Diagnostic practice and awareness of SDH- and FH-deficient renal cell carcinoma: results from an Italian Study Group of uropathology (GIUP) survey

Metabolic renal cell carcinomas (RCC) deficient in succinate dehydrogenase (SDH) or fumarate hydratase (FH) are rare but clinically significant entities formalized in the last WHO classification. Their recognition typically starts from morphology and is corroborated by targeted immunohistochemistry (IHC) and, where appropriate, molecular and germline testing. In routine practice, however, implementation may be uneven. Hence, we conducted a nationwide, web-based survey (made by 25 items) among members of the Italian Study Group of Uropathology (GIUP) to map real-world awareness, diagnostic pathways, and test availability across Italian centers. Twenty-one pathologists responded; 18/21 (85.7%) reported dedicated uropathology practice with heterogeneous seniority (≤ 5 years, 28.6%; 5-10 years, 19.0%; 10-20 years, 14.3%; > 20 years, 38.1%). Despite substantial renal-tumor workloads (12/20, 57.1% handled > 100 cases in the previous 5 years), direct exposure to metabolic RCCs remained limited (FH-deficient ≥ 1 case, 11/21, 52.4%; SDH-deficient ≥ 1 case, 9/21, 42.9%). Suspicion was predominantly morphology-led: for SDH-deficient RCC, morphology ranked first in 16/21 (76.2%) with the commonest sequence morphology > age > number of lesions (76.2%); for FH-deficient RCC, morphology was top-ranked in 19/21 (90.5%). Key morphologic cues were mixed architectural patterns/papillary elements/macronucleoli for FH-deficient RCC, and eosinophilic cytoplasm with solid-alveolar architecture for SDH-deficient RCC. IHC mirrored these priorities (FH top for FH-deficient, 85.7%; SDHB top for SDH-deficient, 76.2%), whereas 2-succinocysteine (2SC) was rarely available (1/21, 4.8%). Critically, this FH-loss-only workflow can miss non-truncating FH variants (FH immunoreactive but enzymatically inactive) tumors, contributing to under-recognition. Molecular testing would be requested in all suspected cases by 12/21 (57.1%); among selective users, equivocal IHC was the leading trigger (6/8, 75%). Overall, metabolic RCC recognition in Italy is primarily morphology-driven but constrained by uneven access to confirmatory IHC, particularly 2SC, and to molecular assays. The findings argue for harmonized diagnostic algorithms, regional reference laboratory networks, and routine involvement of molecular tumor boards, supported by targeted educational initiatives (including curated digital slide repositories), to standardize practice and improve patient pathways from morphologic suspicion to genetic counselling and tailored surveillance.