Clinicopathological and molecular features of so-called low-grade oncocytic fumarate hydratase–deficient renal cell carcinoma: a study of 5 cases

Low-grade oncocytic fumarate hydratase-deficient renal cell carcinoma (FHdRCC), resembling succinate dehydrogenase-deficient RCC morphologically, is a recently described uncommon variant of FHdRCC. We report five additional cases to enhance the understanding of this rare tumor type. These tumors had variably thick fibromuscular capsules with frequent intracapsular invasions and had prominently compact nests and/or tubules. The tumor cells were characterized by abundant dense eosinophilic cytoplasm imparting a ground glass-like appearance and by variable bubbly cytoplasm. Despite a predominantly low histology grade, focal nuclear pleomorphism was observed in two cases. Two cases showed FH negativity and 2SC positivity, while the remaining cases exhibited both FH and 2SC positivity. All cases were positive for PAX8, Vimentin, P504s, and SDHB, but negative for CD117, CA9, CK20, ALK, and cathepsin-K. CK7 and TFE3 positivity were seen in 2 and 4 of 5 cases, respectively. The whole exome sequencing and multiplex PCR-based next generation sequencing identified pathogenic or likely pathogenic FH mutations in three cases and failed in one case showing the FH-negative and 2SC-positive immunophenotype. The remaining case exhibiting both FH and 2SC positivity had a germline FH mutation of uncertain significance and single copy loss of chromosomes 1, 14, and 18. None of three cases who underwent FISH detections had TFE3 translocations. Follow-up time for the 5 cases ranged from 7 to 94 months (median 46 months; mean 52 months). All cases were alive without disease, except for case 4 being alive with a stable contralateral renal mass. While low-grade oncocytic FHdRCC has a relatively better prognosis than conventional FHdRCCs, further research is required to confirm this in the future.