Efficacy of Immunohistochemistry for SDHB in the Screening of Hereditary Pheochromocytoma–Paraganglioma

SIMPLE SUMMARY: The majority of hereditary pheochromocytoma and paraganglioma (PPGL) is caused by germline mutations in the SDHB, SDHC, or SDHD genes, which encode three (SDHB, SDHC, SDHD) of five subunits of succinate dehydrogenase (SDH) enzyme (SDHA, SDHDB, SDHC, SDHD, SDHAF2). The inactivation of any of the SDHx genes leads to the proteolysis of SDH. This can be detected with negative immunohistochemistry (IHC) for SDHB. However, there is no consensus of the interpretation of “weakly positive” staining. Hence, we carried out a retrospective single centre study comprising 58 patients to evaluate the efficacy of using SDHB IHC for detecting SDHx mutation in PPGL cases. Our analyses revealed that SDHB-negative IHC is a cost-effective and reliable method to predict SDHx mutations in the Korean population. Nonetheless, in the case of weakly positive staining, an additional gene study should be considered. ABSTRACT: The most common genetic backgrounds of hereditary paraganglioma and pheochromocytoma (PPGL) are SDHx germline mutations. Given the fact that the immunohistochemistry (IHC) result for SDHB is always negative regardless of the type of SDHx mutation, we aimed to evaluate the efficacy of using SDHB IHC for screening SDHx mutations in PPGL cases. In total, 52 patients who underwent surgery for PPGL treatment between 2006 and 2020 and underwent genetic analysis at diagnosis were included. Tissue microarrays (TMAs) were constructed with PPGL tissues and IHC for SDHB was performed on TMA sections. All 10 patients with SDHB-negative IHC contained SDHB or SDHD mutations. The genetic test results of patients with SDHB-weakly positive IHC varied (one SDHB, two RET, one VHL, and three unknown gene mutations). There were no SDHx mutations in the SDHB-positive IHC group. Six patients with weakly positive SDHB IHC with primarily unknown genetic status were re-called and underwent next-generation sequencing. None of them had SDHx mutations. In conclusion, SDHB-negative IHC is a cost-effective and reliable method to predict SDHx mutations. However, in the case of weakly positive SDHB staining, an additional gene study should be considered.