Paragangliomas and the Pheochromocytoma—Paraganglioma Syndrome, the SDHX-Factor

Pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare neuroendocrine tumors that occur sporadically and in the context of hereditary tumor syndromes. One of these tumor syndromes is the PCC-PGL syndrome, where patients have multiple PGLs and/or PCCs. Although it has been known that most PGLs show loss of 11q, the associated tumor suppressor gene SDHD was only recently discovered. Mutations in this tumor suppressor gene were found in up to 60% of PGL patients. Recent investigations have shown that SDHD mutations not only cause this syndrome, but also that SDHB and SDHC are involved in the pathogenesis of the PCC-PGL syndrome. These studies have also shown that clinical indications (family history of PCC or PGL, multifocal disease, younger age) have high specificity but low sensitivity for the detection of PCC-PGL syndrome. In an international collaboration, we have shown, with SDHB immunohistochemistry (IHC), that SDH-related PCCs and PGLs can be easily distinguished from PCCs and PGLs with other genetic backgrounds. This detection of the inherited PCC-PGL syndrome is of major importance for PCC and PGL patients, as well as for their family members, because they are at increased risk for development of multiple, various, and malignant neoplasms. In addition, after identification of an SDHB, C, or D germline mutation, surveillance can be offered to family members carrying the mutation.