Fumarate hydratase-deficient renal cell carcinoma: a single institution-based study of 29 patients by clinicopathological, immunohistochemical and genetic approaches.

Fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) is a renal neoplasm associated with FH loss, aggressive behaviour, and poor survival. We present a histopathological and immunohistochemical overview of FH-deficient RCC to infer significant features for its differential diagnosis. In this study, FH-deficient RCC tissue samples from patients who underwent surgical resection or biopsy at a single institution between July 1995 and August 2022 were reviewed by conventional haematoxylin and eosin staining, immunohistochemistry, and whole genome analyses. Twenty-nine FH-deficient RCC specimens were examined ​based on immunohistochemistry findings regarding FH and S-(2-succino)cysteine (2SC). The histopathological findings included conspicuous nucleoli with a perinucleolar halo, resembling viral inclusion, eosinophilic cytoplasm, papillary and tubular growth patterns, and lack of stromal foam cell collection. Some tumours showed desmoplastic stroma, tumour-infiltrating lymphocytes, and solid growth pattern. One tumour presented low-grade oncocytic-like histomorphology. Widespread negativity for CD10, keratin 7, keratin 20, anaplastic lymphoma kinase, and GATA3 were observed in 24 specimens. All samples were positive for paired box gene 8, and the level of alpha-methylacyl-CoA racemase expression was variable. Whole exome sequencing of 19 tumours revealed nonsynonymous mutations, including missense mutations, splice donors, splice acceptors, frameshifts, and deletions in 15 tumours. Eleven tumours showed novel mutations. In conclusion, results revealed generally unfavourable clinical presentations and outcomes with a diverse range of FH mutations. These findings, along with the histopathological and immunohistochemical features, can be used to guide diagnosis and treatment.