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Pheochromocytoma
Pheochromocytomas (PH or PCC) are tumors arising from chromaffin cells of the adrenal
gland. They make, store, metabolize and usually but not always release catecholamines.
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. The term is from the Greek phaios (dark), chroma (color), kytos (cell), and -oma
(tumor).
Contents Pheochromocytoma
Skin sensations
Flank pain
High magnification micrograph of a
Elevated heart rate
pheochromocytoma, showing the nested
Elevated blood pressure, including arrangement of cells (Zellballen) and stippled
paroxysmal (sporadic, episodic) high chromatin. H&E stain.
blood pressure, which sometimes can
Specialty Oncology
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
Pallor
Weight loss
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 large, but most are smaller than 10 centimetres (4 in).
Complications
Cause
The RET protein is a tyrosine kinase receptor that plays an integral role in development of
sympathetic neurons [2]. Mutations in the gene via germ-line (MEN-2) or somatic
acquisition activate multiple signaling pathways involved in PCC, as well as other
neuroendocrine tumors in humans. MEN-2 generally results from a gain-of-function variant
of this RET gene, and MEN-2 is commonly associated with pheochromocytoma and
amyloid producing medullary thyroid carcinoma.
Mutations in two subunits of the succinate dehydrogenase gene, SDHB and SDHD, have
been strongly associated with cancer presenting at a younger age as well as extra-adrenal
location, multiple tumors/metastasis, and poor prognosis.
Diagnosis
These tumors can form a pattern with other endocrine Pheochromocytoma (dark circular
shadow near body center) localized
gland cancers which is labeled multiple endocrine by MIBG scintigraphy. Front and
neoplasia (MEN). Pheochromocytoma may occur in back views also show radioiodine
collection in thyroid (neck) and
patients with MEN 2 and MEN 3 (MEN 2B). Von Hippel
bladder (pelvis)
Lindau patients may also develop these tumors.[7]
Testing
Testing prior to tumor excision helps ascertain whether the tumor is a singular tumor or if
there are multiple, if it is ectopic or adrenal originating, malignant or benign, and isolated or
present with other tumors in context of inherited disease. CT is the most commonly used
imaging technique, however MRI is preferred. MIBG scanning should be used when
possible, as it is the most accurate way to locate cancer in catecholamine producing
cancers, as catecholamine plasma membrane and vesicular transport systems are
especially abundant in pheochromocytoma cells. Imaging using MIBG would yield specific
and sensitive results compared to CT and MRI, as the latter two are non-specific
generalized imaging techniques
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.[8]
Pheochromocytoma. Pheochromocytoma.
CT abdomen. CT abdomen.
Tumor location
In adults, approximately 80% of pheochromocytomas are unilateral and solitary, 10% are
bilateral, and 10% are extra-adrenal. In children, a quarter of tumors are bilateral, and an
additional quarter 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.
Differential diagnosis
Paragangliomas
Essential hypertension
Hyperthyroidism
Insulinoma
Mercury poisoning
Renovascular hypertension
Carcinoid[9]
Treatment
Surgical resection of the tumor is the treatment of first choice, either by open laparotomy
or laparoscopy.[10] 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 or a short acting alpha antagonist (e.g. prazosin,
terazosin, or doxazosin).[11] 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 nonselective
beta-adrenergic receptor blocker such as propranolol must never be used, without
adequate alpha blockade, in the presence of a pheochromocytoma. The mechanism for β-
adrenoceptor blocker-associated adverse events is generally ascribed to inhibition of β2-
adrenoceptor-mediated vasodilatation, leaving α1-adrenoceptor-mediated vasoconstrictor
responses to catecholamines unopposed and, thus, severe and potentially refractory
hypertension. However some clinical guidelines permit beta-1 blockade use together with
alpha blockers during surgery for control of tachycardia.
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.
Prognosis
There is increased life-time risk of secondary cancers (relative risk 3.63), with a slightly
increased mortality risk (1.21) according to a 2004 Swedish study of 481 patients.[12]
Epidemiology
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 can only be drawn after
surgical resection.
About 11.1% of adrenal cases are malignant, but this rises to 30% for extra-adrenal cases
About 14% of affected individuals do not have arterial hypertension (Campbell's Urology)
History
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]
References
5. ^ Pacak, K.; Eisenhofer, G.; Carrasquillo, J. A.; Chen, C. C.; Li, S. T.; Goldstein, D. S.
(July 2001). "6-[18F]Fluorodopamine Positron Emission Tomographic (PET) Scanning
for Diagnostic Localization of Pheochromocytoma". Hypertension.
Hyper.ahajournals.org. 38 (1): 6–8. doi:10.1161/01.HYP.38.1.6 . PMID 11463751 .
10. ^ 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.; Hinder, R. A. (2003). "Laparoscopic
Adrenalectomy for Pheochromocytoma". Mayo Clinic Proceedings. 78 (12): 1501–4.
doi:10.4065/78.12.1501 . PMID 14661679 .
12. ^ Khorram-Manesh, A.; Ahlman, H.; Nilsson, O.; Odén, A.; Jansson, S. (2004).
"Mortality associated with pheochromocytoma in a large Swedish cohort". European
Journal of Surgical Oncology. 30 (5): 556–559. doi:10.1016/j.ejso.2004.03.006 .
PMID 15135486 .
14. ^ Greene LA, Tischler AS; Tischler (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. Bibcode:1976PNAS...73.2424G .
doi:10.1073/pnas.73.7.2424 . PMC 430592 . PMID 1065897 .
Notes
Goldman, Lee (2011). Goldman's Cecil Medicine (24th ed.). Philadelphia: Elsevier
Saunders. p. 1362. ISBN 978-1437727883.
External links
MedlinePlus Overview
Classification D
pheochromocytoma ICD-10: D35.0 ,
C74.1 •
GeneReviews entry on "Hereditary
Paraganglioma-Pheochromocytoma ICD-9-CM:
Syndromes " 227.0 , 194.0 ,
255.6 •
"General Information About
ICD-O:
Pheochromocytoma and
M8700/0 •
Paraganglioma " from the National
Cancer Institute OMIM: 171300 •
MeSH:
D010673 •
DiseasesDB: 9912
External MedlinePlus:
resources 000340 •
eMedicine:
med/1816
radio/552
ped/1788 •
Patient UK:
Pheochromocytoma
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