Pheochromocytomas are tumors of the neural crest-derived chromaffin cells. The hallmark of this rare and fascinating neoplasm is the synthesis and secretion of catecholamines in an unregulated and potentially life-threatening manner. Most pheochromocytomas produce an abundance of norepinephrine. Epinephrine- or dopamine-secreting pheochromocytomas are less common. Pheochromocytomas can also be nonfunctional. Approximately 10% of pheochromocytomas can be categorized as either bilateral, multifocal, extra-adrenal, familial, or malignant; thus, pheochromocytomas are often remembered by medical students as the "10% tumor." Newer reports, however, suggest that pheochromocytomas may be extra-adrenal in up to 30% of cases.[2,3] This brief review will address the diagnosis and management of benign and malignant pheochromocytoma.
Pheochromocytomas can occur sporadically or with syndromic associations. The vast majority—approximately 90%—are believed to be sporadic. Familial syndromes associated with pheochromocytomas include multiple endocrine neoplasia (MEN) types 2A and 2B, von Recklinghausen's neurofibromatosis (NF1), and von Hippel-Lindau disease (VHL). Pheochromocytomas in patients with familial syndromes are unlikely to be malignant.[4,5] Pheochromocytomas may also accompany nonfamilial syndromes such as Sturge-Weber syndrome, tuberous sclerosis, and Carney's triad.
The genetic basis of the MEN2 syndromes has been identified as a germline mutation in the RET proto-oncogene. Germline mutations in the tumor-suppressor genes NF1 and VHL are responsible for their respectively named syndromes. In some cases of familial pheochromocytoma, somatic mutations in the succinate dehydrogenase subunit B (SDHB), C (SDHC), and D (SDHD) have been identified. These advances make possible the genetic screening of individuals at risk of inheriting a pheochromocytoma related syndrome.
The incidence of pheochromocytoma is believed to be approximately 2 cases per 1 million persons per year in the United States. In hypertensive patients the prevalence is higher: 0.1% to 1%. In autopsy series, a prevalence between 0.3% and 0.95% has been found. In biochemical screening series, the prevalence has been reported to be as high as 1.9%.
The hallmark of pheochromocytoma is hypertension, which may occur in paroxysms against a backdrop of normal blood pressure, or the patient my have baseline hypertension with or without paroxysms of more extreme hypertension. Patients may even be identified with only occult disease (incidentaloma), or they may present with florid hypertensive crisis and multisystem organ failure. The classic triad of symptoms is relatively nonspecific and consists of headache, palpitations, and diaphoresis. Symptoms are often paroxysmal and usually last no longer than 15 minutes. Episodes have been found to increase in severity and frequency as the disease progresses. When the classic triad of symptoms is found in a patient with paroxysms of hypertension, the diagnosis of pheochromocytoma is likely, and work-up must be initiated.
Biochemical testing should be performed on all patients who display the classic paroxysmal triad. Incidentally found adrenal tumors (incidentalomas) also require a work-up for pheochromocytoma and other functioning adrenal neoplasms. Screening tests should be considered for patients with a history of hypertension that is extraordinarily labile or unresponsive to antihypertensive therapy, new-onset hypertension during pregnancy or childhood, or a family history of pheochromocytoma or syndromes associated with pheochromocytoma (as discussed earlier). Biochemical testing should always precede localization studies.
Once pheochromocytoma is suspected, biochemical tests are used to establish the diagnosis. Fine-needle aspiration (FNA) biopsy has no role in this setting and should not be attempted for adrenal neoplasms unless pheochromocytoma has been ruled out. FNA cannot distinguish benign from malignant pheochromocytoma. This practice is very hazardous and should be strongly discouraged because it may precipitate a potentially fatal hypertensive crisis. The proper sequence of tests should be history and physical exam followed by biochemical confirmatory testing, pharmacologic adrenergic blockade, and subsequent localization.
There is no consensus on the best test for screening and diagnosis. The combination of 24-hour urinary vanillylmandelic acid (VMA) test and metanephrines has historically been used in many institutions. When either test is abnormal, the addition of confirmatory 24-hour fractionated urinary catecholamines should yield an accuracy of approximately 98%.[12,13] A large number of disease states and dietary or pharmacologic substances can interfere with these biochemical studies. More detailed texts on the subject should be consulted for a complete discussion of factors leading to a misleading biochemical test for pheochromocytoma. Most patients with true pheochromocytoma have urinary catecholamine levels that are two to three times higher than the upper limit of the normal reference range. In the case of equivocal results, the clonidine suppression test may help make the diagnosis.
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