Succinate dehydrogenase-deficient renal cell carcinoma: detailed characterization of 11 tumors defining a unique subtype of renal cell carcinoma

Abstract

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 ¼ 10) or 3 (n ¼ 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.

Toward an improved definition of the genetic and tumor spectrum associated with SDH germ-line mutations

“…43 SDH-deficient RCCs display a slight male predisposition, present as bilateral tumors in 25% of cases, and have stereotypical morphologic features, that is, solid or focally cystic growth, uniform cytology with eosinophilic flocculent cytoplasm, intracytoplasmic vacuolations and inclusions, round to oval low-grade nuclei, and SDHB immunonegativity. 44,45 SDHA-negative IHC was reported once, but no mutational screening of SDHA was performed. 44 Despite the fact that SDH-deficient RCC is capable of progression, metastatic disease is rare in the absence of high-grade nuclear atypia or coagulative necrosis.…”

“…44,45 SDHA-negative IHC was reported once, but no mutational screening of SDHA was performed. 44 Despite the fact that SDH-deficient RCC is capable of progression, metastatic disease is rare in the absence of high-grade nuclear atypia or coagulative necrosis. 44,45 Finally, SDH-deficient PAs seem likely to be prolactin-secreting (and/or prolactin-immunopositive) and, to a lesser extent, growth hormone-secreting macroadenomas.…”

“…44 Despite the fact that SDH-deficient RCC is capable of progression, metastatic disease is rare in the absence of high-grade nuclear atypia or coagulative necrosis. 44,45 Finally, SDH-deficient PAs seem likely to be prolactin-secreting (and/or prolactin-immunopositive) and, to a lesser extent, growth hormone-secreting macroadenomas. They are usually accompanied by a personal history of PCC/PGL and have a slight male predisposition.…”

Classification of gastrointestinal stromal tumor syndromes

“…Collectively, these changes are thought to drive tumorigenesis in the multiple organ systems that demonstrate increased incidence of neoplasia in individuals harboring germline SDHx mutations, which include paragangliomas/pheochromocytomas, GISTs and, among a subset, a histologically distinctive type of renal cell carcinoma (Gill et al 2014, Williamson et al 2015. Importantly, with regard to GISTs, SDH-deficient GISTs can be due to either genetic (SDHA, B, C or D mutations) or epigenetic (SDHC promoter methylation) changes.…”

Diagnostic criteria for oncocytic renal neoplasms: a survey of urologic pathologists

“…Most participants (59%) reported that they perform succinate dehydrogenase (SDH) immunohistochemical staining only with unusual or borderline morphology (59%), or when morphology is highly suggestive of SDHdeficient renal cell carcinoma (29%). [13,14] None of the participants reported screening oncocytic tumors routinely for SDH status.…”