Pheochromocytoma

A pheochromocytoma or phaeochromocytoma (PCC) is a neuroendocrine tumor of the medulla of the adrenal glands (originating in the chromaffin cells), or extra-adrenal chromaffin tissue that failed to involute after birth and secretes excessive amounts of catecholamines, usually noradrenaline (norepinephrine), and adrenaline (epinephrine) to a lesser extent. Extra-adrenal paragangliomas (often described as extra-adrenal pheochromocytomas) are closely related, though less common, tumors that originate in the ganglia of the sympathetic nervous system and are named based upon the primary anatomical site of origin.

Signs and symptoms
The signs and symptoms of a pheochromocytoma are those of sympathetic nervous system hyperactivity, including:
 * Skin sensations
 * Flank pain
 * Elevated heart rate
 * Elevated blood pressure, including paroxysmal (sporadic, episodic) high blood pressure, which sometimes can be more difficult to detect; another clue to the presence of pheochromocytoma is orthostatic hypotension (a fall in systolic blood pressure greater than 20 mmHg or a fall in diastolic blood pressure greater than 10 mmHg upon standing)
 * Palpitations
 * Anxiety often resembling that of a panic attack
 * Diaphoresis (excessive sweating)
 * Headaches
 * Pallor
 * Weight loss
 * Localized amyloid deposits found microscopically
 * Elevated blood glucose level (due primarily to catecholamine stimulation of lipolysis (breakdown of stored fat) leading to high levels of free fatty acids and the subsequent inhibition of glucose uptake by muscle cells. Further, stimulation of beta-adrenergic receptors leads to glycogenolysis and gluconeogenesis and thus elevation of blood glucose levels).

A pheochromocytoma can also cause resistant arterial hypertension. A pheochromocytoma can be fatal if it causes malignant hypertension, or severely high blood pressure. This hypertension is not well controlled with standard blood pressure medications.

Not all patients experience all of the signs and symptoms listed. The most common presentation is headache, excessive sweating, and increased heart rate, with the attack subsiding in less than one hour.

Tumors may grow very large, but most are smaller than 10 cm.

Statistics

 * About 10% of adrenal cases are bilateral (suggesting hereditary disease)
 * About 10% of adrenal cases occur in children (also suggesting hereditary disease)
 * About 15% are extra-adrenal (located in any orthosympathetic tissue): of these 9% are in the abdomen and 1% are located elsewhere. Some extra-adrenal pheochromocytomas are probably actually paragangliomas, but the distinction is only possible after surgical resection.
 * About 11.1% of adrenal cases are malignant, but this rises to 30% for extra-adrenal cases
 * About 26% are hereditary (earlier opinion had 10%)
 * About 3% recur after being resected
 * About 14% of affected individuals do not have arterial hypertension (Campbell's Urology)

Cause
Up to 25% of pheochromocytomas may be familial. Mutations of the genes VHL, RET, NF1(Gene 17 Neurofibromatosis type 1), SDHB and SDHD are all known to cause familial pheochromocytoma/extra-adrenal paraganglioma.

Pheochromocytoma is a tumor of the multiple endocrine neoplasia syndrome, type IIA and type IIB (also known as MEN IIA and MEN IIB, respectively). The other component neoplasms of that syndrome include parathyroid adenomas, and medullary thyroid cancer. Mutations in the autosomal RET proto-oncogene drives these malignancies . Common mutations in the RET oncogene may also account for medullary sponge kidney as well.

Pheochromocytoma linked to MEN II can be caused by RET oncogene mutations. Both syndromes are characterized by pheochromocytoma as well as thyroid cancer (thyroid medullary carcinoma). MEN IIA also presents with hyperparathyroidism, while MEN IIB also presents with mucosal neuroma. It is now postulated that Lincoln suffered from MEN IIB, rather than Marfan's syndrome as previously thought, though this is uncertain.

Pheochromocytoma is also associated with neurofibromatosis.

Diagnosis


The diagnosis can be established by measuring catecholamines and metanephrines in plasma (blood) or through a 24-hour urine collection. Care should be taken to rule out other causes of adrenergic (adrenalin-like) excess like hypoglycemia, stress, exercise, and drugs affecting the catecholamines like stimulants, methyldopa, dopamine agonists, or ganglion blocking antihypertensives. Various foodstuffs (e.g. vanilla ice cream) can also affect the levels of urinary metanephrine and VMA (vanillylmandelic acid). Imaging by computed tomography or a T2 weighted MRI of the head, neck, and chest, and abdomen can help localize the tumor. Tumors can also be located using an MIBG scan, which is scintigraphy using iodine-123-marked metaiodobenzylguanidine.

Pheochromocytomas occur most often during young-adult to mid-adult life.

These tumors can form a pattern with other endocrine gland cancers which is labeled multiple endocrine neoplasia (MEN). Pheochromocytoma may occur in patients with MEN 2 and MEN 3 (MEN 2B). Von Hippel Lindau patients may also develop these tumors.

Patients experiencing symptoms associated with pheochromocytoma should be aware that it is rare. However, it often goes undiagnosed until autopsy; therefore patients might wisely choose to take steps to provide a physician with important clues, such as recording whether blood pressure changes significantly during episodes of apparent anxiety.

Testing

 * Blood Tests: analysis of free metanephrine in blood plasma. High levels are indicative of pheochromocytoma


 * Urine Tests: Although this test is slightly less effective than plasma testing it is still considered highly effective in diagnosis. Usually the metabolites of norepinephrine and epinephrine, vanillylmandelic acid (VMA) and homovanillic acid (HVA) are found in relatively small amounts in normal humans. The increased intermittent excretion of these metabolites is indicative of the disease, but does not completely rule out other diseases which may cause the same excretion values.


 * Other Tests:
 * One diagnostic test used in the past for a pheochromocytoma is to administer clonidine, a centrally-acting alpha-2 agonist used to treat high blood pressure. Clonidine mimics catecholamines in the brain, causing it to reduce the activity of the sympathetic nerves controlling the adrenal medulla. A healthy adrenal medulla will respond to the clonidine suppression test by reducing catecholamine production; the lack of a response is evidence of pheochromocytoma.


 * Chromogranin A is elevated in case of pheochromocytoma.


 * Another test is for the clinician to press gently on the adrenal gland. A pheochromocytoma will often release a burst of catecholamines, with the associated signs and symptoms quickly following. This method is NOT recommended because of possible complications arising from a potentially massive release of catecholamines.


 * Warning: Testing via histamine and tyramine is dangerous and should not be used.

Tumor location
In adults, approximately 80% of pheochromocytomas are unilateral and solitary, 10% are bilateral, and 10% are extra-adrenal. In children, a fourth of tumors are bilateral, and an additional fourth are extra-adrenal. Solitary lesions inexplicably favor the right side. Although pheochromocytomas may grow to large size (>3 kg), most weigh <100 g and are <10 cm in diameter. Pheochromocytomas are highly vascular.

The tumors are made up of large, polyhedral, pleomorphic chromaffin cells. Fewer than 10% of these are malignant. As with several other endocrine tumors, malignancy cannot be determined from the histologic appearance; tumors that contain large number of aneuploid or tetraploid cells, as determined by flow cytometry, are more likely to recur. Local invasion of surrounding tissues or distant metastases indicate malignancy.

Extra-adrenal Pheochromocytomas: Extra-adrenal pheochromocytomas usually weigh 20 to 40 g and are <5 cm in diameter. Most are located within the abdomen in association with the celiac, superior mesenteric, inferior mesenteric ganglia and Organ of Zuckerkandl. Approximately 10% are in the thorax, 1% are within the urinary bladder, and less than 3% are in the neck, usually in association with the sympathetic ganglia or the extracranial branches of the ninth cranial nerves.

Differential diagnosis
The differential diagnoses of pheochromocytoma include:
 * Anxiety disorders
 * Paragangliomas
 * Essential hypertension
 * Hyperthyroidism
 * Insulinoma
 * Mercury poisoning
 * Paroxysmal supraventricular tachycardia
 * Renovascular hypertension
 * Carcinoid

Treatment
Surgical resection of the tumor is the treatment of first choice, either by open laparotomy or else laparoscopy. Given the complexity of perioperative management, and the potential for catastrophic intra and postoperative complications, such surgery should be performed only at centers experienced in the management of this disorder. In addition to the surgical expertise that such centers can provide, they will also have the necessary endocrine and anesthesia resources. It may also be necessary to carry out adrenalectomy, a complete surgical removal of the affected adrenal gland(s).

Either surgical option requires prior treatment with the non-specific and irreversible alpha adrenoceptor blocker Phenoxybenzamine (Irreversible blockade is important because a massive release of catecholamines from the tumor may overcome a reversible blockade). Doing so permits the surgery to proceed while minimizing the likelihood of severe intraoperative hypertension (as might occur when the tumor is manipulated). Some authorities would recommend that a combined alpha/beta blocker such as labetalol also be given in order to slow the heart rate. Regardless, a "pure" beta blocker such as atenolol must never be used in the presence of a pheochromocytoma due to the risk of such treatment's leading to unopposed alpha agonism and, thus, severe and potentially refractory hypertension.

The patient with pheochromocytoma is invariably volume depleted. In other words, the chronically elevated adrenergic state characteristic of an untreated pheochromocytoma leads to near-total inhibition of renin-angiotensin activity, resulting in excessive fluid loss in the urine and thus reduced blood volume. Hence, once the pheochromocytoma has been resected, thereby removing the major source of circulating catecholamines, a situation arises where there is both very low sympathetic activity and volume depletion. This can result in profound hypotension. Therefore, it is usually advised to "salt load" pheochromocytoma patients before their surgery. This may consist of simple interventions such as consumption of high salt food pre-operatively, direct salt replacement or through the administration of intravenous saline solution.

Epidemiology
Pheochromocytoma is seen in between 2–8 in 1,000,000, with approximately 1000 cases diagnosed in United States yearly. It mostly occurs in young or middle age adults, though presents earlier in hereditary cases.

History
In 1886, Fränkel made the first description of a patient with pheochromocytoma; however, the term was first coined by Ludwig Pick, a pathologist, in 1912. In 1926, Roux (in Switzerland) and Mayo (in U.S.A.) were the first surgeons to remove pheochromocytomas.

Cell lines
The PC12 cell line was derived from rat pheochromocytoma by Greene and Tischler in the 1970's.

Society and culture

 * Pheochromocytomas were mentioned a few times in the NBC TV series ER (aired in 1994–2009) and usually generated interest from the doctors due to the rarity of the diagnosis.
 * In the second season premiere of the TV series House in the episode "Acceptance" (aired on 13 September 2005), House's patient, a death row inmate Clarence (played by LL Cool J), was diagnosed with pheochromocytoma — he killed his fourth victim unintentionally, during an episode of anger caused by adrenaline spike from the tumor.
 * In Heaven Sword and Dragon Sabre (along with its various film, television and graphic novel adaptations), the third novel on the popular Condor Trilogy, the martial artist Xie Xun suffers from an 'endocrine disorder' that is most likely a pheochromocytoma. This disorder, caused by his mastery of Kongtong Sect's Seven Harms Fist, causes him to suffer bouts of 'insanity' sporadically in a manner similar to that of Heracles, flying into violent rages and wrongly identifying even his loved ones as his hated enemies.
 * In the third season of the TV series Private Practice in the episode "The Way We Were" (aired on 8 October 2009), 11-year-old patient (Tammy Larsen, played by Emily Evan Rae) suffers from ectopic pheochromocytoma on her ovary, which caused her episodes of anger, and during one of them she stabbed her father with a knife.
 * An episode of Mystery Diagnosis dealt with a woman who had a pheochromocytoma.
 * In season 10 of TV series MASH 4077 in the episode "Sons and Bowlers" Hawkeye receives news that his father is undergoing surgery after having been diagnosed with pheochromocytoma.
 * British actress Katrin Cartlidge died at the age of 41 due to complications from Pheochromocytoma.
 * President Eisenhower's death may have been caused by a pheochromocytoma.