Paragangliomas (PGLs) are neuroendocrine tumors that can arise sporadically or be associated with inherited pathogenic variants (PV), specifically among the succinate dehydrogenase (SDH) genes. Though patients with multiple PGLs typically have a germline PV, gene-specific phenotype has been limited by the rarity of the familial paraganglioma syndrome. Herein a cohort of patients with multiple PGLs and their associated PV is described to better characterize the relationship between genotype and tumor burden.
METHODS: All patients diagnosed with multiple PGLs at any anatomical location and underwent genetic testing or counseling for their condition were included. We further evaluated patients with head and neck involvement, including carotid body tumors, jugulotympanic PGLs, and glomus vagale tumors. Patients were evaluated at a single tertiary level cancer center between 2005 and 2021. Eligibility criteria included a PV of an SDH gene (SDHA, SDHB, SDHC, SDHD, or SDHAF2) and the presence of multiple PGLs. There were no age restrictions for participants.
RESULTS: A total of 29 patients were included in the study, of which 51.7% were male and 48.3% were female. The median age of included patients was 46 years (range 18-90 years). The mean number of PGL tumors was 3.6 (range 2-6). Among study participants, 93.1% had a head and neck PGL, with the distribution of types as follows: carotid body 72.4% (n=21), glomus jugulare 34.5% (n=10), glomus vagale 13.8% (n=4), glomus tympanicum 6.9% (n=2), thymus or paratracheal PGL 6.9% (n=2), and glomus faciale 3.4% (n=1). Approximately 55% of patients had multiple tumors confirmed only to the head and neck, but 44.8% (n=13) of patients had a tumor at a distant anatomical site, including: intrabdominal/retroperitoneal 31% (n=9), pelvis 10.3% (n=3), mediastinal 6.9% (n=2), and spine 3.4% (n=1). There were 3 secreting tumors (10.3%), all of which were pheochromocytomas. A total of 7 PGLs (24.1%) were found to be malignant at the following locations: glomus jugulare (n=3), pheochromocytoma (n=3), and carotid body (n=1). A majority of patients with multiple PGLs had the SDHD mutation, accounting for 58.6% (n=17) of patients, with 31% (n=9) of patient with an SDHB mutation and 10.3% (n=3) having an SDHC mutation. Among patients with a malignant tumor, 71.4% (n=5) had an SDHD mutation and 28.6% (n=2) had an SDHB mutation.
CONCLUSION: Using one of the largest single center series with genotype data, this study found that a majority of patients with multiple PGLs have the SDHD mutation, which emphasizes the role of genetic counseling and regular imaging in the management of these patients. Traditionally, SDHB mutations are thought to be the most common mutation in malignant PGLs, however, when multiple PGLs are present, the SDHD mutation is more common. Patients with multiple PGLs and an SDH PV require close clinical follow-up and thoughtful decision-making regarding surgery given the complexity posed by bilateral and secreting PGLs. Given that a majority of patients with multiple PGLs have a head and neck PGL, head and neck surgeons play an important role in the management of their care.