Advances in genetics and recognition of a high prevalence of pheochromocytoma in certain familial syndromes is now making it mandatory for routine screening of the tumor in patients with identified mutations, even in the absence of normally considered clinical signs and symptoms. Accumulating data also indicates that many more pheochromocytomas are due to germ-line mutations than previously recognized, raising the importance of considering an underlying hereditary condition even when there is no obvious familial condition.
Mutations in six genes to date have been identified to be responsible for familial phaeochromocytomas/paragangliomas: 1. the von Hippel-Lindau (VHL) gene leading to VHL syndrome; 2. the RET gene leading to multiple endocrine neoplasia type 2; 3. the neurofibromatosis type 1 (NF-1) gene associated with von Recklinghausen’s disease; and 4 and 5. mutations of genes encoding the B, C, and D subunits of mitochondrial succinate-dehydrogenase (SDHB, SDHC, and SDHD) associated with familial paragangliomas and pheochromocytomas.
Mutation testing, now routinely available for four of the above genes (RET, VHL, SDHB, and SDHD), demonstrates that germline mutations are responsible for at least 20 to 30% of all pheochromocytomas, well in excess of the 10% of tumors previously thought to be hereditary . Most importantly, between 12-24% of tumors with no obvious syndrome or family history appear to be due to otherwise unsuspected germline mutations in one of the above four genes. It has therefore been suggested that mutation testing should be considered in all patients with pheochromocytoma, independently of the presence of any obvious syndrome or family history.
Approximately 50% of patients with MEN 2A or -2B develop pheochromocytoma, usually following the manifestation of medullary thyroid cancer, which has a higher penetrance. Pheochromocytomas in MEN 2A are most often diagnosed between 30-40 years of age are almost exclusively benign (with less than 5% reported to be malignant) and localized to the adrenals . The risk for development of pheochromocytoma is the highest in codon 634 mutation . In MEN 2B germline ret mutations represented by a single methionine to threonine substitution at codon 918 in exon 16 of ret, the tyrosine kinase domain, is associated with the development of pheochromocytoma . About one third are bilateral at diagnosis, and about 50% of patients with unilateral disease, develop a second pheochromocytoma in the contralateral adrenal within 10 years. Prognosis is good after surgical resection. Due to the rarity of the condition, there are no adequate data to reliably assess survival of MEN 2 patients with malignant pheochromocytoma. In children with MEN 2B-associated pheochromocytomas, a higher risk of malignancy compared to MEN 2A or sporadic disease is found.
On average about 10 to 20% of patients with VHL disease develop pheochromocytoma, but this incidence varies dramatically from family to family depending on the specific mutation . The mean age at diagnosis is 28 years, and in about 50% of cases pheochromocytomas are bilateral. Most vhl mutations associated with pheochromocytoma also predispose to renal cell carcinoma .
Although neurofibromatosis type 1 as an autosomal dominant disorder is the most common familial cancer syndrome predisposing to pheochromocytoma, the risk of pheochromocytoma in this disorder is about 1% . Pheochromocytomas in patients with neurofibromatosis type 1 occur at the fifth decade.
Mutations of genes encoding SDHB, SDHD, and rarely SDHC are the most recently identified genetic causes of paraganglioma . Mutations of both genes are associated with relatively high rates of extra-adrenal compared to adrenal tumors, but SDHB mutations appear to be associated with more aggressive tumor behavior and a higher rate of malignancy . In several separate studies, malignant disease was found in 38% and 83% of patients with tumors associated with germline SDHB mutations . These are much higher rates compared with catecholamine-producing tumors due to other mutations or in patients with sporadic adrenal paragangliomas where rates of malignancy are less than 10%.
At the First International Symposium on Pheochromocytoma held in Bethesda, USA a panel of experts convened to outline recommendations for genetic testing agreed that there is now a reasonable argument for more widespread genetic testing than would have been previously considered. It is neither appropriate nor currently cost-effective to test every disease-causing gene in every patient with a pheochromocytoma. Rather, it was stressed that the decision to test and which genes to test requires judicious consideration of numerous factors. The importance of a complete clinical work-up and a specialized genetic consultation to collect family history, outline potential repercussions of genetic testing, and obtain appropriate informed consent was outlined as of paramount importance to any decision about genetic testing. Since hereditary tumors usually occur at a younger age than sporadic tumors, age at presentation was also outlined as an important consideration for the likelihood of an underlying mutation. A hereditary basis is particularly important to consider in children with pheochromocytoma. Recent papers suggested that patients younger than 50 years old should undergo genetic testing .
Apart from the obvious clinical manifestations that may indicate a specific hereditary syndrome (e.g. medullary thyroid cancer in patients with MEN 2), the decision to test a particular gene can also benefit from consideration of tumor location, the presence of metastases and the type of catecholamine produced by the tumor. Pheochromocytomas in patients with RET mutations invariably have an adrenal location, very rarely present with malignant disease, and are always associated with increases in plasma levels or urinary excretion of metanephrine, the metabolite of epinephrine. Such increases may occur with or without parallel increases in normetanephrine. This biochemical pattern reflects expression of phenylethanolamine-N-methyltransferase (PNMT), the enzyme that converts norepinephrine to epinephrine. This contrasts with pheochromocytomas in patients with VHL gene mutations, which do not express PNMT, and which consequently do not produce epinephrine. Pheochromocytomas in this setting are therefore characterized by increases in plasma or urinary normetanephrine and normal levels of metanephrine. Similar to pheochromocytomas in MEN 2, malignant disease is rare and a bilateral adrenal tumors are relatively common. Relative to patients with RET mutations, extra-adrenal tumors in VHL patients are, however, more common.
Although mutations of SDHB and SDHD genes are occasionally associated with solitary adrenal tumors, patients with these mutations most commonly present with extra-adrenal pheochromocytomas, often with multifocal disease. Patients with these mutations may also present with head and neck paragangliomas without biochemical evidence or signs and symptoms of a catecholamine-producing tumor. Testing for SDHD and SDHB gene mutations in patients with extra-adrenal tumors can therefore be particularly revealing; furthermore, because SDHB mutations carry a high risk for malignant disease, testing for such mutations in patients with metastases, especially from an extra-adrenal paraganglioma, is particularly warranted.