Histiocyte-Rich Renal Epithelial Neoplasm: A Morphology Associated With Folliculin Mutations and Birt-Hogg-Dubé...

So-called hybrid oncocytic tumor (HOT) is the renal neoplasm most commonly associated with the germline folliculin ( FLCN ) mutations that define Birt-Hogg-Dubé syndrome. However, the spectrum of renal epithelial neoplasms associated with FLCN gene mutations has recently expanded to include neoplasms with somatic FLCN mutations and those with variant morphology. Some of these FLCN -mutated neoplasms overlap morphologically and immunohistochemically with TSC/MTOR -mutated and TFE3/TFEB fusion renal cell carcinomas, which makes sense given their overlapping genetic pathways. One morphology that has been reported in 1 to 2 cases each across multiple studies is that of a "histiocyte-rich" renal epithelial neoplasm, characterized by acinar spaces lined by neoplastic oncocytic epithelial cells variably distended by luminal histiocytes. An unanswered question is how frequently this morphology is associated with FLCN mutations. We identified 11 previously unreported cases of histiocyte-rich renal epithelial neoplasms and performed immunohistochemistry and next-generation sequencing. Five out of 11 cases (45%) demonstrated FLCN mutations, including at least 3 cases with evidence supporting occult Birt-Hogg-Dubé syndrome. All FLCN- mutated neoplasms were diffusely immunoreactive for glycoprotein nonmetastatic B (GPNMB), but so were 3 of the 6 morphologically similar cases in which FLCN mutations were not detected. The 2 syndromic cases with adequate surrounding kidney for evaluation demonstrated GPNMB-positive cysts lined by cells with similar cytology to that of the neoplasms, possibly representing precursor lesions. In summary, histiocyte-rich renal epithelial neoplasm is a morphologic pattern that is strongly but not invariably associated with FLCN mutations. Recognition of this pattern is helpful in that it may provide the first clue to the presence of occult Birt-Hogg-Dubé syndrome.