Objective Mutations in succinate dehydrogenase (SDH) related genes (SDHx) are most frequently identified genetic variations in pheochromocytomas and paragangliomas (PPGLs), and give rise to hereditary paraganglioma syndromes 1-5. Although it has been encouraged that all PPGL patients should receive genetic testing, universal screening is seldom performed. Recently, SDHB and SDHA immunochemistry study have been proposed as alternative methods in the diagnosis of paraganglioma syndromes, especially SDHB/SDHA immunohistochemistry is a reliable tool to identify patients with SDH-x mutation with an additional value in the assessment of genetic variants. The somatic hypermethylation of SDHC was not investigated, and a germline SDHC mutation and harboring somatic loss of heterozygosity of the SDHC locus paradoxically displayed SDHB immunopositivity. In the current study, we investigated the clinical significance of SDHC immunohistochemistry in PPGLs.
Design SDHC and SDHB immunohistochemistry staining were performed on 140 tumor specimens (71 pheochromocytomas, 67 paragangliomas, and 2 metastasis tumor) from 126 PPGL patients. The germline mutation status of 67 patients were previously determined, identifying SDHA (n=2), SDHB (n=18), SDHC (n=2), SDHD (n=5), VHL (n=2), RET(n=7), and NF1 (n=1) mutants. Sixteen patients with cardiac paragangliomas were included in the study.
Results SDHC expression was absent in 23/30 PPGLs with SDHx mutation but preserved in 40/49 tumors without SDHx mutation. All 3 VHL-mutated tumors stained negative for SDHC, but expressed moderate level of SDHB. Catecholamine secretion, extra-adrenal localization, and malignancy were more common in PPGLs without SDHB expression. Negative SDHB and SDHC immunostaining was observed in 15/16, and 10/16 cardiac paragangliomas, respectively.
Conclusion SDHC immunohistochemistry reliably predicts the presence of germline SDHx mutation in PPGLs, providing supplementary value to the existing SDHB/SDHA-based immunohistochemical algorithm. Negative SDHB expression in PPGLs indicates malignancy and calls for intense follow-up. SDH-deficiency is a common feature for cardiac paragangliomas, rationalizing SDH genetic testing in all cardiac paraganglioma patients.