Thyroid Carcinoma in Birt–Hogg–Dubé Syndrome: Case Series and Review of Literature

Abstract

Background:

Thyroid cancer (TC) is infrequently encountered in Birt–Hogg–Dubé (BHD) syndrome. We describe three BHD patients with TC and review the relevant literature.

Patient Findings:

Patient 1, a 55-year-old male with BHD, developed dedifferentiated oncocytic TC with distant metastases, requiring systemic therapy and radiation. Genetic testing revealed pathogenic variants (PVs) in FLCN, DAXX, and TP53. Patient 2, a 51-year-old female, and her 30-year-old daughter (patient 3) were diagnosed with papillary TC and treated with surgery and radioiodine. Tumor testing in patient 3 demonstrated PV in BRAF (V600E). Gene query analysis (n = 2285 patients) identified 2% FLCN PV prevalence in sporadic TCs, but the prevalence increased to 23% in anaplastic TCs. Literature review revealed 15 TC cases in BHD with diverse clinical presentations.

Conclusions:

TCs are rare in BHD. FLCN PVs may not be the sole molecular drivers in TCs but may have a substantial role in the development of aggressive TCs.

Introduction

Birt–Hogg–Dubé (BHD)¹ syndrome is a rare, autosomal dominant disorder due to germline loss-of-function pathogenic variant (PV) in the folliculin gene (FLCN).² Clinical manifestations include multifocal, bilateral pulmonary cysts, spontaneous pneumothorax, cutaneous manifestations (such as fibrofolliculomas, trichodiscomas), and renal cell carcinoma (RCC).² Insertion, deletion, and nonsense mutations lead to premature truncation and loss of function of the FLCN protein.³ Although the precise mechanism is unclear, FLCN likely functions as a tumor suppressor gene (Supplementary Data).^4

–7

Tumors of other sites are rare in BHD; however, colorectal, lung, and breast cancers and parotid oncocytomas have been described.⁸ Thyroid cancer (TC), although reported, is not one of the classical manifestations of BHD.^{1,8

–15} Due to the rarity of this association and the undeciphered potential interactions between FLCN and molecular drivers of TC, currently no causal link between BHD and TC exists.¹⁶

We report a series of three BHD patients: one with oncocytic thyroid cancer (OTC) and two patients (mother and daughter) with papillary thyroid cancer (PTC), and review the current literature on TC in BHD (Table 1). We also perform a gene query analysis of FLCN PVs in TC on cBioPortal (www.cbioportal.org). Our study’s objectives were to report BHD and associated TC and hypothesize that FLCN may be an oncogenic driver in TC. The patients were enrolled under the National Institutes of Health Institutional Review Board-approved research protocols (77-DK-0096 and 10-DK-0102), and all patients signed informed consent.

Table 1.

Summary of Clinical and Pathological Data from Our Case Series and from the Literature

A. Clinical and pathological data of our case series
Patient	Age (years)	Sex	Thyroid cancer subtype	Germline mutations	Tumor mutations	Lymph nodeinvolvement	Distant metastases	Skin lesions	Pulmonary disease	Renal disease	Family history of thyroid cancer	History of radiation exposure	Family history of pulmonary disease	Other medical issues
1	51	Male	OTC	Not tested^a	FLCN (H249fs27), DAXX* (L666fs29), TP53* (R248Q)	Yes	Cerebellum and hilar/pulmonary	None	Bilateral pulmonary cysts	None	No	No	Yes	None
2	51	Female	PTC	FLCN gene translational frameshift (c.1285delC), BLM (p.Arg899*)	N/A	Yes	None	Yes	Bilateral pulmonary cysts and nodules	Two exophytic lesions from the left kidney	Yes	No	Yes	Bipolar disorder, uterine fibroid
3	30	Female	PTC	FLCN gene translational frameshift (c.1285delC), DDX41 (c.3G>A)	BRAF^V600 , PPM1E (c.133T>C)—variant of uncertain significance.	Yes	None	Yes	Bilateral pulmonary cysts and nodules, spontaneous PTx	None	Yes	No	Yes	Bipolar disorder, gestational diabetes, and Guillain–Barré
B. Clinical and pathological data from the literature
Author (year)	Age (years)	Sex	Thyroid cancer subtype	Germline mutations	Tumor mutations	Lymph node involvement	Distant metastases	Skin lesions	Pulmonary disease	Renal disease	Family history of thyroid cancer	History of radiation exposure	Family history of pulmonary disease	Other medical issues
Panagiotidis et al. (2018)	67	Female	OTC	N/A	N/A	N/A	Right supraclavicular mass	None	Pulmonary cysts	Bilateral renal tumors	N/A	N/A	N/A	Right hemithyroidectomy for adenomatous lesion
Birt et al. (1977)—6 sibships	N/A	N/A	MTC	RET gene (Toro et al.³)	N/A	N/A	N/A	Yes	N/A	N/A	N/A	N/A	N/A	N/A
Kunogi et al. (2008)	28	Female	Thyroid cancer, unspecified	N/A	N/A	N/A	N/A	None	Pulmonary cysts and PTx	None	N/A	N/A	Yes (PTx)	Vocal cord nodules, myoma of the uterus
Benusiglio et al. (2014)	72	Male	Primary clear cell carcinoma of the thyroid	c.1062G>C mutation in Exon 9 (FLCN gene)	c.1062G>C wild type allele (LOH)	No	Pulmonary	Yes (face fibrofolliculomas)	Pulmonary cysts and PTx	None	N/A	N/A	Yes (PTx)	Hypertension and early-stage colon cancer
Dong et al. (2016)	49	Male	PTC (bilateral and multifocal)	FLCN gene mutation variants in Exon 1 (c.−487G>C and c.−302G>C), Exon 10 (c.1095C>G), and Exon 14 (c.1645C>G, c.2132G>A, and c.2297T>C)	N/A	Yes	None	Yes	None	Clear cell RCC	N/A	N/A	N/A	N/A
Dong et al. (2016)	44	Male	PTC (bilateral and multifocal)	FLCN gene mutations variants in Exon 1 (c.−487G>C and c.−302G>C), Exon 3 (c.−84G>A), Exon 13 (c.1481A>G), and Exon 14 (c.2132G>A and c.2297T>C)	N/A	Yes	None	Yes	None	Left papillary RCC	N/A	N/A	N/A	Hypertension
Furuya et al. (2016)	N/A	N/A	OTC	c.1285dupC (FLCN gene)	Mutate wild-type allele (LOH)	N/A	N/A	N/A	N/A	N/A	N/A	N/A	N/A	N/A
Pérez García et al. (2017)	42	Female	MTC	c.1546A>T (p.Lys516) heterozygous carrier (FLCN* gene)	N/A	None	None	None	8 × 5 mm nodule LLL	3 mm right renal cyst	N/A	N/A	N/A	None
Bongetti et al. (2020)	45	Female	FTC (poorly differentiated)	FLCN gene mutation in Exon 14	N/A	Yes	Bone (lytic lesions T8 and T12) and lung	Yes, skin tags on her neck and chest	Bilateral pulmonary cysts, normal PFTs	Left chromophobe RCC and right hybrid oncocytic/chromophobe tumor, nephrectomy complicated with hemodialysis	None	Not mentioned	N/A	N/A
Hehar et al. (2021)	71	Male	FTC	Mutations of the CHEK2 and FLCN gene	NRAS Q61R mutation, CHEK2 mutation, coding variants in the ATR gene on chromosome 3, and IDH2 gene on chromosome 13	None	Not mentioned	Yes (auricular trichodiscomas, fibrofolliculomas)	N/A	N/A	N/A	N/A	N/A	Colon cancer

Patient was diagnosed based on strong family history, but FLCN mutation in tissue serves as confirmation for BHD in patient.

OTC, oncocytic thyroid cancer; MTC, medullary thyroid cancer; PTC, papillary thyroid cancer; FTC, follicular thyroid cancer; N/A, not available; LOH, loss of heterozygosity; PTx, pneumothorax; LLL, left lower lobe; PFT, pulmonary function test; RCC, renal cell cancer.

Patient 1

A 55-year-old Caucasian male with BHD, identified through pulmonary cysts and family history of BHD, was referred to our center for management of metastatic TC. Originally, TC presented as a neck swelling upon routine examination. He denied symptoms of hyper- or hypothyroidism, family history of TC, or radiation exposure. Thyroid ultrasound (US) revealed a 3.9 cm right lobe hypoechoic nodule with punctate echogenic foci (Fig. 1a). Fine needle aspiration (FNA) biopsy of the nodule revealed follicular lesion of undetermined significance with oncocyte-like cells (Bethesda III) (Fig. 1b). After a total thyroidectomy with central neck dissection, histopathology revealed OTC (Fig. 1c–e) measuring 3.9 cm, with capsular and lymphovascular invasion, involving three out of six central lymph nodes (American Thyroid Association [ATA] high-risk for recurrence¹⁷; American Joint Committee on Cancer 8th Edition [AJCC 8th Ed.]¹⁸ pT2N1aM0, Stage II). He received 156 mCi (5.8 GBq) of [¹³¹I]-radioactive iodine (RAI) therapy.

FIG. 1.

Thyroid US, FNA of thyroid nodule, histopathology, and imaging for distant metastases in patient 1. (a) Thyroid US revealed a 3.9 cm hypoechoic nodule on the right side with punctate echogenic foci. (b) FNA biopsy of right thyroid nodule showing a follicular lesion of undetermined significance with oncocyte-like cells, characterized by enlarged round nuclei and abundant granular cytoplasm (Bethesda IV). (c) Histopathology of the nodule following thyroidectomy demonstrating OTC. (d) Capsular invasion of OTC (arrow). (e) Lymph node metastasis: involvement of a central lymph node by OTC. (f) Brain MRI T1 sagittal view showing 0.6 cm metastasis in the right cerebellum. (g) CT scan with contrast demonstrating pulmonary metastases. (h) An [¹⁸F]-FDG-PET demonstrating right pulmonary metastatic disease. US, ultrasound; FNA, fine needle aspiration; OTC, oncocytic thyroid cancer, MRI, magnetic resonance imaging.

One-year post-therapy scan revealed residual neck disease. Lymph node dissection revealed a 1.8 cm metastatic OTC, involving 3 out of 28 nodes. Tumor genetics revealed FLCN (H429fs*27), DAXX (L666fs*29), and TP53 (R248Q) PVs. Inoperable, bulky right parapharyngeal disease encasing the carotid artery was noted one year later, and he was treated with 4000 cGy ×5 fractions of stereotactic radiotherapy. Two years later, brain magnetic resonance imaging (MRI) (Fig. 1f) showed right cerebellar metastasis, which was treated with 2000 cGy gamma knife radiation. Computed tomogram (CT) of the chest and an [¹⁸F]-fluorodeoxyglucose positron emission tomography/CT (Fig. 1g and h) demonstrated hilar, pulmonary, and pleural metastases. Biopsy of one pleural nodule confirmed poorly differentiated TC (PDTC) bearing histopathological similarity to the initial OTC. Systemic therapy with everolimus and lenvatinib was initiated due to rapid disease progression, but everolimus was discontinued due to pneumonitis. He is currently undergoing evaluation for immune checkpoint inhibitor therapy.

Patient 2

A 51-year-old Caucasian female with BHD harboring germline FLCN PV (H429Tfs*39) presented with a neck lump. BHD manifested as bilateral pulmonary cysts and nodules, and two exophytic lesions from the left kidney. Medical history included bipolar disorder and uterine fibroid; family history included TC and pulmonary disease. Thyroid US and FNA confirmed PTC. After total thyroidectomy and central neck dissection, histopathology revealed multifocal classical PTC, with the largest focus measuring 1.2 cm, involving surgical margins, with microscopic involvement of strap muscles and lymphovascular invasion, involving 11 out of 14 central lymph nodes (AJCC 8th Ed. pT1bN1aM0, Stage II). Due to inadequate material, tumor genetic testing was not performed. Two RAI treatments with a cumulative dose of 130 mCi (4.81 GBq) were administered, and excellent response to therapy was noted three years after initial therapy.

Patient 3

A 30-year-old Caucasian female, daughter of patient 2, visited our center for evaluation of one-year history of throat discomfort, dysphagia to solids, and voice changes. Medical history included pulmonary cysts, spontaneous pneumothorax, bipolar disorder, gestational diabetes, and Guillain–Barré syndrome without residual deficits. Physical examination was unremarkable without palpable cervical adenopathy. Genetic testing confirmed germline FLCN PV similar to her mother (H429Tfs*39). Thyroid US showed a 1.9 × 1.8 cm heterogeneous nodule with punctate echogenic foci, and a suspicious 2.4 cm left level III lymph node. FNA of the nodule was inconclusive (Bethesda I). After total thyroidectomy and central lymph node dissection, histopathology revealed multifocal PTC, with the largest focus being 2.2 cm, without surgical margin involvement or gross extrathyroidal extension, but all seven central neck lymph nodes harbored metastases, with the largest metastatic deposit of 0.6 cm (AJCC 8th Ed. pT2N1aM0, Stage I). RAI with 100 mCi (3.7 GBq) was administered under thyrotropin stimulation. Post-therapy scan revealed uptake in the left neck without local or distant metastasis. Tumor genetics identified BRAF^V600E and the known FLCN germline PVs.

FLCN as a somatic driver in TC

We analyzed 2334 TC samples from 2285 patients with PTC, PDTC, and anaplastic TC (ATC) on cBioPortal (www.cbioportal.org). FLCN PVs were found in 2% of all the TC cases; however, FLCN PV prevalence was as high as 23% in ATC samples. While the overall survival in TC patients with FLCN PVs was significantly worse compared with those without FLCN PVs (hazard ratio: 19.86, 95% confidence interval: 2.91–135.76), the overall survival was similar between ATC patients with FLCN PVs and ATC patients without FLCN PVs (Supplementary Data).^19,20

Discussion

We describe three patients with BHD and TC, along with associated molecular driver data. We then show FLCN PVs are more likely to be found in highly aggressive TC subtypes, such as ATC.

Over 400 families affected with BHD have been described,²¹ and there are 15 documented TC cases in BHD (Table 1), with a median age of presentation of 47 years (range: 28–72), and similar sex predilection (50% female, four out of eight subjects).^{1,8

–15} Eight of the 15 patients had confirmed germline FLCN PVs.

Among the reported cases,^{1,8

–15} the TC subtypes were as follows: two OTC,^9,15 seven medullary TC,^1,12 two PTC,⁸ two follicular TC,^13,14 one primary clear cell TC,¹¹ and one unspecified TC subtype.¹⁰ Three out of six patients with lymph node involvement had evidence of lymphovascular invasion.^8,13 Three patients had distant metastasis.^1,11,13 OTC is associated with a poorer prognosis among differentiated TCs.²² Ten-year disease-free interval for FTC and OTC is about 75% and 41%, respectively.²² Furthermore, OTC has a higher recurrence rate, as evidenced in patient 1 from our series.²³ These findings may corroborate with our cBioPortal analysis revealing FLCN PVs predominating in aggressive tumors like ATC.

In a five-year prospective French study, thyroid nodules were prevalent in (13 out of 20) 65% of patients with BHD¹⁶; however, all of these nodules were benign, and no TC cases were identified.¹⁶ Additionally, 9 out of 10 (90%) families affected by BHD with germline FLCN PVs had individuals with thyroid nodules, but this increased prevalence may be due to selection bias.¹⁶

To date, there are two other reported cases of patients with BHD and OTC.^9,15 One case was discovered when an ¹⁸FDG-PET scan was conducted to investigate RCC, but further details on OTC were not provided.⁹ The second OTC case was noted in a BHD cohort of 120 families from Japan and Taiwan.¹⁵ Although the clinical details on this patient were not provided, interestingly, somatic mutation analysis of the OTC tissue demonstrated the FLCN PV (c.1285dupC) almost entirely replacing the wild-type FLCN, indicative of loss of heterozygosity (LOH).¹⁵

FLCN haploinsufficiency may enhance apoptosis, impair cellular attachment, and alter cell adhesion protein function as evidenced in pleural mesothelial cells.²⁴ Whether such FLCN haploinsufficiency could have caused defective cell adhesion in TC needs further research. Haploinsufficiency in the FLCN gene may not be the predominant molecular driver for TC tumorigenesis but might synergize with coexisting PVs to promote tumorigenesis. For instance, patient 1 in our cohort harbored PVs in TP53 and DAXX, which are known PVs in OTC, and these PVs may have contributed toward tumorigenesis along with FLCN haploinsufficiency.²⁵ However, LOH in FLCN gene may possess a higher potential to be the sole molecular driver rather than FLCN haploinsufficiency in the pathogenesis of TC.¹⁵

Among seven patients with known renal disease,^8

–13 five had renal manifestations, including three with confirmed RCC,^8,11,13 one with bilateral renal masses,⁹ and one with a renal cyst.¹² Renal tumors exhibit LOH in FLCN due to somatic second-hit mutation in about 53% of cases.²⁶ Therefore, LOH in the FLCN gene might play a substantial role in the pathogenesis of renal tumors in BHD; however, this may not be the case with other BHD tumors.²⁶ For example, skin fibrofolliculomas in BHD were shown to strongly express FLCN mRNA, and LOH was not detected in these tumors,²¹ suggesting that LOH in FLCN is not the sole oncogenic driver in these tumors, and such might be the case with other nonrenal BHD tumors, including TC.

An additional case of BHD with noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) has been described.²⁷ This case was not included in Table 1, as NIFTP is no longer considered a malignancy.²⁸ Patient was a 44-year-old female with BHD, a germline FLCN PV (A90S), skin tags, bilateral pulmonary cysts, and clear cell RCC, without family history of TC or history of radiation exposure.²⁷

The canonical pathway associated with FLCN function is RAS-PI3K-Akt-mTOR, and loss of FLCN function may lead to overactivation of mTOR (Supplementary Data).²⁹ Tyrosine kinase inhibitors (sorafenib, lenvatinib, and cabozantinib) remain the mainstay of therapy in RAI-refractory, progressive TC. However, mTOR inhibitors may be utilized in patients with FLCN-mutated TCs. In fact, treatment with mTOR inhibitor, everolimus, led to an unusually prolonged treatment response in a patient with ATC harboring FLCN, TSC2, and TP53 PVs.³⁰ FLCN may also function through noncanonical pathways.⁴ For instance, cuboidal cells resembling type II pneumocytes that are frequently observed in the innermost layers of BHD-associated lung cysts exhibit activation of mTORC1 and hypoxia-inducible factor (HIF)–vascular endothelial growth factor pathways.⁴ HIF-1α is a well-known oncogenic driver, with overexpression in tumors linked to poor prognosis and treatment response.³¹ Utilizing HIF-1α inhibitors may be a therapeutic option, having demonstrated promising in vitro results by inhibiting TC growth.³¹ Another potential mode of abnormal FLCN-mediated tumor growth could involve increased Wnt-β-catenin signaling, which is often observed in late-stage TCs, and in vitro siRNA-mediated knockdown of FLCN can be associated with increased Wnt signaling.³² Several inhibitors of Wnt signaling are being evaluated in clinical trials that may hold promise in treatment of TCs with defective FLCN function.^32
–34

In conclusion, BHD may be associated with TC, including aggressive histological subtypes. The molecular signature of TC in BHD patients suggests that FLCN is likely not the only oncogenic driver. But in instances of LOH, FLCN may indeed become a prominent molecular driver for TC tumorigenesis, but this warrants further research. The rarity of TC in BHD, and of BHD in general, precludes provision of a tailored, comprehensive guidance toward management of TC in BHD population. Continued accrual of knowledge on this condition and TC data from larger BHD cohorts is needed in order to delineate a true pathological association between FLCN and TC. Our data on FLCN prevalence should also be interpreted with a caveat that cancer databases such as cBioPortal undergo constant revision, and pathogenic status of a gene variant may be reassigned thereby affecting the prevalence of the said variant. Larger sample sizes, along with improved molecular characterization and mechanistic studies evaluating the downstream effects of mutated FLCN in TCs, may assist with tailoring the monitoring and with optimizing therapy of TC in BHD patients.

Footnotes

Acknowledgments

The authors would like to thank the patients for participating in the study and the health care providers who cared for them at the authors’ institution and referred them for evaluation through the authors’ clinical protocol.

Authors’ Contributions

S.V. and E.C. are joint co-first authors. S.G. and J.K. conceptualized and designed the study. S.V., E.C., J.K., S.G., K.B., and P.V. were involved in patient care and formal evaluation, as well as supervising the study subjects. All authors contributed to the acquisition and interpretation of clinical data. S.V., E.C., J.K., and S.G. drafted the article. M.J. assisted in creating ‘figure 1' in the supplementary material. All authors revised the report and approved the final version before submission. S.V. and E.C. are the guarantors and attest that all listed authors meet authorship criteria and that no individuals meeting the criteria have been omitted.

Author Disclosure Statement

All authors declare no competing interests.

Funding Information

This research was supported by the Intramural Research Programs of the National Institute of Diabetes and Digestive and Kidney Diseases and the Center for Cancer Research, National Cancer Institute, National Institutes of Health. Clinical trial registration number: NCT-01109420.

Principal Investigator: J.K., Intramural Funding #ZIA DK047053-17.

Supplementary Material

Supplementary Data

References

Birt

, Hogg

, Dubé

. Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons. Arch Dermatol, 1977; 113(12):1674–1677.

Sattler

, Steinlein

. Birt-Hogg-Dubé Syndrome. GeneReviews® [Internet]: Seattle (WA): University of Washington, Seattle; 2006.

Toro

, Wei

, Glenn

, et al. BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dubé syndrome: A new series of 50 families and a review of published reports. J Med Genet, 2008; 45(6):321–331; doi: 10.1136/jmg.2007.054304

Hasumi

, Baba

, Hasumi

, et al. Birt-Hogg-Dubé syndrome: Clinical and molecular aspects of recently identified kidney cancer syndrome. Int J Urol, 2016; 23(3):204–210; doi: 10.1111/iju.13015

Singer

, Bratslavsky

, Middelton

, et al. Impact of genetics on the diagnosis and treatment of renal cancer. Curr Urol Rep, 2011; 12(1):47–55; doi: 10.1007/s11934-010-0156-y

Baba

, Hong

, Sharma

, et al. Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling. Proc Natl Acad Sci U S A, 2006; 103(42):15552–15557; doi: 10.1073/pnas.0603781103

Clausen

, Stein

, Grønbæk-Thygesen

, et al. Folliculin variants linked to Birt-Hogg-Dubé syndrome are targeted for proteasomal degradation. PLoS Genet, 2020; 16(11):e1009187; doi: 10.1371/journal.pgen.1009187

Dong

, Gao

, Hao

, et al. Case report of birt-hogg-dube syndrome: Germline mutations of flcn detected in patients with renal cancer and thyroid cancer. Medicine (Baltimore), 2016; 95(22):e3695; doi: 10.1097/MD.0000000000003695

Panagiotidis

, Seshadri

, Vinjamuri

. Renal manifestation of birt-hogg-dube syndrome depicted by 18f-fludeoxyglucose positron emission tomography/computed tomography in a patient with hurtle cell thyroid malignancy. World J Nucl Med, 2018; 17(2):123–125; doi: 10.4103/wjnm.WJNM_93_16

10.

Kunogi

, Kurihara

, Ikegami

, et al. Clinical and genetic spectrum of Birt-Hogg-Dube syndrome patients in whom pneumothorax and/or multiple lung cysts are the presenting feature. J Med Genet, 2010; 47(4):281–287; doi: 10.1136/jmg.2009.070565

11.

Benusiglio

, Gad

, Massard

, et al. Case Report: Expanding the tumour spectrum associated with the Birt-Hogg-Dube cancer susceptibility syndrome. F1000Res, 2014; 3:159; doi: 10.1268/8/f1000research.4205.1

12.

Pérez García

, Antón Miguel

, Fuentes Gómez

. Medullary thyroid carcinoma in a patient with Birt-Hogg-Dube syndrome. Med Clin (Barc), 2017; 148(11):528–529; doi: 10.1016/j.medcli.2017.01.007

13.

Bongetti

, Raj

, Cooke

, et al. Metastatic follicular thyroid cancer in a patient with Birt-Hogg-Dube syndrome. Clin Case Rep, 2021; 9(1):102–104; doi: 10.1002/ccr3.3454

14.

Hehar

, Bhan

. Birt hogg dube syndrome and thyroid cancer—Is there an association? Journal of the Endocrine Society, 2021; 5(Supplement_1):A883–A883; doi: 10.1210/jendso/bvab048.1803

15.

Furuya

, Yao

, Tanaka

, et al. Genetic, epidemiologic and clinicopathologic studies of Japanese Asian patients with Birt-Hogg-Dubé syndrome. Clin Genet, 2016; 90(5):403–412; doi: 10.1111/cge.12807

16.

Kluger

, Giraud

, Coupier

, et al. Birt-Hogg-Dube syndrome: Clinical and genetic studies of 10 French families. Br J Dermatol, 2010; 162(3):527–537; doi: 10.1111/j.1365-2133.2009.09517.x

17.

Haugen

, Alexander

, Bible

, et al. 2015 american thyroid association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: The american thyroid association guidelines task force on thyroid nodules and differentiated thyroid cancer. Thyroid, 2016; 26(1):1–133; doi: 10.1089/thy.2015.0020

18.

Amin

, Greene

, Edge

, et al. The Eighth Edition AJCC Cancer Staging Manual: Continuing to build a bridge from a population-based to a more “personalized” approach to cancer staging. CA Cancer J Clin, 2017; 67(2):93–99; doi: 10.3322/caac.21388

19.

Integrated genomic characterization of papillary thyroid carcinoma. Cell, 2014; 159(3):676–690; doi: 10.1016/j.cell.2014.09.050

20.

Gao

, Aksoy

, Dogrusoz

, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. 2013. Available from: http://www.cbioportal.org/results/oncoprint?gene_list=FLCN&cancer_study_list=thpa_tcga_gdc%2Cthca_tcga_pub%2Cthca_tcga%2Cthca_tcga_pan_can_atlas_2018%2Cthyroid_gatci_2024%2Cthyroid_mskcc_2016&case_set_id=all&Z_SCORE_THRESHOLD=2.0&RPPA_SCORE_THRESHOLD=2.0&profileFilter=mutations%2Cstructural_variants%2Ccna%2Cgistic&geneset_list=%20&tab_index=tab_visualize&Action=Submit&comparison_subtab=overlap [Last Accessed: November 2024].

21.

Menko

, van Steensel

, Giraud

, et al.; European BHD Consortium. Birt-Hogg-Dube syndrome: Diagnosis and management. Lancet Oncol, 2009; 10(12):1199–1206; doi: 10.1016/S1470-2045(09)70188-3

22.

Kushchayeva

, Duh

, Kebebew

, et al. Comparison of clinical characteristics at diagnosis and during follow-up in 118 patients with Hurthle cell or follicular thyroid cancer. Am J Surg, 2008; 195(4):457–462; doi: 10.1016/j.amjsurg.2007.06.001

23.

Grebe

, Hay

. Follicular thyroid cancer. Endocrinol Metab Clin North Am, 1995; 24(4):761–801.

24.

Okamoto

, Ebana

, Kurihara

, et al. Folliculin haploinsufficiency causes cellular dysfunction of pleural mesothelial cells. Sci Rep, 2021; 11(1):10814; doi: 10.1038/s41598-021-90184-9

25.

Kumari

, Adewale

, Klubo-Gwiezdzinska

. The molecular landscape of hürthle cell thyroid cancer is associated with altered mitochondrial function-a comprehensive review. Cells, 2020; 9(7); doi: 10.3390/cells9071570

26.

Vocke

, Yang

, Pavlovich

, et al. High frequency of somatic frameshift BHD gene mutations in Birt-Hogg-Dubé-associated renal tumors. J Natl Cancer Inst, 2005; 97(12):931–935; doi: 10.1093/jnci/dji154

27.

Moguillansky

, Ataya

. A 44-Year-Old woman with multiple neoplasms and cystic lung disease. Chest, 2021; 159(6):e381–e384; doi: 10.1016/j.chest.2021.01.005

28.

Cubero Rego

, Lee

, Boguniewicz

, et al. Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is rare, benign lesion using modified stringent diagnostic criteria: Reclassification and outcome study. Ann Diagn Pathol, 2020; 44:151439; doi: 10.1016/j.anndiagpath.2019.151439

29.

Hasumi

, Baba

, Ajima

, et al. Homozygous loss of BHD causes early embryonic lethality and kidney tumor development with activation of mTORC1 and mTORC2. Proc Natl Acad Sci U S A, 2009; 106(44):18722–18727; doi: 10.1073/pnas.0908853106

30.

Wagle

, Grabiner

, Van Allen

, et al. Response and acquired resistance to everolimus in anaplastic thyroid cancer. N Engl J Med, 2014; 371(15):1426–1433; doi: 10.1056/NEJMoa1403352

31.

Kim

, Lee

, et al. Hif-1α Inhibitors Could Successfully Inhibit the Progression of Differentiated Thyroid Cancer in Vitro. Pharmaceuticals (Basel), 2020; 13(9); doi: 10.3390/ph13090208

32.

Luijten

, Basten

, Claessens

, et al. Birt-Hogg-Dube syndrome is a novel ciliopathy. Hum Mol Genet, 2013; 22(21):4383–4397; doi: 10.1093/hmg/ddt288

33.

Abbosh

, Nephew

. Multiple signaling pathways converge on beta-catenin in thyroid cancer. Thyroid, 2005; 15(6):551–561; doi: 10.1089/thy.2005.15.551

34.

, Yu

, Li

, et al. Wnt/β-catenin signaling in cancers and targeted therapies. Signal Transduct Target Ther, 2021; 6(1):307; doi: 10.1038/s41392-021-00701-5

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

2.77 MB

0.00 MB