The utility of SDHB and FH immunohistochemistry in patients evaluated for hereditary paraganglioma-pheochromocytoma syndromes

Publication date: January 2018
Source:Human Pathology, Volume 71
Author(s): Aaron M. Udager, Martin J. Magers, Dayna M. Goerke, Michelle L. Vinco, Javed Siddiqui, Xuhong Cao, David R. Lucas, Jeffrey L. Myers, Arul M. Chinnaiyan, Jonathan B. McHugh, Thomas J. Giordano, Tobias Else, Rohit Mehra
A significant portion of paragangliomas (PGL) and pheochromocytomas (PCC) occur in patients with hereditary PGL/PCC syndromes, including those with germline mutations in succinate dehydrogenase (SDHx) subunit genes. Recently, germline fumarate hydratase (FH) mutations have been identified in a subset of PGL/PCC, and patients with hereditary leiomyomatosis and renal cell carcinoma (HLRCC) may have an increased risk of developing PGL/PCC. SDHB immunohistochemistry (IHC) has previously been shown to be useful for identifying SDHx-deficient PGL/PCC, however, FH IHC has never been explored in these tumors. Thus, we characterized SDHB and FH IHC in a large cohort of PGL/PCC patients (n = 41) at our institution who were evaluated for hereditary PGL/PCC syndromes. Overall, there was strong, positive correlation between germline SDHx subunit gene mutation status and SDHB IHC status (rφ = 0.77; P < .0001), with high corresponding sensitivity, specificity, positive predictive value, and negative predictive value (95.0%, 81.8%, 82.6%, and 94.7%, respectively). Although SDHB loss by IHC was highly correlated with germline SDHx gene mutations, its utility in this population was dependent on clinicopathologic context: while all head and neck PGL patients with SDHB-deficient tumors had germline SDHx gene mutations, only a small subset (25.0%) of PCC patients with SDHB-deficient tumors harbored a germline SDHx gene mutation. Finally, although our cohort contained only one HLRCC patient, their tumor was FH-deficient by IHC, and all other PGL/PCC showed retained FH IHC. Thus, in the appropriate clinical setting, SDHB and FH IHC may be useful for identifying PGL/PCC patients for Medical Genetics evaluation.



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