| Pheochromocytoma |
| Classification and external resources |
High magnification micrograph of a pheochromocytoma showing the nested arrangement of cells (Zellballen) and stippled chromatin. H&E stain. |
| ICD-10 |
D35.0, C74.1 |
| ICD-9 |
227.0, 194.0, 255.6 |
| ICD-O: |
M8700/0 |
| OMIM |
171300 |
| DiseasesDB |
9912 |
| MedlinePlus |
000340 |
| eMedicine |
med/1816 radio/552 ped/1788 |
| MeSH |
D010673 |
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This article needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. (August 2011) |
A pheochromocytoma (Etymology: Greek "phaios =dark, chroma = color, kytos =cell, oma = tumor") 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 [1] and secretes high amounts of catecholamines, usually noradrenaline (norepinephrine), and adrenaline (epinephrine) to a lesser extent.[2] 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.
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Contents
- 1 Signs and symptoms
- 2 Cause
- 3 Diagnosis
- 3.1 Testing
- 3.2 Tumor location
- 3.3 Differential diagnosis
- 4 Treatment
- 5 Complications
- 6 Epidemiology
- 7 History
- 8 Society and culture
- 9 References
- 9.1 Additional references
- 10 External links
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Signs and symptoms[edit]
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 - most common symptom
- 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.
Cause[edit]
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 .[3] Common mutations in the RET oncogene may also account for medullary sponge kidney as well.[4]
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 Abraham Lincoln suffered from MEN IIB, rather than Marfan's syndrome as previously thought, though this is uncertain.
Pheochromocytoma is also associated with neurofibromatosis.[5]
Diagnosis[edit]
Histopathology of adrenal pheochromocytoma. Adrenectomy specimen.
Pheochromocytoma (dark circular shadow near body center) localized by MIBG scintigraphy. Front and back views also show radioiodine collection in thyroid (neck) and bladder (pelvis)
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. coffee, tea, bananas, chocolate, cocoa, citrus fruits, and vanilla) can also affect the levels of urinary metanephrine and VMA (vanillylmandelic acid).[6]
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. Even finer localization can be obtained in certain PET scan centers using PET/CT with F-18-fluorodopamine (FDOPA)[7]
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.[8]
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[edit]
- Blood Tests: Some authorities[weasel words] (Buters et al.) have suggested that analysis of free metanephrines (normetanephrine and metanephrine) in blood plasma is the most accurate test for detecting phaeochromocytoma.
- 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, normetanephrine (NMN) and metanephrine (MN) are found in relatively small amounts in normal humans. The increased 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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- 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.
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- Chromogranin A is elevated in case of pheochromocytoma.[9]
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- 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.
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- Warning: Testing via histamine and tyramine is dangerous and should not be used.
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Micrograph of pheochromocytoma.
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Micrograph of pheochromocytoma.
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Micrograph of pheochromocytoma.
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Bilateral pheochromocytoma in MEN2.
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Pheochromocytoma. CT abdomen.
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Pheochromocytoma. CT abdomen.
Tumor location[edit]
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 tumors 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[edit]
The differential diagnoses of pheochromocytoma include:
- Anxiety disorders
- Paragangliomas
- Von Hippel-Lindau Disease
- Essential hypertension
- Hyperthyroidism
- Insulinoma
- Mercury poisoning
- Paroxysmal supraventricular tachycardia
- Renovascular hypertension
- Carcinoid [10]
Treatment[edit]
Surgical resection of the tumor is the treatment of first choice, either by open laparotomy or else laparoscopy.[11] 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 a treatment 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.
Complications[edit]
The massive release of catelcholamines in pheochromocytoma can cause damage to cardiac cells (myocytes).[12] This damage may be due to either compromising the coronary microcirculation or by direct toxic effects on the heart cells.[12]
Epidemiology[edit]
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 and it is also called 10% tumor .
- 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 15-20% are hereditary[13]
- About 5% are caused by VHL disease
- About 3% recur after being resected
- About 14% of affected individuals do not have arterial hypertension (Campbell's Urology)
History[edit]
In 1886, Felix Fränkel made the first description of a patient with pheochromocytoma. The term "pheochromocytoma" was first coined by Ludwig Pick, a pathologist, in 1912. In 1926, César Roux (in Switzerland) and Charles Horace Mayo (in the U.S.A.) were the first surgeons to successfully remove pheochromocytomas.
In the 1970s, Greene and Tischler derived a line of cells, called the PC12 cell line, from a rat pheochromocytoma.[14]
Society and culture[edit]
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- 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.[15]
- A skit during the Harvard Medical School annual show in 1978 included a song entitled "Pheo" (recited exactly in the manner of the Western song "Ringo") as a parody of a guest professor whose lecture on hypertension causes was oddly dominated by the extremely rare pheochromocytoma. The song began "The pulse I was feeling was thready and fast/So I thought I'd come upon at last/The cause of hypertension of Harvard fame/My steel-trap mind recalled the name of Pheo ...".
References[edit]
- ^ Boulpaep, Emile L.; Boron, Walter F. (2003). Medical physiology: a cellular and molecular approach. Philadelphia: Saunders. p. 1065. ISBN 0-7216-3256-4.
- ^ Sweeney, Ann T; Griffing, George T (August 2, 2011). "Pheochromocytoma". eMedicine.
- ^ Online 'Mendelian Inheritance in Man' (OMIM) MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIA; MEN2A -171400
- ^ Diouf, B. (2000). "Association of medullary sponge kidney disease and multiple endocrine neoplasia type IIA due to RET gene mutation: is there a causal relationship?". Nephrology Dialysis Transplantation 15 (12): 2062–3. doi:10.1093/ndt/15.12.2062.
- ^ Goldman 2011, pp. 1194
- ^ "Catecholamines - urine - Penn State Hershey Medical Center". Pennstatehershey.adam.com. 2011-01-06. Retrieved 2013-02-23.
- ^ "6-[18F]Fluorodopamine Positron Emission Tomographic (PET) Scanning for Diagnostic Localization of Pheochromocytoma". Hyper.ahajournals.org. Retrieved 2013-02-23.
- ^ Goldman 2011, pp. 185
- ^ Cotesta, D; Caliumi, C; Alò, P; Petramala, L; Reale, MG; Masciangelo, R; Signore, A; Cianci, R et al. (2005). "High plasma levels of human chromogranin A and adrenomedullin in patients with pheochromocytoma". Tumori 91 (1): 53–8. PMID 15850005.
- ^ Giannini, A. James; Black, Henry R.; Goettsche, Roger L. (1978). Psychiatric, Psychogenic and Somatopsychic Disorders Handbook. Garden City, NY: Medical Examination. pp. 213–4. ISBN 0-87488-596-5.
- ^ Jaroszewski, D. E.; Tessier, D. J.; Schlinkert, R. T.; Grant, C. S.; Thompson, G. B.; Van Heerden, J. A.; Farley, D. R.; Smith, S. L. et al. (2003). "Laparoscopic Adrenalectomy for Pheochromocytoma". Mayo Clinic Proceedings 78 (12): 1501–4. doi:10.4065/78.12.1501. PMID 14661679.
- ^ a b Goldman 2011, pp. 327
- ^ Goldman 2011, pp. 1470
- ^ Greene LA, Tischler AS (1976). "Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor". Proc. Natl. Acad. Sci. U.S.A 73 (7): 2424–8. doi:10.1073/pnas.73.7.2424. PMID 1065897.
- ^ Messerli, Franz H.; Loughlin, Kevin R.; Messerli, Adrian W.; Welch, William R. (2007). "The President and the Pheochromocytoma". The American Journal of Cardiology 99 (9): 1325–9. doi:10.1016/j.amjcard.2006.12.043. PMID 17478167.
Additional references[edit]
- Goldman, Lee (2011). Goldman's Cecil Medicine (24th ed.). Philadelphia: Elsevier Saunders. p. 1362. ISBN 1437727883.
External links[edit]
- MedlinePlus Overview pheochromocytoma
- GeneReviews entry on Hereditary Paraganglioma-Pheochromocytoma Syndromes
- General Information About Pheochromocytoma and Paraganglioma from the National Cancer Institute
- Neuroendocrine Tumor from the American Society of Clinical Oncology
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Gonadal tumors, paraganglioma, and glomus (ICD-O 8590-8719)
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Gonadal/
sex cord-gonadal stromal (8590-8679) |
sex cord (Granulosa cell tumour, Sertoli cell tumor, Sex cord tumour with annular tubules)
stroma (Thecoma, Leydig cell tumor)
both (Sertoli-Leydig cell tumour, Luteoma)
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Paragangliomas And
Glomus tumors (8680-8719) |
Neuroendocrine tumor: Paraganglioma (Pheochromocytoma)
Vascular tissue neoplasm: Glomus tumor (Glomangiosarcoma)
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Tumors: endocrine gland neoplasia (C73–C75/D34–D35, 193–194/226–227)
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Pancreas/
islets of Langerhans |
- neuroendocrine tumors/islet cell carcinoma: α: Glucagonoma
- β: Insulinoma
- δ: Somatostatinoma
- G: Gastrinoma
- VIPoma
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Hypothalamic/
pituitary axes
+parathyroid |
| Pituitary |
- Pituitary adenoma: Prolactinoma
- ACTH-secreting pituitary adenoma
- GH-secreting pituitary adenoma
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| Thyroid |
- Thyroid cancer (malignant): epithelial cell carcinoma
- Papillary
- Follicular/Hurthle cell
- parafollicular cell
- Anaplastic
- Lymphoma
- Squamous cell carcinoma
- Benign: Thyroid adenoma
- Struma ovarii
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| Parathyroid |
- Parathyroid adenoma
- Parathyroid carcinoma
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| Adrenal tumor |
- adrenal cortex
- Adrenocortical adenoma
- Adrenocortical carcinoma
- adrenal medulla
- Pheochromocytoma
- Neuroblastoma
- see also: Paraganglioma
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| Gonads |
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| Pinealoma |
- Pinealoblastoma
- Pineocytoma
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| MEN |
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noco (d)/cong/tumr, sysi/epon
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proc, drug (A10/H1/H2/H3/H5)
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