Clinically Sporadic Folliculin-mutated Renal Epithelial Neoplasms Represent a Mixture of True Somatic Folliculin-mutated and Occult Birt-Hogg-Dubé Syndrome-associated Cases

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.