in dust. Demographic and lifestyle information were collected via questionnaire. Study participants ranged from 21 to 80 years of age, and the majority were female (79%), reflecting a known gender difference in PTC risk. One third of cases had nodal metastases (36%), and 64% were positive for the BRAFV600E mutation. FRs were found in dust samples from every home, and levels in dust collected in cases' homes were generally higher than those of controls. Differences were most striking for triphenyl phosphate and BDE-209, which were >50% higher in cases' homes compared to matched controls (p = 0.02 and p = 0.06, respectively). Associations between FRs and PTC differed by the presence of the BRAFV600E mutation; BDE-209 was only higher in the homes of cases absent the BRAFV600E mutation. BDE-47 and BDE-153 were commonly detected in serum samples (>74% of participants). Higher BDE-47 and 153 levels are associated with more aggressive tumors (i.e. nodal metastases). Our results suggest that exposure to FRs may well be associated with the occurrence and severity of PTC. The strongest associations were observed for FRs for which there are not reliable biomarkers of long-term exposure, suggesting alternative methods of environmental exposure assessment (e.g. dust FRs) may be necessary in future research.
Thyroid Cancer Saturday Poster Translational
1α, 25(OH)2D3 (calcitriol), the active form of vitamin D, exert antiproliferative effects in many cancers. Overexpression of CYP24A1, the primary vitamin D-inactivating enzyme, is observed in many human cancers including thyroid cancer. It is not clear whether CYP24A1overexpression can directly drive tumor progression or the consequence of tumor progression. The present study investigates the role of Cyp24a1 on the progression of BrafV600E -induced papillary thyroid cancer (PTC) in a mouse model. Mice with thyroid specific expression of BrafV600E (TPO-BrafV600E ) develop PTC rapidly. TPO-BrafV600E with Cyp24a1-null mice (BVE-PTCCyp24a1-null) were obtained by several rounds of breading among LSL-BrafV600E , TPO-Cre, and Cyp24a1+/-mice. TPO-BrafV600E mice with wild-type Cyp24a1 (BVE-PTCCyp24a1-wt) were used as controls. Thyroid tumor growth was significantly reduced in BVE-PTCCyp24a1-null as compared to BVE-PTCCyp24a1-wt mice. Among 7 age-matched pairs of BVE-PTCCyp24a1-null and BVE-PTCCyp24a1-wt mice, the average thyroid tumor weight was 0.32 ± 0.06 mg in Cyp24a1-null and 1.23 ± 0.39 mg in Cyp24a1-wt mice (p < 0.05). In BVE-PTCCyp24a1-null mice, the papillary architecture of thyroid tumor was lost and tumor became more compact with reduced immunestaining of Ki67. The tumorigenicity of BVE-PTCCyp24a1-null tumor cells was also reduced in nude mice: 0.1 ± 0.01gm from Cyp24a1-null cells vs 1.9 ± 0.17gm from Cyp24a1-wt cells. The tumorigenic potential of BVE-PTCCyp24a1-null cells was partially restored by transfection of Cyp24a1 into the cells, resulting in a tumor load of 0.51 ± 0.09gm. Furthermore, reduction in three major signaling pathways (MAPK, AKT, and TGF-β) and loss of epithelial-mesenchymal transition (EMT) were observed in the BVE-PTCCyp24a1-null cells. Although calcitriol alone did not cause any significant decrease in cell proliferation in BVE-PTCCyp24a1-null cells, it synergized the anti-tumor effects of BrafV600E inhibitor PLX4720 in both BVE-PTCCyp24a1-null and BVE-PTCCyp24a1-wt cells. Cyp24a1 is a proto-oncogene. Its overexpression activates multiple signaling cascades for tumor progression and causes resistance to PLX4720. Combination of calcitriol and PLX4720 enhances therapeutic effects and reduce resistance.
Thyroid Cancer Saturday Poster Clinical
Acromegaly is a chronic illness characterized by increased production of growth hormone, which is mainly caused by pituitary macroadenomas. Exposure of tissues to high amount of circulating growth hormone (GH) and insulin like growth factor-1 (IGF-1) is responsible for increased morbidity and mortality. Previous studies indicated increased risk of benign and malignant tumor development in acromegalic patients. Although majority of acromegalic patients die of cardiovascular diseases, cancer is the third leading cause of death [1]. Acomegaly patients followed in Ankara University Ibn-i Sina Hospital between 2005–2015 were included in this study. Data were collected including demographic data, size of adenomas, serum IGF-1 and GH level, serum prostate markers, history of cancer, colonoscopy, mammography and thyroid ultrasonography result collected from patients records retrospectively.83 patients 40 (48.2 %) of whom were male and 43 (51.8%) female were included. Mean age of patients was 41 (18–68) at the time of diagnosis. Mean duration of follow up was 58.7 months (3–312 months). The most common symptoms at presentation were acral growth (94%), sweating (48%) and headache (48.2%). Thyroid ultrasonography were performed in 65 of the patients (78.3%) periodically, colonoscopy and mammography were also conducted 71.1% and 69.8% of the patients at least once over the course of disease respectively. Cancer was detected 13 (15.6%) of the patients and 8 (9.6%) of them was well-differantiated thyroid cancer, 2 of them were breast cancer. Prostate cancer, malign cordoma and colon cancer were identified each in one patient also. In this study, we demonstrated that thyroid cancers is the most common (10.8%) malignancy in acromegalic patients, consistent with the result of previous studies [2–4]. We showed increased thyroid malignancy risk in acromegalic patients compared to population based studies (2–3.5 %) [5, 6]. However this risk does not seem to correlate with serum level of GH (p = 0.623), IGF-1 (p = 0.957) at the time of diagnosis and cure rates (p = 0.764). Unlike previous studies we found low risk of breast, colon and prostate cancers in our population which may be attributed to patient incompatibility.
Thyroid Cancer Saturday Poster Clinical
Postoperative ablation of functioning thyroid tissue has become standard in the management of differentiated thyroid cancer (DTC). Historically, a high dose of radioactive threapy with 131I (RAI), usually 30–100 mCi with follow up whole body scan (WBS) has been often used to ensure successful albation and improve surveillance and prognosis. This abstract describes RAI ablative prescibing practices in central New Jersey over the last decade. Records from Radiology/Nuclear Medicine Department from a single academic university medical center from Jan 2004-June 2014 were reviewed; all images with post RAI ablative WBS for DTC were included. A total of 137 patients received 146 doses of ablative RAI dose with follow up WBS were done over this time frame. Eight patients received at least 2 doses; 1 received 3 doses of RAI ablation. All WBS suggested thyroid bed uptake; a few were highly suggestive of pathological cervical lymphadenopathy as well. Females received 68% of the doses and males 32%; this proportion is unchanged over the decade. The mean age of patients receiving ablation has dropped from 52 from 2004–2009 to 48 from 2010–2014.
The median RAI ablative dose dropped from 100 mCi in 2004–2013 to 50 mCi in 2014. Only 1 patient received a dose of less than 100 mCi between 2004–2010. The presciption of 50 mCi or less dose has grown susbstantially, from zero in the previous 8 years to over 50% in the last year. National Cancer Institute Surveillance, Epidemiology and End Results database suggests a robust increase in the incidence and prevalence of DTC. However, the mortality risk remains low and long term disease free state is seen in over 98% of the patients. Recently, ATA and NCCN guidelines suggest use of lower doses of ablative RAI in patients at moderate risk of recurrence and avoiding RAI ablation in low risk patients. The practice patterns at our institution have been following these guidelines and indeed started making that transition about 2 years before the guidelines were finally released. Individulaized care of all patients with DTC with special emphasis to recurrence risk is likely to improve outcome in these patients.
Thyroid Cancer Saturday Poster Clinical
Radioactive 131I (RAI) whole body scans (WBS), either post ablation or surveillance are commonly utilized in patients with differentiated thyroid cancer (DTC). Artifacts that mimic metastases may contribute to additional, costly and often invasive testing. All WBS, either post RAI or surveillance, from Jan 2006-June 2014 done at Nuclear Medicine department of an academic university medical center from were reviewed. Correlative Thyroglobulin (Tg) levels and additional imaging/studies/procedures were also reviewed from the hospital records and patient charts. A total of 224 patients had an ablative RAI or a surveillance WBS with 146 post RAI ablative and 242 surveillance WBS. All post RAI ablative scans had expected thyroid bed uptake; a few were highly suggestive of pathological cervical lymphadenopathy as well. Ten patient (4.5%) had persistent thyroid bed uptake; 4 of these were noted 6–8 months post ablation and 6 others had persistence even after 1 year (13–23 months post RAI).
A total of 16 patients (7.1%) were found to have distant uptake away from the neck/thyroid bed. Only 5 (2.2%) of these had true pulmonary/bone metastases. The other 12 (5.3%) had false postive uptake once correlated with Tg and additional imaging/studies/procedures. One patient had both, a true pulmonary metastases and a false positive uptake on occipital calvarium. The false postive uptake was noticed in calvarium (3), superior mediastinum (3), a vertical streak along the mediastinum (1), lower extremity wound (1), scrotum/testicular (1), left lung base (1), lateral chest wall (1) and proximal femur (1). DTC typically follows a biologically non aggressive pattern. Distant metastases in our review were only seen in 2% patients. Over 5% patients have a false postive WBS. Based on literature reivew, these are likely due to RAI uptake with sweating (calvarium), thymus (mediastinum), wound scab (lower extremity), poor personal hygeine (scrotum, proximal femur), gatro-esophageal reflux (mid epigastic), bronchiectasis (lateral chest) and prevous bariatric surgery induced scarring (lung base). Nonthyroidal pathology should be excluded in patients that have atypical characteristics on WBS.
Thyroid Cancer Saturday Poster Clinical
Differentiated Thyroid Cancer (DTC) typically has an excellent prognosis with 5-year disease free survival of over 98%. A subset, however, presents with more aggressive and refractory disease. A personalized, targeted multidisciplinary approach may improve outcomes in such patients. We present here 2 cases of Stage IVC DTC which have been comanaged with a nultidisciplinary team.
Thyroid Cancer Saturday Poster Clinical
Medullary thyroid carcinoma (MTC) is a rare thyroid malignancy originating from parafollicular C cells with potential for aggressive behavior. The extent of lymph node (LN) dissection at the time of surgery is controversial since there is a high false-negative rate in radiological imaging. Some groups advocate the use of preoperative calcitonin (CT) levels as a way to ascertain the likelihood of local LN metastasis. We retrospectively assessed the correlation between preoperative CT levels and clinico-pathological factors among 51 patients with MTC between 1994 and 2015. Preoperative CT levels correlated independently with tumor size (p < .001), number of metastatic lymph nodes (p < .03), declining rates of biochemical cure, and increased rates of distant metastasis respectively. Patients without LN metastasis had CT levels below 500 mg/mL. A CT level of 1000 pg/mL was found to be a representative threshold above which the surgical cure declines considerably and a good predictor of the involvement of central compartment and lateral neck lymph nodes, regardless of the findings on imaging. Finally, TNM stage (p < .0001) also correlated with preoperative CT levels. In our experience, preoperative CT is a sensitive and specific risk stratification marker for MTC in predicting the extent and recurrence of disease. We demonstrated that CT levels >1000 pg/ml predict positive LNs in both the central compartment and lateral neck despite findings on radiological imaging.
Thyroid Cancer Saturday Poster Clinical
To provide a modern update on the incidence and trends of thyroid cancer and primary hyperparathyroidism (PHPT) after radiation exposure. Retrospective review of patients treated within a multi-center, high-volume endocrine practice between 2000–2015. All patients were routinely screened for history of radiation exposure (HXRT). Thyroid microcarcinomas (TMC) were defined as ≤1 cm. Univariate analyses were performed with JMP Pro 12. We identified 228 patients with HXRT: 70% were female, median age was 62 (range 21–90), and median age of exposure was 13 (range 1–63 years). Despite significant increase in surgical volume by the practice, the number of patient referred with XRT decreased from 31 patients in 2007 to two in 2015. Referrals were 64% thyroid disease (n = 145), 25% PHPT (n = 58), and 11% both (n = 25). After our evaluation, an additional 62 patients were found to have both (38% overall). The mean latency period between HXRT and initial patient evaluation was longer for PHPT than thyroid disease (52.5 ± 12.4 vs. 38.4 ± 17.4, p = 0.0001). The incidence of thyroid cancer was 26%: 40% were papillary and 34% were follicular-variant papillary cancers. The incidence of TMC was similar in patients with cancers compared to those without (36% vs. 30%, p = 0.4). When compared to a cohort of our patients without exposure, patients with HXRT had similar incidence of thyroid cancer and TMC (26% vs. 28% and 35% vs. 31%, respectively). However, patients with HXRT had less incidence of TMC compared to the cohort of patients without exposure who also had clinical cancers (31% vs. 45%, p = 0.003). In 105 patients who underwent parathyroidectomy: 77% had single adenoma, 22% had multigland disease, and 1% had cancer. The era of treating thyroid disease in patients with HXRT for antiquated indications is coming to an end; however, the longer latency period for PHPT presentation and the high rate of concomitant disease signifies the importance of screening and follow-up. Although less than previously reported, in this modern and large series, the incidences of cancer and TMC with HXRT were 26% and 31%, respectively.
Thyroid Cancer Saturday Poster Clinical
The simultaneous existence of medullary thyroid cancer (MTC) and papillary thyroid cancer (PTC) is increasingly being identified. The majority of concurrent MTC and PTC might simply be coincidental. Currently there are no guidelines for management of concurrent MTC and PTC. This case report presents a case of concurrent MTC and PTC, with a decrease in calcitonin level after radioactive iodine therapy for PTC. A 35 year old Caucasian female with a history of hypertension, vitiligo, and Hashimoto's hypothyroidism underwent neck imaging due to unresolved coughing after starting lisinopril. Neck ultrasound revealed a thyroid nodule. She underwent total thyroidectomy and central neck dissection for an indeterminate FNA of this nodule. There was no family history of thyroid cancer.
Final pathology revealed bilateral multifocal MTC (largest focus 0.8 cm) and papillary microcarcinoma in the left lobe. Left neck dissection revealed 8/17 peritracheal nodes positive for MTC without extranodal extension. Surgical margins were negative and extrathyroidal extension was not identified.
She underwent right neck and superior mediastinal dissection for enlarged lymph nodes, with final pathology showing 2/43 nodes positive for metastatic papillary thyroid cancer.
Calcitonin level prior to second neck dissection was 162 pg/ml. One month after second surgery, patient received adjuvant radioactive iodine therapy. Repeat calcitonin level 2.5 months after radioiodine therapy decreased to 40.5 pg/ml. No evidence of distant metastases was seen on anatomic or post RAI imaging. Screen for MEN2 was negative. Genetic testing results are pending. She is on thyroxine replacement for TSH target. The simultaneous existence of medullary and papillary thyroid carcinoma as a collision tumor with metastases from both lesions in the regional lymph nodes is a rare phenomenon. Management of these cases poses a high complexity of clinical decision making. The underlying pathogenesis of these tumors is unknown. This patient's calcitonin level significantly decreased after radioactive iodine therapy. This suggests that radioactive iodine therapy for PTC likely resulted in decreased calcitonin levels, probably by affecting neighboring parafollicular cells.
Thyroid Cancer Saturday Poster Clinical
Medullary thyroid carcinoma (MTC) and papillary thyroid carcinoma (PTC) arise from independent cells of origin, but rarely may be found in the same patient. The finding of two separate tumors with distinct clinical courses and treatment options may prove to be challenging for clinicians. We therefore examined the outcomes of patients with both MTC and PTC with the primary objective of determining the dominant subtype that would dictate recurrence. The cancer registry at our tertiary care referral center was reviewed to identify all patients from 1995–2015 who had been diagnosed with both MTC and PTC on initial total thyroidectomy. Patient demographic, pathology and recurrence data were collected and reviewed.
Thyroid Cancer Saturday Poster Clinical
Three Mile Island, Chernobyl, Fukushima - all the places where happened to the nuclear accident. As a thirty-year experience after the Chernobyl accident has shown international cooperation and an exchange of experience are very important in early diagnosis of thyroid cancer and mitigation of consequences of nuclear accidents.
It is well known now that the dramatic increase in the incidence of thyroid cancer in individuals exposed to ionizing radiation in childhood is the most significant health consequence of the Chernobyl accident in Belarus, Ukraine and the Russia. Comparison of data obtained by different screening international and local projects in Belarus in 1990–2010 shows that the prevalence of thyroid carcinoma among the young population varied within 0.2%–0.62%. The incidence of thyroid cancer in the United States is increasing faster than any other cancer and the reasons of this situation are not completely clear. To detect the relationship between radiation exposure and thyroid cancer induction and for early diagnosis of radiation-related thyroid cancer, a “Project Chernobyl” has been established in New-York. Two cohorts of people (a total of 6,870 subjects currently living in New-York area) emigrated from Belarus and Ukraine after Chernobyl accident, were underwent ultrasound screening of the thyroid in 2008–2012 yy. The first group included 2,550 subjects (mean age 59 ± 7 yrs) exposed to fallout from Chernobyl. The second group included 4,320 non-exposed subjects (mean age 53 ± 2 yrs). During the screening, the prevalence of thyroid cancer was found to be higher in irradiated subjects as compared to non-irradiated (8.6% vs. 4.0%, P < 0,001, respectively). According the morphological data follicular cancer was diagnosed with higher frequency in non-irradiated subjects (33,0% vs 4,5%, P < 0,001). Irradiated patients with thyroid cancer were underwent more aggressive surgical treatment than non-irradiated: total thyroidectomy 77% vs. 60% (P < 0,05). Further international cooperation are very important for screening and early detection of thyroid cancer in people living in the areas around Chernobyl as well in those who moved to other places after they had received radiation doses.
Thyroid Cancer Saturday Poster Clinical
Both breast cancer (BC) and thyroid cancer (TC) are common malignancies in female people. The former has a much higher mortality than the latter, but the latter has a rapidly increasing incidence in recent years. Many studies have demonstrated an increased risk for the development of TC in patients with BC; primary cancers of the two types often occur in the same patient. However, how one may affect the clinical behavior of the other, if any, has not been investigated. In the present study, we particularly investigated how BC behaved in patients who also developed TC.
We used the SEER 9 database from 1973 to 2011 to identify female patients who were first diagnosed with BC (BC-1st) and subsequently diagnosed with primary TC and female patients who were diagnosed only with BC (BC-only) without TC in their life. A total of 1,037 patients diagnosed with TC after a prior diagnosis of BC-1st and 409,995 patients diagnosed with BC-onlywere identified from SEER 9. BC-1st patients developedBCearlier than BC-only patients did by an average of 5years. Compared with BC-only patients, BC-1st patients had smaller BC tumor size (median 11 mm vs 18 mm, P < 0.01), less common lymph nodes metastasis (32.3% vs 35.8%, P < 0.05), less common distant metastasis (2.8% vs 7.4%, P < 0.05) and, remarkably, a much lower BC-specific mortality (10.2% vs 24.9%, P < 0.01). More comprehensive analyses of other parameters are currently ongoing to further characterize the unique protective effect of TC on BC patients. Patients who develop BC with subsequent diagnosis of TC have a better prognosis, including a remarkably lower mortality, than patients who only have BC. Thus, TC is associated with a strong protective effect on BC patients. Prospective studies are warranted to confirm this exciting novel finding and establish the better prognosis of BC patients who also have TC.
Thyroid Cancer Saturday Poster Clinical
Radioactive iodine (I131) of the remaining thyroid tissue after total/near total thyroidectomy is well recognized as part of treatment of patients with differentiated thyroid carcinoma. Patients receiving high doses of I131, their families and the community are liable for radiation hazards more than the ones receiving low doses, also the incidence and the severity of the side effects are more in higher doses. A randomized double-armed trial comparing low and high doses radioiodine ablation.
The trial was conducted to 121 patients their ages ranged from 20 to 77 years at the start of treatment, with differentiated thyroid cancer, with disease confined to the thyroid or cervical lymph nodes were treated with I131 after total thyroidectomy and pathologic lymph node resection, if present.
52 patients received low dose 1110MBq and 69 patients received high dose 3700 MBq. Six months after the administration of radioiodine, measuresment of serum thyroglobuline level, anth-thyroglobulin antibodies, together with neck ultrasound exam and I131 wholebody scan were performed. The success rate of ablation is determined by negative whole body I131 scan, negative neck ultrasonography and serum thyroglobulin level less than 2 ng/mL. Complete, successful ablation occured in 83 out of 121 patients (68.6%). In the group recieving low 131-RAI dose (1110 MBq), complete successful ablation was reported in 33 out of 52 cases (63.5%), versus 50 out of 69 cases (72.5%) in the group recieving the high dose (3700 MBq). P-vaue = 0.291. From this ongoing data, no significant difference in the successful ablation rate between the low and high 131-RAI doses in the post operative thyroid remnant ablation in differentiated thyroid cancer.
Thyroid Cancer Saturday Poster Clinical
Quality measures for thyroid cancer management are lacking. Four outcomes and one composite process measure to assess thyroid fine needle aspiration (FNA), completeness of thyroid cancer surgery, and follow-up for differentiated thyroid cancer were analyzed in our health system (1727 FNAs, 611 operations).
1. Percent non-diagnostic FNAs = (non-diagnostic FNAs) ÷ (total FNAs)
3.1% of FNAs by Endocrine Surgery (ES) were non-diagnostic, versus 12.0% by endocrinology, p < 0.0001.
2. Percent complete cervical surgery in RAI-ablated patients = (patients without cervical nodes and <2% RAI-uptake) ÷ (RAI-ablated patients)
89% of RAI-ablated ES patients had complete neck surgery versus 76% of other-surgeons' patients, p = 0.0258
3. Percent complete cervical surgery in non-RAI-ablated patients = (patients with thyroglobulin <2 ng/mL 6–8 months after surgery) ÷ (non-RAI-ablated patients)
89% of non-RAI-ablated ES patients had complete neck surgery versus 89% of other-surgeons' patients, p = 0.999
4. Percent without cervical structural disease 6–8 months after surgery = (patients without cervical structural disease by ultrasound) ÷ (patients followed-up 6–8 months after surgery by ultrasound)
98% of ES patients had no cervical structural disease versus 91% of other-surgeons' patients, p = 0.0465.
5. Percent comprehensive 6–8 month follow-up = (patients with TSH, thyroglobulin, neck ultrasound, and expert cervical exam 6–8 months after surgery) ÷ (patients who underwent surgery)
54% of ES patients had comprehensive follow-up versus 35% of other-surgeons' patients, p = 0.0548. These measures met NQF criteria and demonstrated differential outcomes between groups. Non-diagnostic FNA and comprehensive follow-up were targeted for improvement and mentoring was provided for individuals with room for improvement.
Thyroid Cancer Saturday Poster Clinical
Recently, the Endocrine Pathology Society Working Group (EPSWG) has recommended that a sub-group of encapsulated follicular variant of papillary thyroid cancers (EFVPTC) be reclassified as non-invasive follicular tumors with papillary-like features (NIFTP's) to reflect their highly indolent clinical behavior. We report on the clinical characteristics of 20 consecutive patients with NIFTP's diagnosed in an endocrine surgical practice over the past 36 months. We interrogated our practice registry for all EFVPTC pathologic diagnoses over the period from 3/2013- 3/2016. We then applied the new EPSWG diagnostic criteria and studied the clinical characteristics of the reclassified NIFTP patients.55 EFVPTC's in 48 patients were discovered. 20 of these were reclassified as clinically significant NIFTP's. In our practice the typical NIFTP patient was female and 45. Their tumors were large (average 3.3 cm) with variable echo texture, clearly defined borders and mild hypervascularity. When molecular marker testing was performed, 8 of 9 patients with indeterminate cytology were “suspicious” by Afirma GEC. One other patient had an NRAS mutation by Thyrosec 2.1 testing. Eight patients were treated with thyroidectomy and 12 underwent ipsilateral lobectomy. No patient received radioiodine adjuvant therapy. Interrogation of a community-based endocrine surgical registry reveals that the EPSWG's non-malignant reclassification of some EFVPTC's as NIFTP's segregates a subset of patients who do not require full thyroidectomy or RAI. In our community-based practice, 42% of patients with clinically significant EFVPTC diagnoses were reclassified as having NIFTP's. These patients are typically young females with large, clearly demarcated, mildly hypervascular tumors demonstrating Afirma GEC suspicious, indeterminate cytology. The EPSWG reclassification of a subset of EFPTC's to NIFTP's should allow thyroid clinicians a new rationale for offering lobectomy and avoiding RAI therapy in a unique group of younger patients with large tumors and positive molecular marker results.
Thyroid Cancer Saturday Poster Clinical
Patients with differentiated thyroid carcinoma refractory to radioactive iodine treatment (RAI rDTC) treated with the multikinase inhibitor sorafenib also often receive levothyroxine for thyroid-stimulating hormone (TSH) suppression. In the phase 3 RAI rDTC trial (DECISION), sorafenib exposure was higher than previously observed in other cancer types. This study assessed sorafenib pharmacokinetics (PK), without and with levothyroxine, resulting from hyperthyroidism mimicked by levothyroxine. In this open label study in healthy volunteers, all subjects received a single dose of sorafenib 400 mg on Day 1 of Period 1. After a washout period, levothyroxine 300 μg was administered once daily for 14 days from Day 1 of Period 2 and a single dose of sorafenib 400 mg was given on Day 11 after 10 days of levothyroxine dosing. Blood samples for sorafenib PK analysis were obtained predose and at time points up to 96 h after each sorafenib dose, and for thyroid tests pre- and post-levothyroxine dosing. All 25 male subjects (aged 18–45 y) dosed, completed the study, and were evaluable. Levothyroxine mimicked hyperthyroidism, producing full suppression of TSH (0.033 ± 0.027 mU/L) and increased free T3 (4.24 ± 0.66 pg/mL) and T4 (1.77 ± 0.33 ng/dL) by Day 11 of Period 2. Mean (% CV) maximum observed concentration (Cmax) for sorafenib without and with levothyroxine was 2.09 (68.1) and 1.78 (63.9) mg/L, respectively; with corresponding mean sorafenib area under the concentration time curve from 0 to infinity (AUC) of 68.1 (68.2) and 64.3 (66.3) mg*h/L, respectively. Median (range) time to Cmax (tmax) was 4.00 (2.98–16.0) h for sorafenib and 4.02 (1.98–36.0) h for sorafenib + levothyroxine; mean (%CV) half-life (t1/2) was 24.0 (25.3) and 25.7 (21.0) h, respectively. Mild and moderate treatment-emergent adverse events (AEs) were reported by 22 and 5 subjects, respectively. All study drug–related AEs were mild. Levothyroxine 300 μg once daily was well tolerated, mimicked hyperthyroidism, and had no effect on sorafenib PK. Findings suggest no concerns with coadministering levothyroxine and sorafenib in patients with RAI rDTC.
Thyroid Cancer Saturday Poster Clinical
Molecularly targeted agents, i.e. kinase inhibitors, have emerged as promising therapies for advanced thyroid cancers. However, the role of tumor interrogation for mutations remains of uncertain benefit in the selection of personalized therapies; we examined this in our practice. We analyzed the frequency and impact on care of Foundation OneTM tumor interrogation among patients (pts) with poor-prognosis thyroid cancers deemed candidates for systemic therapy. Samples from 41 pts were evaluated, 23 from males (56%); 16 were anaplastic (ATC, 39%), 15 papillary (PTC, 37%), 4 medullary (MTC, 10%), 3 poorly differentiated (PDTC, 7%), and 3 “other” (7%); 68% of assessed pts remain alive.
Mutational burden paralleled aggressiveness of disease, with mean 4.4 mutations per ATC, 3.7 per PDTC, 3 per PTC, 1 per HCC, 2 per MTC. Mutations seen in >10% of samples were: TERT promoter 51% (seen in 67% of ATCs, 33% PDTCs, 67% PTCs and in 1 HCC), TP53 41% (73% of ATCs, 100% PDTCs, 13% PTCs), BRAFV600E 37% (33% of ATCs, 0% PDTCs, 67% PTCs), CDKN2A/B 15% (13% of ATCs, 33% PDTCs, 20% PTCs), RET 12% (0% of ATCs, 33% PDTCs, 0% PTCs, 75% MTCs and in 1 thyroid sarcoma), PTEN 12% (13% of ATCs, 33% PDTCs, 7% PTCs and in 1 sarcoma), NF1 10% [20% of ATCs, 0% PDTCs (but 33% had NF2 mutation), 7% PTCs], NRAS 10% (20% of ATCs, 0% PDTCs, 7% PTCs, 0% of HCCs/MTCs; 1 MTC had HRAS mutation) and DNMT3A 10% (6% of ATCs, 33% PDTCs, 13% PTCs).
Overall 80% (33) of tumors were reported as having targetable alterations per Foundation OneTM, 54% (22) by our reckoning. However, these results ultimately prompted altered therapy in only 3 pts (7%), yielding no RECIST responses. In contrast, empiric treatment with multikinase inhibitors yielded RECIST PRs in 4 of 17 pts (23%; best mean RECIST response 88% for 1st line therapy; 83% for 2nd line, and 79% for 3rd line). Observed mutational spectra varied by histology in accord with published genomic data, saving for a higher frequency of TP53 mutations in PDTCs. In our hands, mutational analyses seldom altered therapy or outcomes, but many alterations were encountered that may allow development of novel therapies into the future, especially TERT promoter.
Thyroid Cancer Saturday Poster Clinical
Thyroglobulin levels in washout fluid from lymph node (washout LN Tg) are useful for early detection of lymph nodes (LN) metastasis in well-differentiated thyroid cancers. However, the definite cutoff value for metastatic lymph nodes in patients with papillary thyroid cancer (PTC) has been unclear. The aim of this study was to define the optimal cutoff value of washout LN Tg according to the status of the thyroid in PTC patients with suspicious sonographic findings in cervical LNs. Washout LN Tg levels from 160 cervical lymph nodes in 139 patients with PTC who underwent surgery at Chonnam National University Hwasun Hospital from 2011 to 2015 and surgical pathology were evaluated retrospectively. Washout LN Tg levels were classified by the status of the thyroid. In pre-operative group with intact thyroid gland, 134 suspicious LNs were removed surgically and 84 LNs (62.6%) were metastatic. The optimal cutoff value of washout LN Tg was 0.75 ng/ml (sensitivity 92.9%; specificity 96.0%). In post-thyroidectomy and radio-iodine therapy group, 23 suspicious LNs were removed and the optimal cutoff value of washout Tg level was 0.45 ng/ml (sensitivity 90.5%; specificity 88.9%). The appropriate cutoff values of washout LN Tg in patients with PTC are different according to the status of the thyroid. For monitoring of LN recurrences in PTC patients after total thyroidectomy, lower cutoff value of washout LN Tg should be employed for early diagnosis of LN recurrences.
Thyroid Cancer Saturday Poster Clinical
Graves' disease (GD) has historically been associated with a low risk for thyroid malignancy. The purpose of this study was to review our experience of GD patients who underwent total thyroidectomy to determine the incidence and predictive variables for thyroid cancer. A multi-institution, retrospective cohort review was conducted across four tertiary referral centers of all patients who underwent total thyroidectomy for GD from 2005–2015. Patient variables and pathology results were reviewed. The primary outcome was malignancy on surgical pathology. Data was analyzed with the presumed diagnosis of noninvasive follicular thyroid neoplasm with papillary-like nuclear features as a benign lesion. Descriptive analyses were performed using student's t-test and Chi-square. Multivariable logistic regression was performed to identify significant predictor variables.567 patients underwent total thyroidectomy for GD. 242 (43%) patients had nodules and, of those, 108 (45%) patients had fine needle aspiration (FNA) biopsies. Of the 567 patients, 74 (13%) patients had thyroid cancer, 51 (21%) patients with nodules and 23 (7%) patients without nodules. In the cancer patients with nodules, FNA had been performed in 30 patients. These resulted Bethesda V or VI in 16 patients and, surprisingly, Bethesda II in 9 patients. Cancers were multifocal in 20 patients (39%) vs 6 patients (25%) and greater than 1 cm in 20 patients (39%) vs 1 patient (4%), in nodular vs non-nodular disease, respectively. On logistic regression, the presence of nodules (p < 0.001) and a positive family history (P = 0.028) were the only independent predictors of thyroid cancer. Prior RAI ablation was a negative predictor (p = 0.023). The overall incidence of thyroid cancer in our multi-institutional GD population that underwent thyroidectomy was 13%. Nodules and a positive family history of thyroid cancer were the only significant predictors for thyroid cancer. In GD patients with nodules, the cancer incidence was 21% and they were more likely to have multifocal and clinically significant (>1 cm) cancers. Our results indicate that nodular GD patients have a substantial risk for thyroid cancer and surgery should be preferred over RAI in this patient population.
Thyroid Cancer Saturday Poster Clinical
To investigate the relationship between the level and change of pre-ablative thyroid-stimulating hormone (TSH) and the response to subsequent radioiodine (RAI) therapy in patients with low to intermediate risk DTC after total or near total thyroidectomy. A total of 120 DTC patients with serial pre-ablative TSH measurements were enrolled in this study. TSH levels measured on the day of thyroid hormone withdrawal (THW) and on the day of RAI administered were marked as TSH1 and TSH2 respectively. The duration of THW was marked as t, while the change of TSH and its rate were defined as ▵TSH (TSH2-TSH1) and v (▵TSH/t). Responses to RAI therapy were classified as excellent, indeterminate, biochemical incomplete and structural incomplete response (ER, IDR, BIR and SIR) according to the 2015 ATA (American Thyroid Association) guidelines. Patients with a TSH2 level of 30–60, 60–90, 90–120,120–150 and above 150 mU/L were divided into G1-5 groups accordingly. Clinical and pathological features as well as v, t were compared among these groups. To further evaluate the impact of v on clinical response, people were then divided into V1-3 groups as per the v value of below 2.5, 2.5–5 and above 5. The differences of clinical and pathological features as well as RAI dose were compared between patients with incomplete response (IR, including BIS and SIR) and those with non-IR. Logistic regression was also performed to identify factors associated with IR. Male (p = 0.018), younger age (p = 0.001) and higher V value (p < 0.001) presented a higher level of TSH2. G3 group, with a TSH level at 90–120 mU/L, presented the highest rate of ER (83.8%). V2 presented the highest percentage of non-IR (92.4%) among the three v groups, though statistical significance (U = 407.5, p = 0.848). Pre-ablative TSH level (OR = 0.835, P = 0.030) and pre-ablative Tg (OR = 1.196, p < 0.001) were independent factors in predicting IR. The changing rate of pre-ablative TSH may not be associated with the response to RAI therapy in patient with low to intermediate risk DTC, while the level of TSH before ablation may. Patients with a pre-ablative TSH ranging from 90 to 120 mU/L might be more likely to achieve a better clinical response.
Thyroid Cancer Saturday Poster Clinical
Radioiodine (RAI) therapy is recommended in differentiated thyroid cancer (DTC) patients with microscopic extra-thyroidal extension (ETE). Patient with a low pre-ablative stimulated thyroglobulin (ps-Tg) level carries a more favorable prognosis. It remains uncertain whether low-dose RAI could achieve a same efficacy in these patients with low ps-Tg. This study aims to evaluate the efficacy of low-dose RAI therapy in patients with low-level ps-Tg. The inclusion criteria for this retrospective study were as follows: 1. aged 18 years or older, 2. after total or near-total thyroidectomy for DTC, 3. no distant metastasis detected by clinical examination, cross-sectional and/or nuclear medicine imaging after thyroidectomy and before RAI therapy, 4. pT3 stage (with microscopic ETE) with any N stage, 5. with a ps-Tg level of 5 ng/ml or less, 6. first time of RAI therapy. The response of patients was assessed at 20–24 months after RAI therapy in terms of excellent or non-excellent response. Totally 132 patients were involved with 69 patients in low dose (1100 MBq) and 63 in high (≥3700 MBq). Excellent response was observed in 86.9% patients of low-dose group (60/69) at 20–24 months' assessment, which did not differ from the high-dose group (P = 0.165). Non-inferior response in patients after low-dose of RAI therapy was also evinced by multivariate analysis (P = 0.546), when compared with those after high-dose therapy. For patients with LN metastases, ER group at 20–24 months demonstrated significantly lower ps-Tg level (P = 0.006) than NER group. For patients with different N statuses (N0, N1a, N1b), low-dose RAI therapy could lead to a similar efficacy when compared with high-dose group (P = 1.000, P = 0.286, P = 0.722, respectively) (Table 4). Though the N1b patients achieved the worst response at 20–24 months' evaluation (N0 32/33, 97.0%, N1a 37/47, 78.7% and N1b 40/59, 67.8%, respectively), high-dose therapy could not further improve their responses. Low-dose RAI therapy is not inferior to high-dose in achieving an excellent response in DTC patients with microscopic ETE, with or without LN metastases, when ps-Tg was used as an adjuvant decision marker with a cutoff of less than 5 ng/ml.
Thyroid Cancer Saturday Poster Clinical
Many problems can arise from the multiple hand-offs of information between specialists treating thyroid cancer patients. Deficits in communication can result in incomplete surgery and inaccurate pathology reporting or interpretation. Miscommunication has been uncovered as the root cause of more than 60% of adverse sentinel events reported to The Joint Commission. There is a need to develop communication practices across multiple settings, as thyroid cancer care is often delivered via multidisciplinary teams located in divergent settings. There are currently no defined solutions to disease-specific communication with regards to thyroid care. We present two illustrative cases of miscommunication that resulted in surgical and pathological errors. In order to avoid these problems in the future, we have built an imaging module as part of the Thyroid Care Collaborative, a HIPAA-compliant disease specific electronic health record, to ensure accurate, portable, real-time information that is available to all clinicians across all disciplines and institutions involved in the management of a specific patient. The main advantages of this interactive disease-map are 1- portability across institutions and disciplines, and 2-disease-specificity to thyroid nodule and cancer, both of which have been identified as areas representing opportunities for quality improvement in health informatics research. We have developed the first disease-specific disease map for use in thyroid nodule/cancer that is HIPAA-compliant and portable across institutions. As this disease map respects the Joint Commission criteria on safe hand-offs, we expect that increased use of an interdisciplinary portable disease map will enhance communication and result in a reduction in surgical and pathological errors.
Thyroid Cancer Saturday Poster Clinical
Traditionally, voice changes after thyroidectomy are thought to be secondary to recurrent or superior laryngeal nerve injury and, therefore, should occur in approximately 1–2% of patients operated upon by an experienced thyroid surgeon. In the North American Thyroid Cancer Survivors Study (NATCSS), 54.9% of participants reported postop voice problems. The aim of this study is to more precisely quantify voice disorders in those patients and understand how this affects quality of life (QoL) after thyroidectomyA previously validated 10 item tool to assess voice disorders, the Voice handicap index-10 (VHI-10), was sent to all NATCSS participants. The tool assesses voice problems on a scale from 0 (no problem) to 40 (major problem). A score of 3.38 or below is considered to be within normal range. Comparisons were performed using unpaired t-test. Pearson correlation was used to assess for correlation between QoL item and VHI-10 score.
A total of 495 participants answered the VHI-10 survey. The 270 participants (55%) with reported voice disorders in the NATCSS survey had a mean score of 11.61+/-8.91, which is significantly worse than the scores of the 179 (36%) participants who did not report voice disorders (2.88+/-4.88). The results were also significantly better for participants with stage I thyroid cancer (n = 145) compared to those with stage IV cancer(n = 42) (p = 0.0017). Importantly, there was a significant increase in voice disorders for participants that reported loss of income compared to those that did not report loss of income (p < 0.0001). There is a positive correlation between the VHI-10 score and several QoL components including: physical (r = 0.401 p < 0.01), psychological (r = 0.355 p < 0.01), and social wellness (r = 0.358) p < 0.01) and total QoL (r = 0.402 p < 0.01). We show that the presence of a voice disorder after thyroidectomy for cancer causes a significant decrease in quality of life. Voice disorders also seem to be related to loss of income and may prove to be a factor in the high rate of bankruptcy seen in thyroid cancer survivors. However, more work needs to be done to understand this relationship.
Thyroid Cancer Saturday Poster Clinical
Up to 30% of patients with papillary thyroid cancer (PTC) have persistent or recurrent disease following initial surgery. Reoperation is recommended in most patients with locoregional recurrence, but the role of adjuvant radioactive iodine (RAI) beyond the initial ablative dose is unclear. The objective of this study was to analyze the impact of post-reoperative RAI ablation on disease-free survival. We performed a retrospective cohort study of patients who underwent reoperation for persistent or recurrent PTC at a single tertiary referral center from 2006–2015. The main outcomes were post-reoperative suppressed serum thyroglobulin (Tg) levels and structural recurrence (abnormal ultrasound findings and pathologic confirmation). Outcomes were compared between patients who received post-reoperative RAI ablation and those who did not. There were 98 patients in the cohort, 49 (50%) of whom received post-reoperative RAI. The median Tg levels for the entire cohort decreased from 3.2 ng/mL prior to reoperation to 0.2 ng/mL within 3 months following reoperation. The Tg levels were similar between patients who did not receive post-reoperative RAI and those who did at 3 months (median Tg, interquartile range [IQR] = 0, 0–0.85 ng/mL vs. 0.5, 0.2–1.6 ng/mL) and 6 months following surgery (median Tg, IQR = 0.3, 0–0.9 ng/mL vs. 0.4, 0–1.8 ng/mL). The rate of a structural second recurrence was 22.9% for patients who did not receive post-reoperative RAI (mean time to recurrence 11.1 months) and 43.8% for patients who did receive post-reoperative RAI (mean time to recurrence 13.6 months). In multivariate analysis, post-reoperative RAI was not associated with a decreased risk of structural recurrence. Patients with locoregional recurrence following initial surgery for PTC had an excellent biochemical response to reoperation. The risk of a second recurrence remained high and may reflect disease biology. Post-reoperative RAI ablation was not associated with decreased biochemical or structural recurrence.
Thyroid Cancer Saturday Poster Clinical
It is well documented that quality of life (QoL) differs across cultures independent of living standards. These differences are related to cultural context, history, and experience. To date there has not been a study specifically addressing these cultural differences in thyroid cancer survivorship. As the field of study grows it is important to acknowledge these differences so the correct study tools can be created. Here we hypothesize that there are differences in the QoL of Canadian versus American thyroid cancer survivorsThyroid cancer survivors were recruited from a multicenter collaborative network of clinics, national survivorship groups, and social media through the North American Thyroid Cancer Survivorship Study. Study participants completed a validated quality of life assessment tool that measured wellbeing on a 0–10 scale. Data were also collected on participant demographics, medical comorbidities, tumor characteristics, and treatment modalities. We used t-tests or the Wilcoxon rank-sum test to compare mean scores between subjects based on demographic and tumor characteristics. A total of 1,604 participants with thyroid cancer completed the questionnaire: 1,502 Americans and 102 Canadians. Fewer Canadians were married and they reported higher education levels than the American cohort. The two populations were similar for gender, race, smoking status, income, pathology, treatment or cancer stage. We observed that Canadians had worse quality of life if they underwent radioiodine ablation (p 0.02) and were significantly more worried about follow-up (thyroid ultrasounds and thyroglobulin testing p 0.02). They were more fearful of having a second cancer (p 0.053). In contrast the Americans had significantly more worry about their financial burden (p0.0248). We did not observe a difference in overall QoL report for Americans and Canadians. However, when we compared the populations on individual QoL measures, we found significant differences relating to: 1. Fear of followup testing and secondary cancers, 2. Work productivity, and 3. Financial burden. Our study points out the role of culture in QoL studies in thyroid cancer survivors, and should serve as a reminder for any future work in the field.
Thyroid Cancer Saturday Poster Clinical
While clinical practice guidelines establish standards for care, they have an impact only to the extent that they are implemented in the delivery of care for individual patients. These guidelines emphasize communication between stakeholders in the care of a specific patient; however, they do not identify the mechanism for achieving such interdisciplinary communication and do not describe it in terms of continuous quality improvement. Feedback information loops are used to promote accountability and improve accuracy in both diagnostic and therapeutic interventions. We argue that the implementation of such feedback loops in the management of thyroid nodule/cancer patients will be a framework for achieving continuous quality improvement. The National Learning Consortium (NLC) emphasizes using Electronic Health Records (EHR) to facilitate such feedback loops of information between clinicians, and we report how the Thyroid Care Collaborative, a disease specific registry, can serve as a vehicle to mobilize this important improvement in quality of care through optimization of interdisciplinary communication. We demonstrate how each step in the management of thyroid nodules/cancer, from ultrasonography and cytology to surgery and nuclear medicine, represent processes of clinical care that benefit from these feedback loops of information. This is especially notable in the clinical arena of thyroid cancer care given its multidisciplinary nature. Enhanced bidirectional multidisciplinary communication would ensure that all relevant clinical outcomes are fed back to each member of the patient care team. We propose that an EHR or disease specific registry, such as the Thyroid Care Collaborative, can provide a clinical platform where informational feedback loops ensure that all health care team members are informed of a patient's clinical outcomes. While the creation of clinical practice guidelines is vital in that it provides recommendations based on the best available evidence, it will not achieve the desired outcome of improving the quality of care unless physicians involved in every aspect of a thyroid cancer patient's treatment individually strive to use each patient intervention as a learning opportunity.
Thyroid Cancer Saturday Poster Clinical
Heterophile and human anti-mouse antibody interferences (HAb/HAMA) with thyroglobulin (Tg) immunometric assay (IMA) methods affect ∼0.5%* of Tg-IMA tests causing falsely high serum Tg. HAb/HAMA interference with TgAb-IMA has not been previously reported.
A 33yo female appeared clinically disease-free after Tx+RAI despite persistently high Tg-IMA (∼48 ng/mL) and TgAb-IMA (∼25 kIU/L) (Beckman methods, Quest). Interference was suspected since Tg-RIA and Tg-LC-MS/MS were undetectable. Blocker tube Rx. (Scantibodies) lowered Tg-IMA confirming HAb/HAMA interference. TgAb was “positive” using two automated IMA methods (Beckman 25 kIU/L) and (Roche 33 kIU/L) but “negative” by radioassay (Kronus) suggesting TgAb-IMA interference. Undetectable Tg-RIA and Tg-LC-MS/MS and absent TgAb by radioassay was consistent with a disease-free clinical status and suggested HAb/HAMA interference was responsible for falsely high Tg-IMA and falsely high TgAb IMA tests (Beckman and Roche).
31 sera from 16 patients with undetectable Tg-RIA and evidence of HAb/HAMA interference with Beckman Tg-IMA (median 12.0, range 0.9 − 2819 ng/mL - lowered on average 88% by blocker tube) were retrieved from frozen archive for TgAb-IMA method comparisons (Beckman and Roche). All were TgAb-negative by Kronus radioassay.21/31(68%) specimens had a “positive” (>20 kIU/L) Roche TgAb result (median 27, range 21–106 kIU/L and 4/31(13%) had a positive (>0.9 kIU/L) Beckman TgAb IMA test (median 8.9, range 1.2–25.1 kIU/L). TgAb status was concordant in specimens from the same patient. Treatment with the Scantibodies antibody-blocker tube failed to lower Roche TgAb values. When HAb/HAMA interferes with Tg-IMA measurements, TgAb may be falsely positive using IMA methodology (Beckman and Roche), whereas radioassays using 125I- Tg binding to TgAb are unaffected. TgAb interference with Tg-IMA methods result in falsely decreased Tg results. Therefore, if the clinician sees elevated levels of both Tg and TgAb using IMA methodologies that are discordant with the clinical thyroid cancer scenario, consider HAb/HAMA interference with both analytes and confirm Tg with RIA or LC-MS/MS and TgAb by Kronus radioassay.
* Spencer Thyroid 20:587, 2010
Thyroid Cancer Saturday Poster Clinical
Differentiated thyroid carcinoma (DTC) has an excellent prognosis. Nevertheless, it remains challenging to distinguish those patients with a worse outcome. Identifying reliable prognostic indicators is essential to optimize postoperative management of these patients. The objective of this study was to evaluate whether tumor extension is independently associated with a worse overall survival (OS) in patients with conventional papillary thyroid carcinoma (CPTC) and to determine whether this occurs at a particular size threshold. Using the National Cancer Data Base (NCDB), we evaluated 34,498 adult patients from 2004 to 2008 who underwent surgery for 0.1–3.9 cm CPTC tumors with clinically negative lymph nodes. Patients were divided into two groups based on presence of EE. A Kaplan-Meier (KM) survival analysis was performed. Cox Proportional Hazards models examining tumor extension stratified by size were used to determine whether tumor extension is independently associated with a worse OS. Finally, the impact of radioactive iodine ablation (RAI) on OS were examined. Of the 34,498 patients with CPTC tumors from 0.1–3.9 cm, 30,273 had tumor confined to the thyroid capsule and 4,072 had EE. On unadjusted KM analysis, tumors 0.1–0.9 cm with EE had no difference in OS (p = 0.87) compared to those without EE, whereas tumors 1.0–1.9 cm and 2.0–3.9 cm with EE did have a worse OS (p < .0001). On adjusted analysis, tumors 0.1–0.9 cm with EE did not have an OS difference, while tumors 1.0–1.9 cm with EE (HR = 1.53, CI 1.12–1.96, p = 0.0009) and tumors 2.0–3.9 cm with EE (HR 1.72, CI 1.36–2.18, p < .0001) did have a worse OS. RAI improved overall survival in tumors 1.0–3.9 cm with EE (HR = 1.44, CI 1.04–2.0, p = .027) but not in patients with tumors less than 1 cm. Extracapsular tumor extension is not an independent predictor of overall survival for tumors less than 1 cm. RAI should be considered in patients with tumors >1 cm with EE.
Thyroid Cancer Saturday Poster Clinical
The incidence of thyroid cancer continues to rise worldwide at a rapid pace. As more patients are treated for thyroid cancer, often at a young age, the long-term sequelae of therapy may cause a significant impact on quality of life. Novel tools to evaluate thyroid specific symptoms have been developed, but data is limited regarding the potential impacts thyroid cancer therapy poses on long-term quality of life for thyroid cancer survivors.
Objectives
To assess patient understanding of disease, compliance with thyroid replacement medication, and long-term risks among thyroid cancer survivors.
To identify the effects of thyroid cancer treatment on Health Related Quality of Life outcomes. This retrospective cross-sectional study involved a written survey mailed to all patients seen within the University of Washington Affiliated Hospitals for treatment or follow-up of thyroid cancer between 2009–2014. Subjects were asked about their treatment of thyroid cancer, use of medications and complementary/alternative therapies, quality of life as assessed by the SF-36 and Thyca-QOL instruments, cancer worry and impact of events scales. Of the 1100 surveys mailed, 230 were returned with a 23% response rate. A majority of patients were married females with a mean age of 49.6 years at the time of diagnosis. Overall worry and concern about risk for recurrence was high among the population, despite over 70% reporting no evidence of current disease. Notably, the perceived risk of recurrence had a strong association with worry (p < 0.01), but no association with current disease status. Compliance with thyroid replacement therapy was high, but overall rates of thyroid specific symptoms were also high with significantly decreased health related quality of life noted. Thyroid cancer survivors reported significant negative effects on body image and relationships with romantic partners. While thyroid cancer does not cause high rates of mortality, the long-term effects of treatment cause significant morbidity for patients. Identifying the specific factors that negatively impact patient reported quality of life may allow for future development of targeted survivorship care plans to improve patient satisfaction.
Thyroid Cancer Saturday Poster Clinical
Growing evidence suggests that the encapsulated follicular variant of papillary thyroid cancer (EFVPTC) acts in an indolent manner and has a very low risk of adverse outcomes. The preoperative cytology findings of patients ultimately diagnosed with EFVPTC have not been well characterized. Review of the preoperative cytology and surgical pathology of 174 patients, with papillary thyroid cancers (PTC) >1 cm in size, operated on between January 2007 and December 2015 at a tertiary referral center.174 patients with 177 PTCs had a preoperative fine needle aspiration (FNA) followed by a thyroidectomy during our study period. 102 (58%) of the cancers were a classical variant, 64 (36%) were a follicular variant of PTC (FVPTC), and 11 (6%) were other variants. In the 21 (12%) patients with an EFVPTC, preoperative cytology was read as PTC in 2 (9.5%), suspicious for PTC in 5 (24%), follicular neoplasm in 10 (47%), atypia of undetermined significance in 3 (14%), and benign in 1 (4.8%). On univariate analysis, patients with an EFVPTC had a similar gender distribution (86% vs. 77% female, p = 0.416), age at presentation (44.5 vs. 47.2 years, p = 0.450), and tumor size, (2.3 cm vs. 2.1 cm, p = 0.459) as those patients with non-EFVPTC variants, but patients with an EFVPTC were more likely to have indeterminate or benign cytology preoperatively (p < 0.001). Patients with an EFVPTC were also more likely to have indeterminate or benign cytology than patients with an invasive FVPTC (p < 0.005). On multivarable regression modeling, indeterminate or benign cytology was independently associated with a diagnosis of EFVPTC (OR = 27.4, CI = 5.98 – 125). Physicians should consider the possibility of an EFVPTC when discussing the treatment options for patients with indeterminate or benign cytology.
Thyroid Cancer Saturday Poster Clinical
Recurrent thyroid cancer occurs in 30% of patients despite initial curative surgery. Appropriate detection of these recurrences is critical for an effective re-operation. Several imaging modalities are available for diagnostic purposes, however superiorities or limitations of each modality is yet to be determined. In this study we aimed to compare the efficiency of these modalities in a group of patients with recurrent thyroid cancer. The study group includes twenty three patients (F/M: 16/7 median age: 53 ± 21 (range: 6–79) with thyroid cancer (7 with medullary 16 with papillary type) and elevated tumor markers. All patients underwent ultrasonography (USG), contrast enhanced tomography (ceCT) and flourodeoxyglucose positron emission tomography-CT (FDG PET-CT) within 6 months. The accuracy of the diagnostic modalities were retrospectively compared with a gold standard obtained by pathology results and clinical follow up dataUSG was superior to ceCT and FDG PET-CT with recurrence detection rates of 87% (20/23) vs 60% (14/23) and 43% (10/23) respectively. All of the recurrences detected only by USG were located in the santral compartment with a median lesion size of 6 ± 3 mm (range: 4–11). The lesion missed by ultrasonography was located in superior mediastinal-level 7 and detected by FDG-PET-CT only in one patient and by CeCT and FDG PET-CT in other patient. In one patient despite elevated tumor markers none of the modalities were able to detect recurrence. USG was the modality of choice in detection of recurrence in thyroid cancer. The superiority of the modality is prominent in santral compartment. Ultrasonographer should be careful in the evaluation of level 7 which could be missed.
Thyroid Cancer Saturday Poster Clinical
Multifocality of papillary thyroid cancer (PTC) is widely treated as a high-risk factor in risk stratification and treatment decision making for PTC. The evidence for this practice, however, has not been firmly established. This study was to investigate the role of multifocality in the clinical outcomes of PTC. Retrospective study of 2,638 PTC patients (623 males and 2,015 females) with a median age of 46 (interquartile range [IQR] 35–58) years at diagnosis and an overall median follow-up time of 58 (IQR 26–107) months after the initial surgery at 11 medical centers in 6 countries. Relationship of mutifocality with disease recurrence and PTC-specific mortality was analyzed. In the overall cohort, the recurrence and mortality in multifocal vs unifocal PTC were 19.8% (198/1000) vs 13.6% (221/1624) (P < 0.001) and 2.0% (20/1000) vs 2.3% (37/1624) (P = 0.636), respectively. The corresponding hazard ratios (HR) were 1.55 (95% CI, 1.28–1.88) and 0.90 (95% CI, 0.52–1.55), which became insignificant at 1.13 (95% CI, 0.93–1.37) and 0.88 (95% CI, 0.49–1.56), respectively, after adjustment for patient age, male sex, tumor size, extrathyroidal extension and lymph node metastasis. In contrast, the effects of each of these other factors remained significant on recurrence and mortality (except for male sex) after multivariate adjustment. In a sub-cohort of 1,423 cases without extrathyroidal extension, lymph node metastasis and distant metastasis, the recurrence and mortality in the multifocal vs unifocal PTC were 4.4% (20/445) vs 4.2% (41/967) (P = 0.892) and 0.0% (0/445) vs 0.3% (3/967) (P = 0.556), respectively. The corresponding HR for recurrence was 1.08 (95% CI, 0.63–1.84), which remained insignificant at 1.14 (95% CI, 0.66–1.95) after adjustment for patient age, male sex, and tumor size. Multifocality similarly lacked independent effect on structural recurrence in a cohort of 1,051 patients from one individual center with the information available. Multifocality has limited impact on clinical outcomes of PTC, which should be taken in consideration in the risk management and decision making for PTC.
Thyroid Cancer Saturday Poster Clinical
Anaplastic thyroid cancer (ATC) is an aggressive malignancy with short survival and poor outcomes. We identified our institutional approach to therapy, response to treatment, survival outcomes, and areas for practice improvement.
An IRB approved database of patients with thyroid cancer at the University of Washington Medical Center from 2009–2014 was reviewed to identify patients with ATC.20 (1.2%) of 1602 patients seen with thyroid cancer were diagnosed with ATC. Male to female ratio was 1.2:1. At diagnosis, median age was 62 (47–88) years, and median tumor size by imaging was 5.9 (3–12) cm. All 20 patients presented with symptoms at diagnosis, including 14 with new/growing mass, 9 with compressive symptoms, 2 with sinusitis, 1 with otalgia, and 1 with eye pain due to intraorbital metastasis. Median time from symptom onset to diagnosis was 3 (0.5–6) months. Initial staging was IVa in 1, IVb in 3, IVc in 14, while 1 patient declined staging and elected for comfort care. Of the 18 patients with complete data available, 5 had thyroidectomy with external beam radiation therapy (EBRT) and chemotherapy, 4 had thyroidectomy and EBRT, 4 had EBRT and chemotherapy, 3 had tracheostomy, EBRT and chemotherapy, 1 had thyroidectomy only, and 1 elected comfort care on diagnosis. 9/18 patients received palliative care services. Of the 17/18 patients with known disposition at time of review, 16 had died, with median time from diagnosis to death of 6 (1–18) months. 1 patient is alive; he presented uniquely with ATC within follicular carcinoma and diffuse pulmonary metastases of follicular carcinoma only. Long-term outcomes were unavailable for 2 patients after the initial diagnosis: 1 returned to her native country, the other pursued treatment at outside facility. There was no significant survival difference between surgery and non-surgery groups (p = 0.49).
Anaplastic thyroid cancer is associated with high mortality at 6 months. The role of surgery should be discussed based on initial staging per 2012 ATA guidelines, as it did not offer a survival benefit in many patients as seen in our analysis. Moreover, palliative care should be engaged early, potentially at diagnosis, to help inform treatment decisions.
Thyroid Cancer Saturday Poster Clinical
Serum thyroglobulin and neck ultrasonography are the major procedures in predincting the recurrenc or persistence of differentiated thyroid carcinoma. Increased sensitivity of the instrument for measuring Tg is likely to monitor basal Tg(b-Tg, under L-T4 therapy) with a lower content. We retrospectively reviewed 123 patients with DTC after thyroidectomy during their followed-up between December 2008 and September 2015 at the Peking Union Medical College Hospital (PUMCH). Patients included in the study were those treated with total or near total thyroidectomy who had a regular measure of b-Tg and neck ultrasonography 3 months after initial treatment. Among these patients, the group of 60 patients with recurrence or persistence had undergone a second surgery for pathological verification; the 63 patients in the disease-free survival (DFS) group were all negative by neck ultrasonography, WBS scanning or other imaging examinations (e.g CT, PET-CT) or were pathologically verified to be negative after the second surgery. ROC (receiver operating characteristic) curve analysis allowed us to select the optimal basal Tg value with the best combination of sensitivity and specificity for predicting recurrent or persistent disease. To evaluate the sensitivity, specificity, positive predictive value and negative predicative value of b-Tg, neck ultrasonography and their combination in predicting recurrence or persistence of DTC. The most accurate b-Tg value for predicting the presence of recurrent or persistent disease was more than 0.26 ng/ml (sensitivity 73.3%, specificity 77.6%, positive predictive value 74.6% and negative predicative value 75.0%). Neck ultrasonography had a diagnostic sensitivity of 85.0%, specificity of 90.5%, positive predictive value of 89.5% and negative predicative value of 86.3% for predicting the recurrence or persistence of DTC. The combination of b-Tg and neck ultrasonography had a sensitivity of 93.3%, specificity of 90.5%, positive predictive value of 90.3% and negative predicative value of 93.4%. The performance of b-Tg levels and neck ultrasonography were well in predicting the recurrence or persistence of DTC. Diagnostic efficiency will be improved by combining these two procedures.
Thyroid Cancer Saturday Poster Case Report
Concurrent medullary and papillary thyroid cancers are rare and represent <1% of all thyroid cancers. This rare occurrence maybe as a result of either dual differentiation – mixed tumor or tumor with spatially distinct and well-defined components – collision tumor. We present this case for its rarity and uncertainty surrounding its management. A 43-year-old woman with family history of thyroid cancer presented for evaluation of thyroid nodules. She underwent total thyroidectomy as FNA of the right thyroid nodule was reported as papillary carcinoma thyroid. Interestingly, the total thyroidectomy specimen demonstrated a 0.5 cm nodule consistent with medullary thyroid carcinoma(MTC) limited to the left thyroid gland and another 0.5 cm nodule consistent with a follicular variant of papillary thyroid carcinoma(PTC) on the right thyroid gland. The two nodules were separated by tumor-free thyroid tissue with evidence of Hashimoto's thyroiditis. She had normal calcium, calcitonin, and carcinoembryonic antigen levels. The results of her genetic testing were reported to be negative. Four months after surgery, laboratory investigations showed a calcitonin level of <2 pg/mL (normal <5 pg/mL), a normal carcinoembryonic antigen (CEA) level, an undetectable thyroglobulin level, and thyroglobulin antibodies. Papillary and medullary cancers of the thyroid develop from the follicular and parafollicular C cells, respectively. The various hypotheses for their oncogenesis are common stem cells which differentiate into both lineages as they ultimately arise from the ultimobranchial body, development of PTC from MTC following super-imposed mutation and simultaneous oncogenesis of both tumors. Since 1981, 34 cases of PTC and MTC coexisting as a collision tumor have been reported in medical literature. The exact genetic defect predisposing the thyroid gland to develop both cancers concomitantly interspersed by normal thyroid tissue has still to be elucidated. The simultaneous occurrence of PTC and MTC in the same thyroid gland is a rare condition, and an underlying genetic background has been hypothesized. Further study is required using a larger patient population to generate enough evidence about the genetic linkage.
Thyroid Cancer Saturday Poster Case Report
Hobnail variant papillary thyroid cancer (HVPTC) is a rare, aggressive histological form of PTC, first described in 2012, with high N/C ratio and apically placed and occasionally grooved bulging nuclei that form characteristic hobnail cells in >30% of neoplastic cells. This is an 84 year-old woman diagnosed with multinodular goiter 10 years prior with a dominant right 1 cm nodule on initial thyroid US which yielded insufficient aspirate on FNA. Repeat US 2 years later showed a 2 cm dominant left lower pole nodule, palpable on exam, with Hashimoto's thyroiditis on FNA. She was then followed clinically for this dominant nodule annually. She presented after 7 years with distended neck veins, flushing and plethora and was seen by multiple providers and specialties without a diagnosis. During Dermatology consultation for these symptoms a positive Pemberton's sign was noted on exam, which raised suspicion for superior vena cava syndrome (SVCS). Urgent CT/CTA of the chest showed a 7.6 cm left thyroid mass extending substernally between the major branches of the aortic arch with partial compression of the left subclavian vein and distortion of the remaining central vasculature. Biopsy showed PTC. She underwent total thyroidectomy with left neck dissection. Pathology showed stage pT4aN0Mx HVPTC with 60% hobnail morphology, 4–10 mitoses/HPF, significant vascular and extrathyroidal invasion, positive margins, and positive BRAF V600E mutation, TTF-1, TG and wild type p53 expression. She was treated with 205mCi I131, with uptake in the thyroid bed on post-treatment TBS. Repeat TBS and PET scans 6 months later did not reveal any uptake. HVPTC is rare and may occur in older women, with larger tumor size, more significant lymphovascular involvement, increased frequency of BRAF mutation and poorer prognosis compared to classic PTC. Our patient had locally advanced disease with substernal extension which was not obvious on thyroid exam or US. Though HVPTC is rare, there should be a high index of suspicion for HVPTC in elderly women with rapidly enlarging thyroid masses. Thyroid exam and US may be misleading as they may miss substernal extenion of the tumor leading to locally advanced disease with complications such as SVCS.
Thyroid Cancer Saturday Poster Case Report
Thyroid cancer (TC) has the highest incidence increase compared to any cancer in the USA, mainly due to papillary thyroid cancer (PTC). PTC has a survival rate of 80–95%. Classic PTC (C-PTC) metastasis generally occurs to the lymph nodes, but Follicular Variant PTC (FV-PTC) behavior remains controversial. A 42-year-old female with a history of Hashimoto's thyroiditis was found to have a growing nodule. Fine needle biopsy result was suspicious for TC and patient was referred for total thyroidectomy. A 3.6 cm multifocal mass with clean margins and absent venous or lymphatic involvement was found consistent with FV-PTC. After surgery, Patient received 103 mci of Iodine 131 ablation therapy (I-131). Serial follow up of Tg levels were normal two months and a year later. Six years after the procedure, Tg was at 4.3 ng/ml. After thyrogen injection, Ultrasound (US) of the neck and Nuclear Medicine (NM) I-131 whole body scan were negative. PET/CT only revealed a mild hypermetabolic focus corresponding to a lymph node at the neck base too small to be characterized. Tg continued to trend up the following year. Repeated neck US, NM I-131 scan, and MRI of the orbit-Face-neck with/without contrast after a second thyrogen injection were all negative. Eight years after the procedure, the fourth PET/CT skull-base to mid thigh revealed a hypermetabolic lesion on the 5th left rib without corresponding uptake in the NM thyroid scan. Initial biopsy by interventional radiology was not diagnostic, but due to a high level of suspicion, the decision was made to resect the 5th rib, later confirmed to be metastatic FV-PTC. Two months after the procedure, Tg remained elevated at 12 ng/ml. Patient received 150 mci I-131. NM whole body thyroid scan revealed a small focus of uptake in the right proximal femur concerning for another possible metastasis. FV-PTC's less aggressive behavior, better long-term survival, lower lymph node metastasis but higher extrathyroidal disease as compared to C-PTC continues to be a debate. This case highlights the importance of monitoring Tg levels even after a 5 years classic surveillance phase. We want to create awareness about a more aggressive behavior in FV-PTC with silent distant bone involvement. N/A
Thyroid Cancer Saturday Poster Case Report
Radioiodine (RAI) therapy is currently the treatment of choice for metastatic differentiated thyroid cancer (DTC). However, Hurthle cell carcinoma and skeletal metastases are usually resistant to RAI. Up to 35% of patients with Hurthle cell carcinoma develop distant metastases. The 10-year survival rate for DTC is 80–95%, however with distant metastases, it decreases to 40%. Surgical removal of distant metastases confers the highest likelihood for survival. 69 year old woman with no significant past medical history experienced persistent sternal pain after heavy lifting. CT of the chest revealed an expansile mass in the sternum measuring 4.9 × 3.1 × 3.8 cm, highly suspicious for neoplasm. PET/CT showed FDG uptake in the expansile lesion in the distal sternum (maximal SUV of 9.5) and an FDG avid left lower pole thyroid nodule (maximal SUV of 5.6). Thyroid ultrasound demonstrated multiple hypoechoic nodules with microcalcifications and a 1.4 × 0.8 × 1.0 cm hypoechoic nodule in the left lower pole. CT guided biopsy of the sternal mas showed Hurthle cell cancer. Physical exam revealed a palpable tender mass in the lower sternum, and no palpable thyroid nodule. Laboratory values were euthyroid: TSH 0.48, Free T4 0.93. The patient underwent total thyroidectomy with concurrent sternal resection and reconstruction using titanium plates and Marlex mesh in conjunction with thyroidectomy. Relatively few cases of sternotomy for DTC metastases have been reported in literature. Surgical resection of distant bony metastases in patients with DTC is an important option to consider. It can confer durable long-term disease control, provide symptomatic palliation, or allow for more effective RAI treatment. For Hurthle cell cancers, resection of an FDG avid sternal metastasis is favored because RAI is seldom effective and large sternal metastases may cause significant morbidity and indeed mortality.
Thyroid Cancer Saturday Poster Case Report
Papillary thyroid carcinoma (PTC) is the most common form of thyroid carcinoma. Conversely, primary thyroid lymphoma (PTL) is a rare type of lymphoma associated with Hashimoto's thyroiditis (HT). Thus, synchronous occurrence of PTC and PTL is exceedingly rare, with 10 cases reported including the case presented here. A 75-year old man with a history of HT presented with progressive neck swelling due to large bilateral thyroid masses. The neck masses grew rapidly in size over several weeks from which the patient experienced difficulty swallowing, requiring pureed food. The patient underwent a core biopsy and was subsequently hospitalized several days later due to difficulty breathing unrelated to the biopsy procedure. He received IV dexamethasone with some improvement, but was still unable to breathe comfortably despite supplemental oxygen administration.
CT soft tissue scan of the neck demonstrated a diffusely enlarged thyroid with encasement of the larynx, extension to the posterior esophagus, and narrowing of the pharyngeal airway with evidence of laryngeal paralysis. Preliminary pathology favored low grade lymphoma, however, the rapid growth of the mass was an indication of a potentially aggressive histology and systemic treatment with rituximab and bendamustine was initiated, totaling four cycles. The core biopsy report was consistent with marginal zone lymphoma. A post treatment PET scan revealed focal uptake on the left side of the thyroid for which the patient underwent a fine needle biopsy with results suspicious for thyroid cancer. The patient subsequently underwent thyroidectomy, with no evidence of residual lymphoma seen on pathology. However, a 5 cm follicular variant of papillary carcinoma with a negative lymph node was present, therefore the patient received radioactive Iodine-131 therapy and a thyroid whole body scan which demonstrated no radiologic evidence of metastatic disease. To complete treatment of the PTL, the patient underwent involved-field radiation therapy to the neck. PTC in the setting of PTL is exceedingly rare. Our case serves as a reminder that clinicians should not exclude the possibility of synchronous malignancies in a patient with a history of HT.NA.
Thyroid Cancer Saturday Poster Clinical
In long term pre-clinical safety studies with long-acting glucagon-like peptide-1 receptor agonists (GLP-1 RAs), C-cell proliferation and C-cell carcinomas have been observed in rodents. The clinical relevance to humans is unknown. A post-marketing active surveillance program for Medullary Thyroid carcinoma (MTC) was established in the US in 2010 and is currently funded by pharmaceutical companies with marketed GLP-1 RAs to evaluate the potential association between long-acting GLP-1 RA treatment and the occurrence of MTC. The objectives are:
1. To systematically monitor the annual incidence of MTC in the US through the North American Association of Central Cancer Registries (NAACCR) to identify any possible increase related to the introduction of long-acting GLP-1 RAs into the market.
2. To establish a registry of incident cases of MTC in adults in the US to characterize their medical histories and possible risk factors, including history of long-acting GLP-1 RAs treatment.
The sponsors have formed a consortium (the MTC Registry Consortium) and have partnered with the American Thyroid Association to work together to conduct this registry.
To meet objective 1, annual MTC incidence rates are obtained from NAACCR. The time period prior to the introduction of long-acting GLP-1 RAs into the marketplace (January 1, 2001 to December 31, 2009) is used as the baseline.
To meet objective 2, cases of MTC are identified by participating State Cancer Registries (SCRs). Once informed consent is obtained from the patient, a telephone interview is conducted to collect risk factors including comorbid conditions, history of diabetes, obesity, and history of exposure to long-acting GLP-1 RAs. If a patient was treated with a long-acting GLP-1 RA or had a diabetes diagnosis, attempts are made to contact the treating physician to obtain verification.
Twenty eight SCRs are participating in the MTC registry, representing 84% of the US population, and at baseline, representing 87% of annual MTC cases. The goal is to capture 75% of incident cases in the US.
The MTC registry is expected to continue for 15 years after the introduction of the last long-acting GLP-1 RA.
Thyroid Hormone Action Saturday Poster Basic
X-linked adrenoleukodystrophy (X-ALD) is a rare disorder that causes adrenal gland dysfunction and cerebral demyelination affecting 1 in 17,000 people in the US and worldwide. X-ALD is caused by a defect in ABCD1, which encodes a peroxisomal transporter responsible for the uptake of very long chain fatty acids (VLCFAs) into the peroxisome for degradation. As a result of defective ABCD1, X-ALD patients accumulate VLCFAs in tissue and plasma leading to either cerebral or spinal cord demyelination.
Thyroid hormone action has an important connection to X-ALD; ABCD2 is a thyroid hormone-regulated gene that is a close homolog of ABCD1 that shows overlapping function. Furthermore, upregulation of ABCD2 has been shown to compensate for defective ABCD1 by lowering VLCFAs. Thus upregulation of ABCD2 by thyroid hormone may lower VLCFAS resulting in therapeutic benefits.
In addition, to a specific role for thyroid hormone action in X-ALD, several studies in animal models of demyelination have shown that thyroid hormone promotes remyelination in the central nervous system (CNS). Thus, thyroid hormone activity could have second mode of action in X-ALD by stimulating myelin repair that would be relevant for other diseases including multiple sclerosis. Thyroid hormone and thyromimetics will be evaluated in several mouse demyelination models. A mouse model of X-ALD (Abcd1 knockout mice) will be used to examine the role of thyroid hormone action in regulating VLCFAs. General demyelination models including the cuprizone and lysolecithin models will be used to examine myelin repair. The data presented in this study will demonstrate that thyroid hormone and related thyromimetics can upregulate Abcd2 and lower VLCFAs in the CNS of Abcd1 knockout mice. Further data will demonstrate that thyromimetics can promote faster CNS myelin repair in the lysolecithin and cuprizone models of demyelination. These results demonstrate the potential for using thyromimetics to treat X-ALD, multiple sclerosis and related myelin disorders.
Thyroid Imaging Saturday Poster Translational
Shear waves are transverse waves that are very slow in comparison with acoustic waves, and are therefore predicted to be easily affected by environmental factors in vivo. However, the degree to which such elements affect shear waves is unknown.
The aim of this study was to elucidate the artifacts in the measurement of shear wave velocity (SWV) by comparing the SWV in vivo with that assessed in resected specimens. The materials were unselected thyroid and lymph node specimens resected during thyroid surgery. We performed shear wave elastography using an ACUSON S2000 ultrasound system (Siemens Medical Systems, Germany).
We performed 5 measurements at the same location in each subject and used the average values for analysis. Immediately after surgery, fresh unfixed thyroid and metastatic lymph node specimens were suspended in gel phantoms and SWV was measured 5 times. The coefficients of variation (CV) of the 5 measurements were compared by lesion type as well as between the in vivo and ex vivo assessments. The SWVs of each lesion derived in vivo and ex vivo were then compared. A total of 101 specimens were evaluated. The CVs of normal thyroid and autoimmune thyroiditis ex vivo were almost equal to those in vivo.
The CVs of normal thyroid and autoimmune thyroiditis were smaller than those of nodule lesions or lymph nodes, not only ex vivo but also in vivo.
The rates of unmeasurable malignant nodules and metastatic lymph nodes were high, around 40 %, while almost all normal samples and benign lesions were measurable. However, the rates of unmeasurable malignant nodules and metastatic lymph nodes ex vivo were lower than those in vivo.
Among the lesions overall, the median SWV values in vivo were higher than those ex vivo. The measurement of SWV was negligibly affected by physical factors such as carotid artery pulsation or respiratory movements. The measurement of SWV was not rendered unstable by either heterogeneous pathology or the refraction or reflection of shear waves at the rounded surfaces of nodules. Heterogeneous pathology may attenuate shear waves. Furthermore, blood flow in vivo gave tension at the tissues and increased SWV.
Thyroid Imaging Saturday Poster Clinical
Laser-ablation is already accepted as effective and safe clinical procedure for treating benign thyroid nodules. A specific 1064 nm Nd-YAG laser is conveyed from the source to the tissue through a specific optical fiber. The procedure is minutely monitored by ultrasonography, but many times other methods (as doppler or sonographic contrast) are used to better confirm and define the extension of thermal effect. In addition, echo-elastography is an emerging technique to evaluate tissue stiffness (liver, breast, thyroid). Latest versions can measure the echo-velocity generated after an acoustic-radiation-force-impulse (ARFI) resulting in a quantitative, precise and faster technique. Twelve patients were selected for additional elastographic monitoring during the usual procedure of laser-ablation of benign thyroid nodules. Laser was generated using EchoLaser (Elesta, Firence, Italy). High definition ultrasonography, as well as ARFI-elastography, were performed using a Acusson S2000 Hellix platform (Siemens, Forchheim, Germany; Inycom, Zaragoza, Spain) equipped with VirtualTouch software. In all patients elastograms were obtained in less than 10 seconds, during and after laser procedure with no major interference in the routine. Elastograms showed areas of clearly increased tissue rigidity (>5 m/s) after thermal ablation. No interferences were observed during laser illumination, compared to doppler. The method was useful, indicative and significant in all cases. Areas of increased rigidity were larger than those of simple echo-precipitation as showed after 1 week, or 1, 3 and 6 months of follow-up. As soon as 1 week after ablation nodule volume started to decrease, and after 1 month tissue rigidity started to be confined. ARFI-elastography resulted very advantageous to confirm, characterize and monitor the extent of thermal laser-ablation in benign thyroid nodules, compared to doppler. In addition, the technique looks helpful, simple, pain-less, fast and may obviate the slower, risky and expensive sonographic contrasts.
Thyroid Imaging Saturday Poster Clinical
The incidence of well-differentiated thyroid cancer has risen dramatically over the last several decades. One proposed explanation for this is the rapid growth in utilization of different radiology studies, which have resulted in large numbers of incidentally identified thyroid nodules. The objectives were to: (1) Determine at our institution, the incidence of incidentally identified thyroid nodules requiring fine needle aspiration, (2) describe the imaging modality and indication for these incidentally identified nodules, and (3) assess the outcomes including surgical rates among these nodules. A retrospective review was performed of all patients who underwent FNAs of thyroid nodules, between January 2006 and December 2010, by the Endocrinology division at a large, academic medical center. Medical records were reviewed to identify whether the biopsied thyroid nodule was discovered incidentally through non-thyroid related imaging or whether it was identified by palpation by patient or physician. Demographic, radiological, surgical, and pathological data were assessed. FNAs were performed on 2,296 total thyroid nodules and 1,794 patients. Twenty-four percent (n = 431) of patients underwent a biopsy for incidentally identified nodules. The most common indications documented for the initial imaging that resulted in an incidental finding of a nodule were neck pain (32.4%), non-thyroid cancer workup (26%), and evaluation for pulmonary embolus (12.8%). Chest CT, MRI of the spine or neck, and CT of the neck were the most common imaging modalities that led to thyroid incidentalomas (29.2%, 19.9%, and 16.1%, respectively). Rates of surgery and identification of cancer did not differ significantly based on the modality or indication for imaging. In this study, nearly a quarter of patients undergoing FNA had their thyroid nodule identified incidentally on imaging. With the continued proliferation of radiology studies this flood of thyroid nodule incidentalomas is likely to continue to expand.
Thyroid Imaging Saturday Poster Case Report
In thyroidectomized patients with differentiated thyroid cancer (DTC), radioiodine whole-body scintigraphy (WBS) is the optimal way to identify either benign or malignant thyroid tissue. Nevertheless false positive images can be seen in clinical practice. We present two cases of false positive WBS. Case #1: 46 years old woman with T1N0M0 papillary thyroid cancer, low risk, based on ATA system, treated with thyroidectomy followed by radioactive iodine (RAI) ablation. The post treatment WBS showed uptake in the thyroid bed. One year after the initial therapy, she showed an excellent biochemical response, however there was an iodine avid area in the pelvic region seen on a repeat WBS. An ultrasound revealed an 8 × 8 × 5 cm hypoechoic vascular mass in the right adnexa. The patient underwent hysterectomy with oophorectomy with a final pathology report consistent with endometrioma.
Case #2: 63 years old woman with T1bN1Mx papillary thyroid cancer, intermediate risk, treated with thyroidectomy followed by RAI ablation. Post treatment WBS revealed uptake in the neck with an additional focus at the level of the left 12th rib. However a distant bone metastasis was not corroborated by the level of her stimulated thyroglobulin which was more consistent with thyroid remnant (7.2 ng/mL). She underwent biopsy of the suspicious bone lesion and pathology was negative for malignancy.
Radioiodine has been used for diagnosis and treatment of patients with DTC, with reliance on the fact that trapping, organification and storage of iodine is a unique characteristic of thyroid tissue. The mechanism behind the multiple false positive results that have been reported is not fully understood but it can be explained as a consequence of either functional sodium-iodine symporter expression in normal tissue, metabolism of radiodinated thyroid hormone, retention of radiodinated body fluids, retention and uptake of radioiodine in inflamed tissue or contamination by physiologic secretions. These cases, illustrate how the accurate evaluation of radioiodine scans is critical in the management of patients with thyroid cancer. Endocrinologists should be aware of the potential pitfalls of radioiodine scans to avoid incorrect management.
Thyroid Nodules & Goiter Saturday Poster Clinical
Fine needle aspiration under Ultrasound guidance is a well established diagnostic tool in the management of thyroid nodules. and Ultrasound risk stratification has been lately suggested as a useful tool to risk stratifdy patients with thyroid nodules.
All samples were subjected to on site adequacy assessment using a quick diff method. Final cytological assessment was performed by the same cytologist. Samples were reported using Thy classification. The results of the FNA were subsequently correlated with the final surgical specimens. The cytologist was blinded to the results of the final pathology.
US risk stratification was calculated using a validated web based US risk calculator.
Of interest, 24/29 (83%) of the Thy3 lesions turned out to be benign. This percentage did slightly change if the Thy3 group was subdivided into Thy3a (9/10 i.e. 90%) or Thy3f (15/19 i.e. 79%).
Using a validated web based US risk calculator, Thy3f lesions scoring <24.5% were found to be 100% benign, hence reducing the percentage of potential candidates for surgery in this group to 47% (versus 79%).
US risk stratification is suggested as a potential tool to help decision making. The management of thyroid nodules should be based on the constellation of clinical, cytological, ultrasound and biological criteria to minimize the inappropriate referral to surgery; The subdivision of the Thy3 group into subgroups is probably not necessary.
Thyroid Nodules & Goiter Saturday Poster Clinical
The aim was to assess if thyroid ultrasonography(US) reports done in out institution provided critical information supporting clinical decision making in accord with the American Thyroid Association(ATA) guidelines. We asked if radiology reports would stand alone as a reliable resource to determine sonographic evidence of growth; defined as 20% increase in at least two nodule dimensions with a minimal increase of 2 mm or more than 50% change in volume. After chart review of the thyroid specialty clinic at a tertiary care center from July to November 2015, included were patients with thyroid nodule(s) 1 cm or greater, who had a follow up thyroid US done during the period of review. Reports were evaluated for significant nodule growth or stability compared to the previous study. We considered any discrepancy between the calculated nodule size change and the statement in the radiology report. We also noted if previous nodule size information was included so that the clinician could analyze the data independently. Of the 69 consecutive patients meeting inclusion criteria, descriptions of 118 thyroid nodules were evaluated. The median follow-up between examinations was 428.5 days. Based on recorded dimensions, 33/118 nodules (30%) met criteria for significant growth. Of the 33, 28 (84.8%) were reported as not having a significant change in size. Specifically, 10/28 were described as “slight changes or minimal increase in size”, and 18/28 were reported as “no changes or stable appearance”. Of note, it was rare to see a separate remark on change in the size of cystic and solid components. Finally, 19 of 69 reports (27.5%) did not include the previous nodule size information in the report. In our QA review, most of the radiology reports failed to reflect sufficient information to enable the clinician to adhere to the contemporary management guideline. We recommend thyroid US reports should include the previous nodule size information, differentiate cystic and solid component size information, calculate volume changes and use more objective descriptions including the percentage of dimension changes. Close communications and educational efforts between endocrinologist and radiologist are needed.
Thyroid Nodules & Goiter Saturday Poster Clinical
Graves' Disease is the most common cause of overt hyperthyroidism in non-endemic areas. In many centers, treatment with antithyroid drugs is the preferred first-line therapy, given the chance of possible remission without inducing the morbidity potencially associated with iatrogenic hypothyroidism. In our Clinic, anti-thyroid drugs for 12–24 months are frequently the preferred first-line therapy.
It was our aim to complement well established predictive factors of remission with others, that could help select for definite therapy, those patients with low probability for remission after the first antithyroid drug course. All patients with the diagnosis of Graves' Disease from january 2008 to december 2015 were selected and retrospectivelly evaluated.
Patients with less than 2 years of follow-up and without all laboratory evaluations performed in our clinic were excluded.
Variables analyzed at diagnosis: age, sex, treatment dose, TRAb titer, TSH, FT4, anti-TPO-Ab, anti-TGL-Ab, presence of nodularity on US, presence of ophthalmopathy. At 12, 18 and 24 months, TRAb, TSH and FT4 were investigated. All TSH and FT4 values during treatment and follow-up where continuously analyzed.71 patients fulfilled the inclusion criteria. The mean time of follow-up after remission was 2 years. 28% achieved remission after 18 months. There were no significant diferences in sex or age among the 2 groups. No correlation was found between the development of hypothyroidism during therapy and remission.
At diagnosis, the group that achieved remission suffered less of ophthalmopathy, had lower TRAb titer (p = 0.004), higher anti-TPO-Ab titer and lower anti-TGL-Ab titer (p = 0.03). The TSH value on its own, at 12 and 18 months of treatment, had no correlation with remission.
Nevertheless, a non-supressed TSH accompained by normal FT4 levels, was able to differentiate the patients achieving remission after inicial therapy, p = 0.004. This profile correlated with TRAb negativation. Achieving a non-suppressed TSH in the presence of normal FT4, during the first 18 months of therapy for Graves' Disease, seems to represent TRAb negativation and to be able to differentiate well patients entering remission. This may help select patients for definite therapy.
Thyroid Nodules & Goiter Saturday Poster Clinical
Recommendations on resection of massive goiters with suprahyoid, retropharyngeal and substernal extension vary widely. Notably, ATA guidelines recommend dissection of the goiter's substernal component before identification of the recurrent laryngeal nerve (RLN). This study evaluates a surgical approach allowing early identification of the RLN and delivery of massive goiters with minimal substernal or suprahyoid dissection. Cases of thyroidectomy for massive goiters with substernal, retropharyngeal, or suprahyoid extension at a single institution from 2005 to 2016 were retrospectively reviewed. The surgical approach utilized involves early identification of the RLN medially or superiorly as the medial thyroid attachments to the trachea are completely mobilized. The distant component is then delivered relatively easily into the neck with minimal mediastinal or suprahyoid dissection. Twenty-six patients with substernal goiter and fourteen patients with suprahyoid or retropharyngeal goiter were included with a mean age of 55.8 years. Substernal goiters extended below the aortic arch in 44% of patients and to the carina in 12%. Mean extension below the thoracic inlet was 3.8 cm (range 1.5–7.5 cm). Suprahyoid goiters extended above the hyoid bone in 4 patients, submandibular gland in 3 patients, and the mandible in 1 patient. Retropharyngeal goiters contacted the prevertebral fascia along 3.4 vertebral bodies on average. Mean thyroid height was 8.8 cm. No patients required sternotomy or tracheotomy. Postoperative seroma or hematoma occurred in five patients (13%) with one requiring return to the OR. Transient RLN paresis occurred in 3 patients (8%) which resolved within 6 weeks, and one patient had persistent vocal cord paresis. No patient had vocal cord paralysis. Six patients (15%) had transient hypocalcemia, and two patients (5%) had persistent hypocalcemia requiring calcium supplementation after 6 months. Large suprahyoid, retropharyngeal and substernal goiters were resected transcervically with low morbidity. Early identification of the RLN with full mobilization of the cervical goiter was consistently achieved, which allows for delivery of the goiter with minimal suprahyoid or mediastinal dissection.
Thyroid Nodules & Goiter Saturday Poster Clinical
Thyroid nodule ultrasound training varies greatly across training environments, programs, and specialties without standardized curriculums or assessment of skills, so establishment of standard education becomes urgent. Most doctors are familiar with the ultrasound features of thyroid nodules, while failed in estimating risk of malignancy. 2015 ATA proposed estimated risk of malignancy of thyroid nodule, which provides scientific basis for thyroid ultrasound training. The use of precision learning provides a framework to facilitate thyroid ultrasound teaching of diverse learners and exemplifies the principles of learner-centered education. This program is intended to help trainees provide standardized ultrasound diagnosis, which would contribute to clinical decision-making on thyroid nodules. 39 residents and refresher fellows were enrolled and randomized divided into two groups. The Group A received precision learning of thyroid nodule and lymph nodule ultrasonography in the first month. The Group B received precision learning in the second month. According to 2015 ATA guidelines (2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer), each ultrasound feature scores of thyroid nodule and lymph nodule in the image test were calculated at the beginning, first month and second month. Precision learning refers to 15 cases that present the typical feature of thyroid nodule or lymph nodule, which were distributed to trainees whose test scores of certain ultrasound feature were below the average. At the beginning, there were no significant difference between Group A and Group B in the image test points. After the first month of precision learning, the Group A showed significantly better ability scores than controls (238.7 ± 27.8 versus 216.9 ± 24.2, P = 0.013). After the precision learning of all the participants, scores are much higher of all trainees compared to the scores at the start of the study (234.5 ± 23.2 versus 217.9 ± 27.5, P = 0.002). Our findings imply that using precision learning in training residents and refresher fellows of thyroid nodule ultrasonography are useful, which would contribute to standardized ultrasound diagnosis.
Thyroid Nodules & Goiter Saturday Poster Clinical
Over the past decade, there has been an increased interest in measuring parathyroid hormone (PTH) levels as an early predictive marker for the development of hypocalcaemia after total thyroidectomy. Although there is abundant literature regarding this topic, the variability in assays, timing of measurements, and cutoff values of hormone levels in each of these studies questions the accuracy of this approach. We therefore performed a systematic review to examine the utility of PTH levels in predicting post-thyroidectomy hypocalcemia. A systematic literature review was performed within PubMed and EMBASE databases using the following terms and keywords: “thyroidectomy,” “ parathyroid hormone,” and “hypocalcaemia,” “calcium,” or “calcitriol.” Upon retrieval of candidate studies, each full-text publication was reviewed by two independent reviewers and selected for data extraction if it examined the prognostic significance of PTH to predict post-thyroidectomy hypocalcaemia. Studies were excluded if calcium supplementation was used routinely or based on a PTH level. Study characteristics, PTH parameters and their accuracy to predict hypocalcemia were summarized. The initial search yielded 1233 abstracts. Only seventy studies including 9,627 patients met criteria and were included. Of those, 44 studies examined only an absolute value of PTH, 12 studies a percentage decline, 11 evaluated both, and 3 evaluated a combination. The timing of obtaining a PTH levels varied from intra-operative to 24 h post-operatively. The absolute cutoff levels of PTH values varied from <10 pg/mL to <54 pg/mL. The range of accuracy reported for an absolute PTH cut-off level was 34–100%, where as the accuracy based on a change over time ranged from 72–100%. The existing literature is extremely heterogeneous in the examination of PTH levels to predict hypocalcaemia. One must exercise caution when using PTH level as the sole predictive factor for the development of hypocalcemia after thyroidectomy. Additional prospective studies controlled for timing of lab draws and PTH cut-off levels need to be performed to ascertain the true prognostic significance of PTH to predict post-thyroidectomy hypocalcaemia.
Thyroid Nodules & Goiter Saturday Poster Case Report
LYG is a progressive EBV-driven lymphoproliferative disease characterized by accumulation of atypical lymphoid cells with infiltrative nodular lesions and T-cell invasion and destruction of blood vessels affecting primarily extra-nodal sites especially lungs, kidneys, skin, and CNS. In the literature, thyroid involvement was briefly described in three patients with LYG and hypothyroidism requiring replacement therapy in one case. Here we describe a case of presumptive LYG thyroid involvement with normal TFT's (thyroid function tests) and significant response to systemic therapy.45 y.o. male presented with profound fatigue, dyspnea, and a sacral skin lesion unsuccessfully treated with antibiotics. Due to increasing SOB and abnormal chest CT, a bronchoscopy was performed that revealed vasculitis. A VATS procedure reported lymphohistiocytic infiltrates. F18FDG PET demonstrated multiple hypermetabolic foci in kidneys, liver, muscle, scalp soft tissue, bones, and thyroid. A liver and skin biopsy showed LYG and focal lymphoid infiltrate with predominantly T-cells. Liver mass pathology reported LYG grade III, positive for CD20, PAX5, MUM1, CD30 and EBV-ISH. Follow up imaging studies demonstrated progression of disease with enlarging lung nodules and cavitary formation up to 12 cm in diameter. Neck US showed no normal thyroid tissue with multiple isoechoic well marginated macronodules up to 5.7 cm with retrosternal extension without lymphadenopathy. Thyroid function was normal with negative anti-thyroid antibodies and mildly elevated thyroglobulin. After two EPOCH-R cycles follow up imaging showed regression of lung lesions and thyroid nodules. Thyroid biopsy was performed after chemotherapy demonstrating normal follicles and no lymphoid elements likely indicating response to treatment. Thyroid gland involvement is extremely rare in LYG however it can lead to complete thyroid involvement that may lead to thyroid dysfunction and can be missed due to non-specific symptoms of lymphoproliferative systemic disease and/or while receiving systemic therapy. Imaging and biochemical evaluation of thyroid galnd is warranted in patients with LYG.