Clinically Sporadic Folliculin-mutated Renal Epithelial Neoplasms Represent a Mixture of True Somatic Folliculin-mutated and Occult Birt-Hogg-Dubé Syndrome-associated Cases
Pedram Argani, Ezra Baraban, Oksana Yaskiv, Huili Li, Swati Bhardwaj, Katya Dombrowski, Tamara L. Lotan, Ying Zou, Sunil Patel, Betina Katz, Qi Cai, Rohit Mehra, Norman Barker, Jonathan C. Dudley, Doreen N. Palsgrove
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.