Fumarate Hydratase-Deficient Renal Cell Carcinoma: A Multicentric Comprehensive Clinical, Pathological, and Molecular...

Fumarate hydratase-deficient renal cell carcinoma (FHd RCC) is a rare, aggressive subtype of kidney cancer associated with hereditary leiomyomatosis and renal cell carcinoma syndrome.

We retrospectively analyzed 12 FHd RCC cases from Hungarian patients, assessing clinical, histopathological, immunohistochemical, and molecular features.

The median age at diagnosis was 48.5 years, with a male-to-female ratio of 1.6:1. Most patients presented symptomatically and in an advanced stage; ten underwent surgery, and seven had metastatic disease at diagnosis. Tumors were unifocal, unilateral, and high-grade, displaying heterogeneous architectural patterns, often with eosinophilic cytoplasm and prominent viral inclusion-like nucleoli. Fumarate hydratase (FH) expression was lost in all but 1 tumor, while aberrant nuclear and cytoplasmic 2SC positivity was observed in all cases. CK7 was consistently negative, whereas AMACR and PAX8 were positive in all tested tumors. GATA3 expression was focal in 2 tumors. PD-L1 positivity was detected in 4 tumors, including 1 with high tumor mutational burden. Pathogenic FH mutations were confirmed in nine cases, including three germline alterations. Systemic therapy was administered in 7 patients, with variable responses.

Our findings highlight the pronounced morphological heterogeneity of FHd RCC and the critical role of combined FH and 2SC immunohistochemistry for accurate diagnosis. FHd RCC should be recognized as a distinct, highly malignant renal neoplasm, warranting comprehensive histological, immunohistochemical, and genetic assessment, along with genetic counseling to identify potential hereditary background.