Abstract
Simple SummaryPheochromocytoma and paraganglioma (together PPGL) are rare neuroendocrine tumors that arise from chromaffin tissue and produce catecholamines. Approximately 40% of cases of PPGL carry a germline mutation, suggesting that they have a high degree of heritability. The underlying mutation influences the PPGL clinical presentation such as cell differentiation, specific catecholamine production, tumor location, malignant potential and genetic anticipation, which helps to better understand the clinical course and tailor treatment accordingly. Genetic testing for pheochromocytoma and paraganglioma allows an early detection of hereditary syndromes and facilitates a close follow-up of high-risk patients. In this review article, we present the most recent advances in the field of genetics and we discuss the latest guidelines on the surveillance of asymptomatic SDHx mutation carriers.Pheochromocytomas (PHEOs) and paragangliomas (PGLs) are rare neuroendocrine tumors that arise from chromaffin cells. PHEOs arise from the adrenal medulla, whereas PGLs arise from the neural crest localized outside the adrenal gland. Approximately 40% of all cases of PPGLs (pheochromocytomas/paragangliomas) are associated with germline mutations and 30–40% display somatic driver mutations. The mutations associated with PPGLs can be classified into three groups. The pseudohypoxic group or cluster I includes the following genes: SDHA, SDHB, SDHC, SDHD, SDHAF2, FH, VHL, IDH1/2, MHD2, EGLN1/2 and HIF2/EPAS; the kinase group or cluster II includes RET, NF1, TMEM127, MAX and HRAS; and the Wnt signaling group or cluster III includes CSDE1 and MAML3. Underlying mutations can help understand the clinical presentation, overall prognosis and surveillance follow-up. Here we are discussing the new genetic insights of PPGLs.
Highlights
Pheochromocytomas (PHEOs) and paragangliomas (PGLs) are rare neuroendocrine (NE) tumors arising from chromaffin cells of the adrenal medulla and extra-adrenal ganglia, respectively
40% of all cases of PPGLs are associated with germline mutations, which makes pheochromocytoma and paraganglioma solid tumors with a high heritability rate
Vanova et al [44] tested 352 patients with apparently sporadic PPGL, using a 54-gene panel developed at the National Institutes of Health that included SUCLG2, and found that 15 patients had eight germline variants located within the GTP-binding domain of SUCGL-2
Summary
Pheochromocytomas (PHEOs) and paragangliomas (PGLs) are rare neuroendocrine (NE) tumors arising from chromaffin cells of the adrenal medulla and extra-adrenal ganglia, respectively. The incidence of PHEOs and PGLs (collectively PPGLs) is estimated at approximately 2–8 cases per million per year [1,2]. This is likely an underestimate, based upon the finding of up to 0.05–0.1% incidentally detected cases in an autopsy series [3]. Patients with PPGL most commonly present with symptoms of excess catecholamine production including headache, diaphoresis, palpitations, tremors, facial pallor and hypertension. These symptoms are often paroxysmal, persistent hypertension between these episodes is common and occurs in 50–60% patients with PPGL [5]. We summarize the latest guidelines by Amar et al for the diagnosis and surveillance of asymptomatic SDHx mutation carriers [21]
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