Immunohistochemistry and Mutation Analysis of SDHx Genes in Carotid Paragangliomas

Abstract

Carotid paragangliomas (CPGLs) are rare neuroendocrine tumors often associated with mutations in <i>SDHx</i> genes. The immunohistochemistry of succinate dehydrogenase (SDH) subunits has been considered a useful instrument for the prediction of <i>SDHx</i> mutations in paragangliomas/pheochromocytomas. We compared the mutation status of <i>SDHx</i> genes with the immunohistochemical (IHC) staining of SDH subunits in CPGLs. To identify pathogenic/likely pathogenic variants in <i>SDHx</i> genes, exome sequencing data analysis among 42 CPGL patients was performed. IHC staining of SDH subunits was carried out for all CPGLs studied. We encountered <i>SDHx</i> variants in 38% (16/42) of the cases in <i>SDHx</i> genes. IHC showed negative (5/15) or weak diffuse (10/15) SDHB staining in most tumors with variants in any of <i>SDHx</i> (94%, 15/16). In <i>SDHA</i>-mutated CPGL, SDHA expression was completely absent and weak diffuse SDHB staining was detected. Positive immunoreactivity for all SDH subunits was found in one case with a variant in <i>SDHD</i>. Notably, CPGL samples without variants in <i>SDHx</i> also demonstrated negative (2/11) or weak diffuse (9/11) SDHB staining (42%, 11/26). Obtained results indicate that SDH immunohistochemistry does not fully reflect the presence of mutations in the genes; diagnostic effectiveness of this method was 71%. However, given the high sensitivity of SDHB immunohistochemistry, it could be used for initial identifications of patients potentially carrying <i>SDHx</i> mutations for recommendation of genetic testing.