The emerging role of NF2 alterations in new and established subtypes of renal cell carcinoma

Genomic alterations are increasingly important in the current paradigms for the classification, diagnosis, and treatment of renal cell carcinoma. Biallelic alterations involving NF2 have been identified across several currently recognized subtypes of renal cell carcinoma including clear cell renal cell carcinoma and papillary renal cell carcinoma among others and may be associated with a more aggressive disease course as well as advanced stage at presentation. In addition, emerging evidence suggests the existence of a clinicopathologically distinct subset of renal cell carcinoma cases driven by biallelic loss of NF2 expression. This subset of tumors is morphologically characterized by a constellation of morphologic features including hyalinizing fibrosis, eosinophilic cytology, psammomatous calcifications, and a nested growth pattern. These tumors include the recently described entities of biphasic hyalinizing psammomatous renal cell carcinoma as well as renal cell tumor with sex cord/gonadoblastoma-like features. Despite their oftentimes aggressive behavior, there is some evidence that these tumors may respond favorably to treatment regimens incorporating immune checkpoint inhibitors.