Aggressive high-grade papillary-patterned renal cell carcinomas harboring FLCN mutations: expanding the clinicopathological spectrum in Birt-Hogg-Dubé syndrome and sporadic cases.

Folliculin (FLCN)-mutated renal tumors, in the setting of Birt-Hogg-Dubé (BHD) syndrome or sporadically, typically show low-grade eosinophilic morphology and follow an indolent clinical course; however, rare high-grade variants with more aggressive behavior remain poorly defined and underrecognized. To better characterize this unusual subset, we identified six high-grade renal cell carcinomas (RCCs) and performed integrated clinicopathologic, immunohistochemical, molecular, and clinical follow-up analyses. All tumors demonstrated infiltrative growth, extensive necrosis, variable desmoplastic stroma, and high-grade nuclear features. They exhibited papillary/tubulopapillary and solid growth patterns, mixed eosinophilic and clear cell cytology, focal biphasic morphology, and prominent nucleoli, overlapping morphologically with high-grade papillary RCC, FH-deficient RCC, and TFE3- or TFEB-rearranged RCC. Targeted DNA sequencing identified FLCN frameshift mutations in all cases, including four germline mutations, one likely germline mutation, and one somatic mutation, without additional alterations characteristic of other established RCC subtypes. In keeping with the FLCN-mutated phenotype, all tumors extensively and strongly expressed GPNMB. Clinically, three patients had features consistent with BHD syndrome; one additional patient lacked typical pulmonary and cutaneous findings but was confirmed to carry a germline mutation; another could not be definitively classified as having BHD and was considered suspected; and the remaining one had no clinical evidence of BHD and was considered likely sporadic. At last follow-up, three patients were free of recurrence or metastasis at 10, 25, and 7 months; the remaining three developed distant metastases, including two who died of disease at 17 and 26 months postoperatively and one who remained alive with metastatic disease at 85 months. Our findings expand the morphologic spectrum of FLCN-mutated renal tumors and the genetic landscape of papillary-patterned RCCs, raising awareness of this aggressive subset and supporting consideration of FLCN testing in morphologically overlapping high-grade papillary tumors.