Pheochromocytomas are catecholamine-secreting tumors that arise from chromaffin cells in the adrenal medulla or extra-adrenal sympathetic ganglia. These tumors constitute a surgically correctable cause of hypertension in 0.1% to 1% of hypertensive persons.
Only about 10% of pheochromocytomas are considered to be malignant. The vast majority (90%) of pheochromocytomas are found in the adrenal medulla, and 97% are located below the diaphragm. Approximately 10% of pheochromocytomas are either bilateral, malignant, multifocal, extra-adrenal, found in children, or associated with a familial syndrome.
Pheochromocytomas in patients with familial syndromes, such as MEN-2 and von Hippel-Lindau syndrome, are less likely to be malignant than are other adrenal lesions. In contrast, pheochromocytomas in patients with a family history of malignant pheochromocytoma are more apt to be malignant.
Pheochromocytomas occur in all age groups, but the incidence peaks in the third to fifth decades of life. Most pheochromocytomas (90%) are sporadic. Approximately 10% of cases are inherited as an autosomal-dominant trait, either independently or as a part of the MEN-2 syndrome; bilateral tumors are more common in this setting.
Both MEN-2A and MEN-2B include medullary thyroid carcinoma and pheochromocytoma. MEN-2A includes hyperparathyroidism, whereas MEN-2B includes ganglioneuromas and marfanoid habitus. In MEN-2 families, pheochromocytoma occurs in 5.5% to 100% (mean, 40%), depending on the kindred studied. Bilateral medullary hyperplasia is almost always present. Pheochromocytomas are bilateral in 70% of cases and usually multicentric, but they are rarely extra-adrenal or malignant. Genetic testing is recommended for patients suspected of having MEN-2.
Patients can present with various symptoms, ranging from mild labile hypertension to hypertensive crisis, myocardial infarction, or cerebral vascular accident, most of which can result in sudden death. The classic pattern of paroxysmal hypertension occurs in 30% to 50% of cases; sustained hypertension may also occur and resembles essential hypertension. A characteristic presentation includes "spells" of paroxysmal headaches, pallor or flushing, tremors, apprehension, palpitations, hypertension, and diaphoresis.
The diagnosis of pheochromocytoma relies on an appropriate history and documentation of excessive catecholamine production.
Measurement of 24-hour urinary catecholamines and their metabolites, vanillylmandelic acid and metanephrine, is commonly done; the metanephrine level is considered to be the most specific single test. Serum catecholamine measurements are more susceptible to false elevations due to stress-related physiologic fluctuations. The evaluation of serum catecholamines after clonidine suppression, however, provides a useful diagnostic tool that is more convenient than urine collection. Dynamic provocative tests are rarely indicated. Recently, the measurement of plasma-free metanephrines has been shown to be an excellent test for excluding or confirming pheochromocytoma.
Almost all pheochromocytomas are localized in the abdomen, mostly in the adrenal medulla; other locations include the posterior mediastinum or any distribution of the sympathetic ganglia. After the diagnosis is established biochemically, radiologic methods may be needed for preoperative localization of the lesion; CT and MRI are most widely used. A 131 iodine-metaiodobenzylguanidine (MIBG) scan and somatostatin(Drug information on somatostatin) receptor scintigraphy (SRS) provide "functional" images; they are most helpful in the detection of occult contralateral or extra-adrenal lesions.
Differentiating benign from malignant tumors
The histologic differentiation between benign and malignant lesions is extremely difficult and often impossible to make; this distinction may require the development of lymph node, hepatic, bone, or other distant metastases. Recurrent symptoms of pheochromocytoma, often emerging many years after the original diagnosis, are suggestive of malignancy. Biochemical confirmation of recurrent catecholamine hypersecretion and localization of metastatic lesion(s) with 131 iodine-MIBG scan constitute diagnostic proof.
Preoperative medical management
Phenoxybenzamine (Dibenzyline), an oral, long-acting, noncompetitive alpha-adrenoceptor blocker, is a helpful, widely used first drug; it is given at a dose of 10–40 mg/day. Propranolol, a beta-blocker (20–80 mg/day), is usually added after a few days to prevent tachycardia or arrhythmia. The use of beta-blockers alone is hazardous, because it may precipitate a paradoxical rise in blood pressure. The tyrosine hydroxylase inhibitor metyrosine (Demser) may be added in patients whose blood pressure is not well controlled with the combination of an alpha-blocker and a beta-blocker.
The principles of pheochromocytoma resection are complete tumor resection, avoidance of tumor seeding, and minimal tumor manipulation. Adrenalectomy can be performed by means of an open anterior transabdominal, open posterior retroperitoneal, laparoscopic lateral transabdominal, or laparoscopic posterior retroperitoneal approach. In the past, an open anterior approach was the standard, because it allowed for complete exploration and inspection of potential tumor foci. However, with the improved accuracy of preoperative imaging and increased experience with laparoscopic procedures, there is little need for exploration in areas in which a tumor has not been identified.
Except in tumors > 6 cm, the laparoscopic approach to pheochromocytoma is probably the technique of choice. In the absence of obvious local tumor invasion or metastatic disease, a laparoscopic procedure is acceptable to many experienced endocrine surgeons.
The most critical intraoperative aspect of surgery is control of blood pressure immediately after removal of the tumor, when all agonistic effects are abolished and the effects of alpha- and beta-blockers are still present. Close cooperation with the anesthesiologist to expand fluid volume and prepare the appropriate infusions of agonists to support vascular stability is critical.
Treatment of metastatic malignant pheochromocytoma
The treatment of choice for metastatic malignant pheochromocytoma remains problematic.
Medical and radiation therapy. Medical therapy with alpha- or beta-blockers, as well as metyrosine, is almost always required to maintain hemodynamic stability. Chemotherapy using streptozocin-based regimens or the combination of cyclophosphamide, vincristine, and dacarbazine(Drug information on dacarbazine) has yielded promising responses. Treatment with 131-iodine-MIBG or with radiolabeled somatostatin (in Europe) has met with only limited success; however, clinical trials continue to investigate these approaches. In most cases, uncontrolled catecholamine hypersecretion eventually escapes biochemical blockade and fatal hypertensive crises ensue.
Surgery. In cases in which limited and resectable lesions can be identified, surgery can effect complete and lasting remission of the disease.