Renal tumors harboring FLCN mutations: Case series from clinical practice

Renal cell neoplasms with FLCN mutations, classically seen in Birt-Hogg-Dubé (BHD) syndrome typically include oncocytoma, chromophobe RCC, and hybrid oncocytic/chromophobe tumors (HOCT). Recent studies have highlighted FLCN-mutated renal cell carcinomas (RCCs) with unclassified morphologies, raising diagnostic challenges.

We retrospectively identified renal tumors with FLCN mutations by targeted next-generation sequencing at our institution (2015-2024). Clinical records, tumor morphology, immunohistochemistry, and genomic profiles were reviewed.

Seven patients were identified. Four exhibited unclassified morphologies with features overlapping with translocation RCC, as well as papillary RCC and eosinophilic solid and cystic (ESC) RCC. One clear cell RCC harbored a secondary probable germline FLCN mutation and TFEB locus amplification, while two were consistent with conventional oncocytic morphology. Germline FLCN mutation was confirmed in two patients with BHD syndrome. Recurrent copy number changes in these tumors included loss of 1p, 15q, 17p and 14q, and gain of 17q. CD117 and CK7 were negative to focal in majority of the cases, TFE3 showed diffuse to focal positivity, while GPNMB was diffusely positive in all 5 cases with material available. Clinical outcomes ranged from indolent disease to metastasis and late recurrence.

FLCN-mutated RCCs comprise a morphologically heterogeneous yet molecularly defined group. Conventional oncoytic morphology was associated with germline alterations while unclassified morphologies could be associated with somatic alterations and possibly germline mutations. FLCN mutations may also be incidental germline mutations in other RCC subtypes. Tumors with unclassified morphologies evoked morphological and immunohistochemical diagnostic consideration of other oncocytic and papillary RCCs and could be associated with adverse outcomes. Recognition may be aided by diffuse GPNMB expression, but definitive classification, especially in cases without conventional morphology, requires molecular testing. These findings broaden the spectrum of FLCN-driven tumors and support their distinction as a unique molecular entity.