Pheochromocytomas
Pheochromocytomas are rare neuroendocrine tumors that primarily develop from the chromaffin cells in the adrenal glands, which are responsible for producing catecholamines like norepinephrine and epinephrine. These tumors can lead to paroxysmal symptoms due to the excessive release of these hormones, resulting in hypertension, headaches, palpitations, and sweating. Pheochromocytomas may occur sporadically or be associated with genetic conditions such as multiple endocrine neoplasia type 2 (MEN 2), von Hippel-Lindau (VHL) disease, and neurofibromatosis type 1 (NF1). Diagnosis typically involves laboratory tests to measure metanephrines and catecholamines in the blood and urine, along with imaging studies like MRI or PET scans to determine tumor location. Treatment usually requires surgical intervention to remove the tumor, and patients may need to manage blood pressure before undergoing surgery. Outcomes can vary, with five-year survival rates for metastatic cases ranging between 34% and 80%. Genetic counseling may be recommended for individuals with a family history of related syndromes.
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Subject Terms
Pheochromocytomas
ALSO KNOWN AS: Chromaffin cell tumors, PCC
RELATED CONDITIONS: Early-onset hypertension, medullary thyroid cancer, multiple endocrine neoplasia type 2 (MEN 2), von Hippel-Lindau (VHL) disease, and neurofibromatosis type 1
DEFINITION: Pheochromocytomas are rare neuroendocrine tumors of the chromaffin cells and neuroendocrine cells of the sympathetic nervous system (SNS). They are primarily located in the medulla of the adrenal glands. Pheochromocytomas secrete catecholamines, hormones such as norepinephrine and epinephrine, contributing to the fight-or-flight stress response.
Extra-adrenal neuroendocrine tumors that arise from the sympathetic and parasympathetic paraganglia are called paragangliomas, which may secrete catecholamines. Sympathetic paragangliomas are catecholamine-secreting tumors, usually in the abdomen, pelvis, or chest, whereas parasympathetic paragangliomas are nonsecreting tumors, usually in the head or neck. Of the catecholamine-secreting tumors, most originate in the adrenal medulla (pheochromocytoma), while a small percentage originate in the extra-adrenal chromaffin tissue (sympathetic paraganglioma). Pheochromocytomas and paragangliomas may be benign or malignant.
Risk factors: The risk factors for most cases of pheochromocytomas are unknown, and pheochromocytomas may be sporadic or familial. In cases where there is a family history of the disease, the primary risk factor is having a parent who had pheochromocytoma, paraganglioma, or related syndromes such as Von Hippel-Lindau (VHL) disease and multiple endocrine neoplasia type 2 (MEN 2). Inheritance is by the autosomal dominant mechanism. A person with these diseases has a 50 percent chance of passing an abnormal gene and the associated disease to their child.
Etiology and the disease process: Approximately 10 to 35 percent of pheochromocytomas have a genetic etiology and are associated with specific syndromes such as MEN 2, VHL disease, and neurofibromatosis type 1 (NF1).
The MEN syndromes make certain endocrine glands become overactive. MEN 2A carries an increased risk for pheochromocytomas, in early adulthood, and hyperparathyroidism, while MEN 2A involves a high risk for pheochromocytomas, medullary thyroid cancer in early childhood, and parathyroid adenoma.
Von Hippel-Lindau disease is characterized by hemangioblastomas of the brain, eye, and spinal cord, renal cell cancer, and pheochromocytomas. The VHL gene on chromosome 3 normally functions in protein degradation and inhibits uncontrolled cell proliferation. Mutations result in tumor growth.
Neurofibromatosis type 1 is a neurocutaneous disorder characterized by changes in skin pigmentation and neurofibromas of the skin, brain, and nerves. Malignant connective or other soft-tissue neoplasms are common—mutations of the NF1 gene cause neurofibromatosis type 1. The NF1 gene is a tumor suppressor. Located on chromosome 17, this gene can undergo mutations that result in abnormal cell growth and tumor formation.
Mutations of the MAX gene on chromosome 14 and the TMEM127 gene on chromosome 2 also increase the risk of developing pheochromocytomas.
Incidence: The rate of occurrence of pheochromocytoma is 2 to 8 per million persons annually in the United States. Most patients are about twenty-five at diagnosis in hereditary cases and forty-four in sporadic cases. Additional occurrences have been detected on autopsy. In patients with hypertension, the prevalence is approximately 0.1 to 0.6 percent.
Symptoms: Pheochromocytoma and sympathetic paraganglioma are related to elevated levels of catecholamines and metanephrines. Since pheochromocytomas release these agents intermittently, symptoms are paroxysmal. The most common symptoms include autonomic disturbances such as hypertension, headache, tachycardia, palpitations, pallor, and sweating. Other common symptoms include headache, flushing of the face, nausea and vomiting, chest pain, anxiety, nervousness, and panic.
Screening and diagnosis: Detection of a pheochromocytoma can involve multiple and repeated testing, which can be time-consuming and expensive. The failure to detect the presence of a pheochromocytoma can be life-threatening to the individual. Pheochromocytoma is suspected in patients who have volatile or therapy-resistant hypertension, a family history of genetic syndromes associated with pheochromocytoma, or sudden panic attacks.
Laboratory evaluation includes urine and blood sampling. Urinary tests are done for the presence of metanephrines and vanillylmandelic acid (VMA). Plasma measurements are done for metanephrines and catecholamines. Urine testing is less sensitive and specific than blood tests.
Metanephrines (normetanephrine and metanephrine) are metabolites of norepinephrine and epinephrine, the catecholamines normally secreted by the adrenal medulla but with increased levels in pheochromocytoma. A negative test reliably excludes the presence of pheochromocytoma and avoids the sometimes false negative results obtained when plasma catecholamine values are obtained. Generally, a negative metanephrine plasma test precludes further testing. Accurate evaluation requires the avoidance of caffeine and acetaminophen before testing.
When laboratory methods diagnose a pheochromocytoma, radiological evaluation helps identify the location and extent of any tumors. Magnetic resonance imaging (MRI), metaiodobenzylguanidine (MIBG) scintigraphy, and positron emission tomography (PET) scanning are the most reliable.
Treatment and therapy: Treatment of benign and malignant pheochromocytomas is by surgical removal, either through a traditional open incision or by laparoscopic techniques using several small incisions, a small camera, and long instruments. Before surgery, catecholamine-induced symptoms must be controlled to prevent life-threatening complications during surgery. Medications to stabilize the patient's blood pressure should be taken approximately two weeks before surgery. If only one adrenal gland is affected, typically, the entire gland is removed in an adrenalectomy. When bilateral involvement is present, attempts may be made to salvage the adrenal cortex. If this is not possible, lifelong adrenal medication supplementation will be required. Future drugs may prevent endocrine gland overactivity and inhibition of angiogenic factors.
In patients with metastatic pheochromocytomas, a regimen of cytoreductive resection; combination chemotherapy with cyclophosphamide, vincristine, and dacarbazine; and iodine 131-metaiodobenzylguanidine (131I-MIBG) radiation therapy may be utilized.
Prognosis, prevention, and outcomes: Some patients with pheochromocytomas have a genetic basis for associated syndromes, making them candidates for genetic counseling and chromosomal analysis. Surgical removal of the pheochromocytoma alleviates symptoms related to sympathetic nervous system involvement. Early and consistent screening for medullary thyroid cancer leads to diagnosis and treatment in earlier stages, making a cure more possible. Total thyroidectomy prevents thyroid cancer but requires the patient to undergo lifelong thyroid medication supplementation. The five-year survival rate for metastatic pheochromocytomas varies from 34 to 80 percent.
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