Expression Patterns of Succinate Dehydrogenase B: An Immunohistochemical Study of 57 Tumors With Known SDHx Germline Pathogenic Alterations

Abstract

A clinical algorithm originally proposed by van Nederveen et al. recommends that succinate dehydrogenase B immunohistochemical testing (SDH IHC) be performed on all pheochromocytomas and paragangliomas to screen for SDH deficiency, with abnormal staining (loss) referred to genetic counselors for confirmatory testing. However, the interpretation of SDHB IHC is challenging, with frequent partial staining or weak diffuse expression. This study sought to better characterize atypical SDHB IHC staining patterns in patients with genetically confirmed germline pathogenic or likely pathogenic variants involving SDH subunit (SDHx) genes. The cohort was identified from patients with known SDHx germline pathogenic or likely pathogenic variants within the familial cancer assessment and paraganglioma clinic of an academic tertiary medical center. Fifty-seven SDH-related tumors were identified (paraganglioma, pheochromocytoma, renal cell carcinoma, gastrointestinal stromal tumor, and seminoma) and stained with the SDHB immunohistochemical stain (polyclonal anti-SDHB antibody, Sigma Aldrich, HPA002868). Fourteen control specimens were identified from similar tumors. Stained slides were analyzed by a subspecialty genitourinary pathologist and a medical student completing a postsophomore fellowship in pathology. Twenty-eight of 57 tumors (49%) showed aberrant retained staining, divided into 4 observable staining patterns: fine granular staining/blush (9/28 abnormally staining tumors), focal retention (15/28), retained staining weaker than internal control (2/28), and retained staining either equal to internal control or without internal control present (2/28). We recognize the clinical utility of SDHB IHC as an affordable, but nuanced, method for screening for SDHx pathogenic or likely pathogenic variants and recommend subsequent genetic testing for any amount of abnormally lost staining.