Clinically Sporadic Folliculin-mutated Renal Epithelial Neoplasms Represent a Mixture of True Somatic Folliculin-mutated and Occult Birt-Hogg-Dubé Syndrome-associated Cases: Morphologic and Molecular Overlap With TSC/MTOR-mutated Eosinophilic Renal ﻿Neoplasms and MiT Family Translocation Renal Cell Carcinoma

Pedram Argani; Ezra Baraban; Oksana Yaskiv; Huili Li; Swati Bhardwaj; Katya Dombrowski; Tamara L Lotan; Ying S Zou; Sunil H Patel; Betina Katz; Qi Cai; Rohit Mehra; Norman Barker; Jonathan Dudley; Doreen N Palsgrove

doi:10.1097/PAS.0000000000002413

Clinically Sporadic Folliculin-mutated Renal Epithelial Neoplasms Represent a Mixture of True Somatic Folliculin-mutated and Occult Birt-Hogg-Dubé Syndrome-associated Cases: Morphologic and Molecular Overlap With TSC/MTOR-mutated Eosinophilic Renal Neoplasms and MiT Family Translocation Renal Cell Carcinoma

Am J Surg Pathol. 2025 May 5. doi: 10.1097/PAS.0000000000002413. Online ahead of print.

Authors

Affiliations

¹ Departments of Pathology, Oncology, Urology and Art as Applied to Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD.
² Department of Pathology, Zucker School of Medicine at Hofstra/Northwell, Lake Success, NY.
³ Department of Pathology, Oslo University, Oslo, Norway.
⁴ Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX.
⁵ Department of Pathology and Michigan Center for Translational Pathology, University of Michigan School of Medicine, Ann Arbor, MI.

PMID: 40321032
DOI: 10.1097/PAS.0000000000002413

Abstract

Germline mutations in the folliculin (FLCN) gene define Birt-Hogg-Dubé syndrome, which is associated with a variety of renal neoplasms; however, the role of FLCN mutations in sporadic renal neoplasms has not been well-defined. We identified 8 oncocytic/cystic renal neoplasms that presented as sporadic tumors and harbored FLCN mutations and no other genetic alterations characteristic of another established subtype. On further workup, 5 seem to harbor true somatic FLCN mutations, whereas the other 3 represent neoplasms associated with occult Birt-Hogg-Dubé syndrome. Patients were all females ranging in age from 25 to 77 years, and all neoplasms were confined to the kidney. The neoplasms overlapped morphologically with TSC/MTOR-mutated eosinophilic renal neoplasms and TFE3/TFEB-rearranged renal cell carcinoma. All neoplasms extensively expressed GPNMB, a downstream marker of TFE3/TFEB pathway activation, which is logical given the known molecular interplay of folliculin with TSC/MTOR/TFE3/TFEB. All 3 occult syndromic cases demonstrated multiple chromosome losses and gains not seen in the 5 sporadic neoplasms. In conclusion, diffuse GPNMB expression in the absence of TSC/MTOR/TFE3/TFEB alterations, particularly when the morphology suggests the presence of the latter, is a clue to FLCN-mutated renal epithelial neoplasms, which in a subset of cases may be a clue to occult Birt-Hogg-Dubé syndrome.

Keywords: Birt-Hogg-Dube; Folliculin; mutation; renal cell carcinoma.