Succinate Dehydrogenase-Deficient Renal Cell Carcinoma

Detailed Characterization of 11 Tumors Defining a Unique Subtype of Renal Cell Carcinoma

Sean R Williamson; John N Eble; Mahul B Amin; Nilesh S Gupta; Steven C Smith; Lynette M Sholl; Rodolfo Montironi; Michelle S Hirsch; Jason L Hornick


Mod Pathol. 2015;28(1):80-94. 

In This Article

Abstract and Introduction


Patients with germline mutation of succinate dehydrogenase (SDH) subunit genes are prone to develop paraganglioma, gastrointestinal stromal tumor, and rarely renal cell carcinoma (RCC). However, SDH-deficient RCC is not yet widely recognized. We identified such tumors by distinctive morphology and confirmed absence of immunohistochemical staining for SDHB. Immunohistochemical features were evaluated using a panel of antibodies to renal tumor antigens. Targeted next-generation sequencing was performed on DNA extracted from paraffin-embedded tissue. Eleven tumors were identified from 10 patients, 22–72 years of age (median 40). Two patients had paragangliomas, 1 bilateral SDH-deficient RCC, and 1 contralateral oncocytoma. Grossly, tumors were tan or red–brown, 2–20 cm in diameter (median 4.25 cm). Fuhrman grade was 2 (n=10) or 3 (n=1). Stage was pT1a–pT2b. One patient developed widespread metastases 16 years after nephrectomy and died of disease 6 years later. All tumors were composed of uniform eosinophilic cells containing vacuoles or flocculent cytoplasmic inclusions. Architecture was primarily solid; entrapped renal tubules and intratumoral mast cells were common. By immunohistochemistry, tumor cells were negative for SDHB (11/11) and rarely SDHA (1/11). Labeling was uniformly positive for PAX8 and kidney-specific cadherin and absent for KIT, RCC, and carbonic anhydrase IX. Staining for broad-spectrum epithelial markers was often negative or focal (positive staining for AE1/AE3 in 4/10, CAM5.2 3/7, CK7 1/11, EMA 10/10). By sequencing, SDHB mutation and loss of the second allele were present in 5/6 tumors; the SDHA-deficient tumor showed no SDHB abnormality. SDH-deficient RCC is a unique neoplasm that is capable of progression, often harboring SDHB mutation. A monomorphic oncocytic renal tumor with solid architecture, cytoplasmic inclusions of flocculent material, and intratumoral mast cells should prompt evaluation of SDH status, as it may have implications for screening the patient and relatives. Negative immunohistochemistry for KIT and heterogeneous labeling for epithelial antigens are other supportive features.


Succinate dehydrogenase (SDH) is a mitochondrial enzyme complex composed of four protein subunits (SDHA, SDHB, SDHC, and SDHD) that functions as a member of the Krebs cycle and electron transport chain. Germline mutations of the genes that encode the SDH subunits result in hereditary paraganglioma-pheochromocytoma syndromes.[1,2] Patients with such mutations also develop gastrointestinal stromal tumors (GISTs) that can be recognized by their distinctive multinodular architecture, predominantly epithelioid morphology, and predilection for lymph node metastasis.[1–3]

In addition to paraganglioma and GIST, there is increasing evidence that patients with germline mutation of SDH subunit genes also develop renal tumors,[4] which, similar to paragangliomas and GISTs in such patients, lack immunohistochemical labeling for SDHB in the neoplastic cells.[5,6] Many of the renal tumors that have been recognized to date in these patients exhibit distinctive morphology, characterized by sheets of uniform cells with eosinophilic or oncocytic cytoplasm that contain cytoplasmic vacuoles or flocculent inclusions.[5–8] However, renal cell carcinomas (RCCs) with other histologic appearances have been reported in patients with germline mutations of SDH subunit genes,[4,9] and a few RCCs of other histologic types have been found to be SDH-deficient in the absence of known germline gene mutation.[8,10] Nonetheless, experience with SDH-deficient RCC demonstrating this unique oncocytic histology remains very limited.[11] Detailed pathologic features and immunohistochemical staining results for renal tumor antigens have been reported in only four tumors with this unique morphology.[5,6] Therefore, the precise constellation of features that differentiates these neoplasms from other subtypes of renal tumors remains poorly understood. To facilitate discrimination of these SDH-deficient oncocytic renal tumors from other benign and malignant renal neoplasms and to elaborate the spectrum of their pathologic features, we performed a detailed analysis of clinicopathologic, immunohistochemical, and genetic features of SDH-deficient RCCs.