Pheochromocytomas

Definition:
Pheochromocytomas are a type of tumor of the adrenal glands that can release high levels of epinephrine and norepinephrine. As the name implies, the “ad-renal” glands are located near the “renal” area. In other words, the adrenal glands are small glands that are located near the top of the kidneys. One adrenal gland sits on top of each of the two kidneys.

Despite their small size, the adrenal glands have many functions. They are complex endocrine (hormone secreting) glands. Cells in different regions of the adrenal glands have different functions in the endocrine system. There is an area (zona fasciculata) where the cells secrete cortisol, a hormone similar to cortisone. There is another area (zona glomerulosa) where cells secrete a hormone called aldosterone which helps in water regulation.

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There is yet another area, referred to as the adrenal medulla, where the cells secrete substances called catecholamines — epinephrine, norepinephrine and dopamine. These are “flight or fight” hormones. They are responsible in part for that feeling of an “adrenaline” rush people feel when they are afraid. It is these cells that are involved in a pheochromocytoma. Basically, a pheochromocytoma is a tumor of these catecholamine-secreting cells, and that causes the clinical signs and symptoms we will discuss below. The catecholamine-secreting cells are sometimes referred to as chromaffin cells, and they are found in other areas of the body as well as in the adrenal medulla.

Sometimes, pheochromocytomas arise from chromaffin cells that are located outside of the adrenal gland. In this case, they are termed extra-adrenal pheochromocytomas or paragangliomas and are usually located in the abdomen.

Pheochromocytomas may occur in persons of any age. The peak incidence is between the third and the fifth decades of life, but approximately 10% occur in children. Pheochromocytomas are, fortunately, quite rare (only about 800 new cases are diagnosed per year in the US) and the majority of them are entirely benign. Only about 10% of pheochromocytomas are malignant.

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.

Causes:
Conditions that are associated with Pheochromocytomas can be a component of certain familial or genetic syndromes. The most common familial condition is called multiple endocrine neoplasia, or MEN for short. Two types of MEN — MEN 2A and 2B — are associated with pheochromocytomas. Both are genetic syndromes that run in families and are transmitted from parent to child in an autosomal dominant manner.

Pheochromocytomas are not the only tumors that occur in MEN 2A and 2B. MEN 2A carries an increased risk of tumors of the parathyroids, glands near the thyroid that help to regulate calcium levels in the body. And both MEN 2A and 2B elevate the risk of thyroid cancer. In families where MEN is suspected, genetic testing can be done to help identify family members at risk.

Pheochromocytomas are a feature of other genetic disorders, including von Hippel-Lindau syndrome and neurofibromatosis. Both of these disorders are associated with the development of numerous benign and malignant tumors.

There are also many individuals who have pheochromocytomas with no known family history of them. These cases are termed sporadic. In general, if these patients have bilateral disease (pheochromocytomas in both adrenal glands) or are diagnosed before the age of 21, genetic screening is recommended.

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)

Other Causes:
Basically, anything that can cause over activity of the sympathetic nervous system can be on the list of diagnoses to rule out when suspecting a pheochromocytoma. The sympathetic system is the main control panel governing the release of the “flight or fight” response in response to stress or fear, as mentioned above. Things that can stimulate this include drugs (even excessive use of decongestants should be considered); withdrawal from drugs (such as suddenly stopping certain blood pressure medications); panic attacks, and spinal cord injuries are among the many conditions that can also lead to some of the symptoms seen in pheochromocytomas.

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.

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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.

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*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....CLICK  & SEE
Differential diagnosis
The differential diagnoses of pheochromocytoma include:

*Anxiety disorders

*Paragangliomas
*Essential hypertension
*Hyperthyroidism
*Insulinoma
*Mercury poisoning
*Paroxysmal supraventricular tachycardia
*Renovascular hypertension
*Carcinoid

Treatment and recovery
Treatment involves drugs to bring blood pressure to normal levels, followed by surgery to remove the tumour. Blood pressure and adrenaline/noradrenaline levels must be checked for some time afterwards to ensure that removal of the tumour was complete. If the tumour was benign then survival rates are high, but in people affected by malignant pheochromocytomas, less than 50 per cent survive longer than five years.

Prevention;
Since the cause of phaeochromocytoma is unknown, it isn’t possible to prevent it.

Disclaimer: This information is not meant to be a substitute for professional medical advise or help. It is always best to consult with a Physician about serious health concerns. This information is in no way intended to diagnose or prescribe remedies.This is purely for educational purpose

Resources:
http://en.wikipedia.org/wiki/Pheochromocytoma
http://www.bbc.co.uk/health/physical_health/conditions/phaeochromocytoma1.shtml
http://www.lexic.us/definition-of/pheochromocytoma

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