MTC accounts for 2% to 3% of new cases of thyroid cancer diagnosed annually in the United States, though this figure may be an underrepresentation of true incidence caused by changes in diagnostic techniques. The total number of new cases of MTC diagnosed annually in the United States is between 1,000 and 1,200, about 75% of which are sporadic, i.e., they occur in the absence of a family history of either MTC or other endocrine abnormalities seen in MEN 2. The peak incidence of the sporadic form is in the fifth and sixth decades of life.[2,16] A study in the United Kingdom estimated the incidence of MTC at 20 to 25 new cases per year among a population of 55 million.
In the absence of a positive family history, MEN 2 may be suspected when MTC occurs at an early age or is bilateral or multifocal. While small series of apparently sporadic MTC cases have suggested a higher prevalence of germlineRET mutations,[17,18] larger series indicate a prevalence range of 1% to 7%.[19,20] Based on these data, it is widely recommended that RETgene mutation testing be performed for all cases of MTC.[21,22,23,24]
Pheochromocytomas (OMIM) arise from the catecholamine-producing chromaffin cells of the adrenal medulla. They are a relatively rare tumor and are suspected among patients with refractory hypertension or when biochemical screening reveals elevated excretion of catecholamines and catecholamine metabolites (i.e., norepinephrine, epinephrine, metanephrine, and vanillylmandelic acid) in 24-hour urine collections or plasma. In the past, measurement of urinary catecholamines was considered the preferred biochemical screening method. However, given that catecholamines are only released intermittently and are metabolized in the adrenal medulla into metanephrine and normetanephrine, the measurement of urine or plasma fractionated metanephrines has become the gold standard.[25,26,27,28,29,30] When biochemical screening in an individual who has or is at risk for MEN 2 suggests pheochromocytoma, localization studies such as magnetic resonance imaging (MRI) or computed tomography (CT) can be performed. Confirmation of the diagnosis can be made using I131 -metaiodobenzylguanidine (MIBG) scintigraphy or positron emission tomography (PET) imaging.[13,31,32,33]
A diagnosis of MEN 2 is often considered in individuals with bilateral pheochromocytoma, those with an early age of onset (age <35 years), and those with a personal and/or family history of MTC or hyperparathyroidism. However, MEN 2 is not the only genetic disorder that includes a predisposition to pheochromocytoma. Other disorders include neurofibromatosis type 1 (NF1), von Hippel-Lindau disease (VHL), and the hereditary paraganglioma syndromes. A large European consortium that included 271 patients from Germany, 314 patients from France, and 57 patients from Italy (total = 642) with apparently sporadic pheochromocytoma analyzed the known pheochromocytoma/functional paraganglioma susceptibility genes (NF1, RET, VHL, SDHB and SDHD). It should be noted that the diagnosis of NF1 in this series was made clinically, while all other conditions were diagnosed based on the presence of a germline mutation in the causative gene. In 166 (25.9%) patients the disease was, in fact, associated with a positive family history; germline mutations were detected in RET (n = 31), VHL (n = 56), NF1 (n = 14), SDHB (n = 34) or SDHD (n = 31). Rigorous clinical evaluation and pedigree analysis either before or after testing revealed that of those with a positive family history and/or a syndromic presentation, 58.4% carried a mutation, compared with 12.7% who were nonsyndromic and/or had no family history. Of the 31 individuals with a germline RET mutation, 28 (90.3%) had a positive family history and/or syndromic presentation, suggesting that most individuals with RET mutations and pheochromocytoma will have a positive family history or other manifestations of the disease.