Folliculin (FLCN) in Thyroid Tumors: Incidence, Significance, and Role as a Driver Gene and Secondary Alteration

Abstract

Thyroid carcinomas are driven by diverse molecular alterations, but the tumor suppressor gene folliculin (FLCN), best known for its role in Birt-Hogg-Dubé (BHD) syndrome, has received limited attention in thyroid tumors. Here, we describe two thyroid tumors with pathogenic FLCN alterations-one germline and one somatic-and analyze the broader prevalence and significance of FLCN in thyroid carcinomas using multiple large sequencing datasets, including ORIEN-AVATAR. Patient 1, with a germline FLCN mutation and a history of BHD syndrome, presented with a well-circumscribed oncocytic adenoma. Molecular testing confirmed biallelic FLCN inactivation, but no additional mutations or aggressive features were observed, and the patient remained disease-free post-thyroidectomy. Patient 2 harbored a somatic FLCN mutation in an oncocytic poorly differentiated thyroid carcinoma, which exhibited extensive angioinvasion, high proliferative activity, and concurrent TP53 and RB1 mutations. The tumor progressed with metastatic disease despite multimodal treatment. Thyroid carcinomas revealed FLCN alterations in 1.1% of cases. Pathogenic mutations were rare but associated with oncocytic morphology, while homozygous deletions occurred more frequently in genomically unstable tumors, including anaplastic thyroid carcinoma. These findings suggest FLCN mutations may act as early oncogenic drivers in oncocytic thyroid neoplasms, while deletions represent secondary events in aggressive tumor evolution. The lack of FLCN coverage in standard thyroid molecular panels likely underestimates its clinical relevance. Including FLCN in genetic testing could improve tumor detection and characterization, particularly in BHD patients who may benefit from routine thyroid screening. Further studies are needed to clarify FLCN's role in thyroid cancer pathogenesis.

Keywords: Brit–Hogg–Dube; folliculin; molecular testing; preoperative molecular testing; thyroid cancer.

Figure 1

Patient 1 oncocytic adenoma. (A) Diffuse solid growth of oncocytic cells without colloid (hematoxylin and eosin stain, 200× magnification, and 100 micron scale bar). (B) Thyroid tumor cell nuclei mimic nuclei of papillary thyroid carcinoma including many cells with bright, eosinophilic nuclear pseudo-inclusions (arrows), cells with ‘orphan annie’ nuclear clearing and cells with crumpled, ‘raisinoid’ nuclei (hematoxylin and eosin, 600× magnification, and 20 micron scale bar). (C) Thyroid tumor shows patchy membranous expression of CD56 (CD56-immunohistochemical stain with hematoxylin counterstain, 400× magnification, and 50 micron scale bar). (D) Patient’s prior kidney tumor shows features consistent with chromophobe carcinoma (hematoxylin and eosin, 600× magnification, 20 micron scale bar).

Figure 2

Patient 2. Oncocytic poorly differentiated thyroid carcinoma. (A) Sharp demarcation between solid (left) and papillary-like (right) architecture (100× magnification and 100 micron scale bar). (B) Papillary-like architectural growth pattern arising from a solid growth pattern background (400× magnification and 100 micron scale bar). (C) Papillary-like frond and adjacent solid growth pattern, both exhibiting oncocytic cytoplasm with an absence of papillary thyroid carcinoma (PTC) nuclear features (400× magnification and 100 micron scale bar). (D) Multiple mitotic figures (arrows), consistent with a poorly differentiated thyroid carcinoma (400× magnification and 100 micron scale bar). ((A–D) hematoxylin and eosin-stained tumor sections). (E,F) Immunohistochemical expression profile (200× magnification and 200 micron scale bar).

Figure 3

(A) Overall survival was compared between patients with FLCN driver alterations versus those without across all public datasets included in this study when survival data were available. Patients with FLCN driver alterations exhibited significantly worse overall survival. (B) Given that 24 of the 25 patients with FLCN driver alterations in the public datasets included in this study had anaplastic thyroid carcinoma, a subgroup analysis was conducted to evaluate the impact of FLCN on overall survival in this aggressive subset. While there was a trend toward poorer survival in patients with FLCN alterations, the difference did not reach statistical significance.