Why Genetics Should Guide Treatment for Pediatric Paragangliomas
Most pediatric paragangliomas are driven by inherited mutations, making genetic testing essential for guiding treatment and assessing metastatic risk.
Paragangliomas, rare tumors that can form in the head and neck, often have a genetic origin. Yet physicians don’t routinely identify the mutations responsible for them. A University of Miami Miller School otolaryngologist wants to change that.
At the North American Skull Base Society meeting in San Diego, Simon Angeli, M.D., a professor of otolaryngology — head and neck surgery and neurosurgery and director of the UHealth Ear Institute, made the case that identifying those mutations should be standard practice from the moment of diagnosis. His presentation on March 7 focused on the pediatric population, where genetic factors are especially prevalent.
“By doing genetic testing, you’re personalizing the management by giving each individual patient the appropriate treatment for his or her tumor,” he said. “You don’t overtreat patients that don’t need the tumor removed, and you can treat aggressively those with a high risk of metastatic disease.”
Most Pediatric Paragangliomas Have a Genetic Cause
In the head and neck, paragangliomas typically arise along the great vessels, such as the carotid artery, and the cranial nerves. In the torso, they often occur in the adrenal glands and mediastinum.
Researchers have linked mutations in roughly a dozen genes to paraganglioma risk, and these defects are present in many children. One study of 55 pediatric patients found that 80 percent had heritable mutations known to drive paragangliomas. Changes in the SDHB and VHL genes were most common.
Dr. Angeli argues that genetic testing is warranted for adults and children alike.
“People are becoming more aware that these tumors can be genetic even when there’s not a family history,” he said.
That awareness matters because family history is an unreliable indicator of a patient’s genetic status. Mutations can arise spontaneously and a heritable predisposition doesn’t guarantee that relatives will develop tumors, for instance. In a retrospective review of 211 patients with head and neck paragangliomas, Dr. Angeli and colleagues found that 76 percent of those who tested positive for genetic defects lacked a family history.
How Tumor Genetics Predict Metastatic Risk
Paragangliomas are not classified as cancerous, but they can metastasize. Since a tumor’s genetic profile can signal whether it will spread, genotyping can guide treatment decisions that could prevent metastasis before it occurs.
A certain defect in the succinate dehydrogenase complex present particular cause for concern. Mutations in its B subunit, for example, carry a significantly elevated risk of metastatic disease.
“When we identify those mutations, we tend to be more proactive in terms of surgery,” he said.
In general, defects in other SDH subunits indicate less aggressive disease.
There is a caveat, however. What we know about hereditary paragangliomas derives from only a few European and North American studies. Evidence of ethnic differences indicates treatment recommendations should be ethnicity-specific, according to Dr. Angeli.
Recent investigations by his team have shown that these tumors in South Florida Hispanics tend to have a different genetic profile and tumor behavior than what has been reported in other populations.
When a tumor’s genetic profile suggests lower metastatic risk, less invasive approaches become viable. Slow-growing tumors, including those without identifiable mutations, may warrant observation alone, though Dr. Angeli notes that option is less often appropriate for children, given their longer life expectancy. Radiation therapy is typically reserved for controlling the progression of slow-growing tumors that have not yet significantly interfered with the cranial nerves.
A mutation in the VHL gene introduces a different issue. Associated with Von Hippel–Lindau disease, it indicates a likelihood of tumors elsewhere in the body, even when the patient is otherwise asymptomatic.
Implications for Families and Long‑Term Care
A genetic result does not end with the patient. Dr. Angeli routinely offers testing to first-line relatives, who may be carrying the same mutation without knowing it. The goal is to catch tumors early, when they are small and more easily removed.
“Then you’re done with it, without waiting for the tumor to grow, and for the patient to need a bigger surgery and with more risks,” he said.
Genetic testing for paragangliomas is not new. But Dr. Angeli noted that its adoption has been uneven.
“It’s been around for five to 10 years, but not everybody is using it,” Dr. Angeli said. “The advantages of knowing this information about a tumor before offering treatment are becoming more and more evident.”
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Tags: Dr. Simon Angeli, Skull-base surgery, UHealth Ear Institute