What are pheochromocytomas?

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, neuroendocrine cells of the sympathetic nervous system (SNS). Their primary
location is in the medulla of the adrenal glands. Pheochromocytomas
secrete catecholamines, hormones such as norepinephrine and
epinephrine that contribute to the fight-or-flight stress
response.

Extra-adrenal neuroendocrine tumors that arise from the sympathetic and
parasympathetic paraganglia are called paragangliomas, which may or may not
secrete catecholamines. Sympathetic paragangliomas are catecholamine-secreting
tumors and are usually located in the abdomen, pelvis, or chest, whereas
parasympathetic paragangliomas are nonsecreting tumors and are usually located in
the head or neck. Of the catecholamine-secreting tumors, 80 to 85 percent
originate in the adrenal medulla (pheochromocytoma) and 10 to 20 percent originate
in the extra-adrenal chromaffin tissue (sympathetic paraganglioma).
Pheochromocytomas and paragangliomas may be benign or malignant.

Risk factors: The risk factors for the majority of the cases of
pheochromocytomas are unknown, and pheochromocytomas may be sporadic or familial.
However, 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, so a person with these diseases has a 50 percent chance of passing an
abnormal gene and therefore the associated disease to his or her child.

Etiology and the disease process: Approximately 25 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, medullary thyroid cancer 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 located 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 as well as 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 between 1 in
6,500 and 1 in 2,500 people. In the United States, the occurrence rate is between
500 and 1,600 cases per year. Additional occurrences have been detected on
autopsy. In patients with hypertension, the prevalence is approximately 0.1
percent to 0.6 percent.

Symptoms: Symptoms of 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. In addition, headache,
flushing of the face, nausea and vomiting, chest pain, and anxiety, nervousness,
and panic are often noted.

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 a 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 a pheochromocytoma is diagnosed by laboratory methods, 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 methods of choice.

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. Prior to 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 for
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. It is possible that in the
future, drugs will be developed to 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: Since about 15 percent of
patients with pheochromocytomas have a genetic basis for associated syndromes,
they are candidates for genetic counseling and chromosomal
analysis. Surgical removal of the pheochromocytoma alleviates symptoms associated
with sympathetic nervous system involvement. Early and consistent screening for
medullary thyroid cancer development leads to diagnosis and treatment in earlier
stages of the disease, 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 is
about 50 percent.

Benn, Diana E., et
al. “Clinical Presentation and Penetrance of Pheochromocytoma/Paraganglioma
Syndromes.” Journal of Clinical Endocrinology and
Metabolism 91.3 (2005): 827–36. Print.

Giubellino, Alessio, et al. "High-Throughput
Screening for the Identification of New Therapeutic Options for Metastatic
Pheochromocytoma and Paraganglioma." PLoS ONE 9.4 (2014):
1–11. Web. 9 Dec. 2014.

Lenders, Jacques W. M., et al.
"Pheochromocytoma and Paraganglioma: An Endocrine Society Clinical Practice
Guideline." Journal of Clinical Endocrinology and
Metabolism 99.6 (2014): 1915. Web. 9 Dec. 2014.

Neumann, Hartmut
P., B. Bausch, et al. “Germ-Line Mutations in Nonsyndromic
Pheochromocytoma.” New England Journal of Medicine 346
(2002): 1459–66. Print.

Neumann, Hartmut
P., A. Vortmeyer, et al. “Evidence of MEN-2 in the Original Description of
Classic Pheochromocytoma.” New England Journal of Medicine
357 (2007): 1311–15. Print.

Scholz, Tim, et al.
“Current Treatment of Malignant Pheochromocytoma.” Journal of
Clinical Endocrinology and Metabolism 92.4 (2006): 1217–25.
Print.

Vogel, Jennifer, et al. "External Beam
Radiation Therapy in Treatment of Malignant Pheochromocytoma and
Paraganglioma." Frontiers in Oncology 4 (2014): 1–8. Web. 9
Dec. 2014.