What is the risk of metastasis for patients with the SDHD mutation and paraganglioma?

Paragangliomas (PGLs) are rare tumors that grow from nerve tissue, often near the carotid arteries or adrenal glands. Some are linked to inherited gene changes, including mutations in the SDHD gene. The question is: if someone has an SDHD mutation and develops a paraganglioma, how likely is that tumor to spread (metastasize) to other parts of the body? The best available evidence suggests the metastatic risk for SDHD-related tumors is low, roughly 4%, which is much lower than for tumors linked to the SDHB gene ⁶. However, this is based on limited data, and individual risk can vary.

What the research says

A 2020 systematic review and meta-analysis of 27 studies looked specifically at metastatic risk in people with SDHx mutations who had pheochromocytoma or paraganglioma (PPGL). It found that the SDHD mutation carried the lowest risk of metastasis, about 4%, compared with SDHB mutations, which had a metastatic risk ranging from 12% to 41% ⁶. The same review noted that SDHD mutations were also less common among PPGL patients, with a prevalence of 6% to 8%, compared with 23% to 31% for SDHB ⁶. This suggests that while SDHD mutations do cause tumors, they are less likely to spread than SDHB-related tumors.

A separate systematic review and meta-analysis focused on SDHD variant carriers found that penetrance (the chance of developing any tumor) rises with age: 20% by age 20, 58% by age 40, and 82% by age 60 ⁵. That review also examined metastatic disease among affected carriers, though the abstract does not provide a single pooled metastatic rate in the text available. It does note that some specific SDHD variants may be linked to multifocal tumors or metastatic behavior, meaning not all SDHD mutations carry the same risk ⁵.

Other research on paragangliomas more broadly shows that certain tumor features can raise metastatic risk regardless of the underlying mutation. A retrospective study of 103 PGL patients found that necrotic alterations (areas of dead tissue inside the tumor) were linked to a much higher metastasis rate: 75% versus 10% in tumors without necrosis ². A meta-analysis in that same paper confirmed this, with metastasis rates of 16% versus 4.5% for necrotic versus non-necrotic tumors ². This matters because it means tumor appearance on imaging or pathology can add important information beyond just the SDHD status.

Finally, a 2018 review on the pathology and genetics of pheochromocytoma and paraganglioma emphasizes that all these tumors have some metastatic potential, so doctors no longer use the terms benign and malignant. Instead, they use risk stratification, looking at features like high cell division, invasive growth, and large tumor nests to estimate risk ⁸. For SDHD specifically, the metastatic risk appears low, but it is not zero, and no single risk scheme is universally endorsed ⁸.

What to ask your doctor

• What is my specific SDHD variant, and does it carry a higher or lower risk of metastasis based on current data?
• How will my tumor be monitored over time for possible spread, and what imaging or tests should I expect?
• Do features like tumor necrosis or size change my risk estimate, and how do they factor into my follow-up plan?
• Are there other family members who should consider genetic testing for SDHD, given the inherited nature of this mutation?
• Should I see a specialist (such as an endocrinologist or genetic counselor) who regularly manages SDHD-related tumors?