4.4 Article

Incidence of succinate dehydrogenase and fumarate hydratase deficient renal cell carcinoma based on immunohistochemical, screening with SDHA/SDHB and FH/2SC

Journal

HUMAN PATHOLOGY
Volume 91, Issue -, Pages 114-122

Publisher

W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1016/j.humpath.2019.07.004

Keywords

Succinate dehydrogenase; SDHA; SDHB; Fumarate hydratase; FH; S-(2-succino)-cysteine; 2SC

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Funding

  1. NCI NIH HHS [P30 CA008748] Funding Source: Medline

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Mutations of the succinate dehydrogenase (SDHX) enzyme subunits commonly lead to a loss of function of the holoenzyme complex, and germline SDHX mutations lead to a genetic predisposition to SDH-deficient neoplasms, including renal cell carcinomas (RCC). Similarly, loss-of-function alterations of fumarate hydratase (FH) leads to a genetic predisposition to hereditary leiomyomatosis and renal cell cancer (HLRCC) associated RCC. Loss of FH leads to an accumulation of fumarate and aberrantly high levels of S-(2-succino)-cysteine (2SC). Subtype-specific consecutively diagnosed renal cell neoplasms were selected for the study and cases were not otherwise selected based on clinicopathologic features. Tissue microarrays were constructed from 1009 renal cell neoplasms (papillary: 400, clear cell: 203, chromophobe: 87, oncocytomas [original diagnosis]: 273, unclassified: 46) and these cases were immunostained for SDHA/SDHB to screen for SDH loss. A smaller subset (n = 730; oncocytomas, papillary and unclassified RCCs) were screened for FH-deficiency using immunohistochemistry for FH/2SC. Loss of SDHA/SDHB was seen in three of 273 tumors originally diagnosed as oncocytomas (1.1%). Diffuse nuclear and cytoplasmic 2SC staining, with retained FH expression was seen in one case (suggestive of dysfunctional FH protein), while absent FH was seen in 3 cases (2/400 papillary RCCs, 0.5% and 2/46 unclassified RCCs, 4.35%). No aberrant FH/2SC expression was noted in 273 cases originally diagnosed as oncocytomas. SDH-deficient RCCs were identified only in the cases originally diagnosed as oncocytomas (1.1%), while FH-deficient RCCs were identified in the papillary (0.5%) and unclassified RCC cohorts (4.35%). These results can help guide immunohistochemistry-based screening strategies for these tumors. (C) 2019 Elsevier Inc. All rights reserved.

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