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Pheochromocytoma

MedGen UID:
18419
Concept ID:
C0031511
Neoplastic Process
Synonyms: Chromaffin cell tumor; Chromaffin paraganglioma; Chromaffin tumor; Chromaffinoma; Medullary paraganglioma
 
Genes (locations): MAX (14q23.3); RET (10q11.21); TMEM127 (2q11.2); VHL (3p25.3)
 
HPO: HP:0002666
Monarch Initiative: MONDO:0008233
OMIM®: 171300

Disease characteristics

Hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes are characterized by paragangliomas (tumors that arise from neuroendocrine tissues distributed along the paravertebral axis from the base of the skull to the pelvis) and pheochromocytomas (paragangliomas that are confined to the adrenal medulla). Sympathetic paragangliomas cause catecholamine excess; parasympathetic paragangliomas are most often nonsecretory. Extra-adrenal parasympathetic paragangliomas are located predominantly in the skull base and neck (referred to as head and neck paragangliomas [HNPGLs]) and sometimes in the upper mediastinum; approximately 95% of such tumors are nonsecretory. In contrast, extra-adrenal sympathetic paragangliomas are generally confined to the lower mediastinum, abdomen, and pelvis, and are typically secretory. Pheochromocytomas, which arise from the adrenal medulla, typically lead to catecholamine excess. Symptoms of PGL/PCCs result from either mass effects or catecholamine hypersecretion (e.g., sustained or paroxysmal elevations in blood pressure, headache, episodic profuse sweating, forceful palpitations, pallor, and apprehension or anxiety). The risk for developing metastatic disease is greater for extra-adrenal sympathetic paragangliomas than for pheochromocytomas. Additional tumors reported in individuals with hereditary PGL/PCC syndromes include gastrointestinal stromal tumors (GISTs), pulmonary chondromas, and clear cell renal cell carcinoma. [from GeneReviews]
Authors:
Tobias Else  |  Samantha Greenberg  |  Lauren Fishbein   view full author information

Additional descriptions

From OMIM
Pheochromocytomas are catecholamine-secreting tumors that usually arise within the adrenal medulla. Approximately 10% arise in extraadrenal sympathetic ganglia, and are referred to as 'paragangliomas.' Approximately 10% are malignant, and approximately 10% are hereditary (Maher and Eng, 2002; Dluhy, 2002). Bolande (1974) introduced the concept and designation of the neurocristopathies, and identified 'simple,' including pheochromocytoma and medullary carcinoma of the thyroid, and 'complex' neurocristopathies and neurocristopathic syndromes, including NF1 and MEN2. Knudson and Strong (1972) applied Knudson's 2-mutation theory to pheochromocytoma (see discussion in 180200) and concluded that it fits. Maher and Eng (2002) reviewed the clinical entities and genes associated with pheochromocytoma.  http://www.omim.org/entry/171300
From MedlinePlus Genetics
Paraganglioma is a type of noncancerous (benign) tumor that occurs in structures called paraganglia. Paraganglia are groups of cells that are found near nerve cell bunches called ganglia. Paragangliomas are usually found in the head, neck, or torso. However, a type of paraganglioma known as pheochromocytoma develops in the adrenal glands. Adrenal glands are located on top of each kidney and produce hormones in response to stress. Most people with paraganglioma develop only one tumor in their lifetime.

Some people develop a paraganglioma or pheochromocytoma as part of a hereditary syndrome that may affect other organs and tissues in the body. However, the tumors often are not associated with any syndromes, in which case the condition is called nonsyndromic paraganglioma or pheochromocytoma.

Pheochromocytomas and some other paragangliomas are associated with ganglia of the sympathetic nervous system. The sympathetic nervous system controls the "fight-or-flight" response, a series of changes in the body due to hormones released in response to stress. Although most sympathetic paragangliomas are pheochromocytomas, some are found outside the adrenal glands, usually in the abdomen, and are called extra-adrenal paragangliomas. Most sympathetic paragangliomas, including pheochromocytomas, produce hormones called catecholamines, such as epinephrine (adrenaline) or norepinephrine. These excess catecholamines can cause signs and symptoms such as high blood pressure (hypertension), episodes of rapid heartbeat (palpitations), headaches, or sweating.

Most paragangliomas are associated with ganglia of the parasympathetic nervous system, which controls involuntary body functions such as digestion and saliva formation. Parasympathetic paragangliomas, typically found in the head and neck, usually do not produce hormones. However, large tumors may cause signs and symptoms such as coughing, hearing loss in one ear, or difficulty swallowing.

Although most paragangliomas and pheochromocytomas are noncancerous, some can become cancerous (malignant) and spread to other parts of the body (metastasize). Extra-adrenal paragangliomas become malignant more often than other types of paraganglioma or pheochromocytoma.  https://medlineplus.gov/genetics/condition/nonsyndromic-paraganglioma

Clinical features

From HPO
Hemangioma
MedGen UID:
5477
Concept ID:
C0018916
Neoplastic Process
A hemangioma is a benign tumor characterized by blood-filled spaces lined by benign endothelial cells. A hemangioma characterized by large endothelial spaces (caverns) is called a cavernous hemangioma (in contrast to a hemangioma with small endothelial spaces, which is called capillary hemangioma).
Neoplasm
MedGen UID:
10294
Concept ID:
C0027651
Neoplastic Process
An organ or organ-system abnormality that consists of uncontrolled autonomous cell-proliferation which can occur in any part of the body as a benign or malignant neoplasm (tumor).
Pheochromocytoma
MedGen UID:
18419
Concept ID:
C0031511
Neoplastic Process
Hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes are characterized by paragangliomas (tumors that arise from neuroendocrine tissues distributed along the paravertebral axis from the base of the skull to the pelvis) and pheochromocytomas (paragangliomas that are confined to the adrenal medulla). Sympathetic paragangliomas cause catecholamine excess; parasympathetic paragangliomas are most often nonsecretory. Extra-adrenal parasympathetic paragangliomas are located predominantly in the skull base and neck (referred to as head and neck PGL [HNPGL]) and sometimes in the upper mediastinum; approximately 95% of such tumors are nonsecretory. In contrast, sympathetic extra-adrenal paragangliomas are generally confined to the lower mediastinum, abdomen, and pelvis, and are typically secretory. Pheochromocytomas, which arise from the adrenal medulla, typically lead to catecholamine excess. Symptoms of PGL/PCC result from either mass effects or catecholamine hypersecretion (e.g., sustained or paroxysmal elevations in blood pressure, headache, episodic profuse sweating, forceful palpitations, pallor, and apprehension or anxiety). The risk for developing metastatic disease is greater for extra-adrenal sympathetic paragangliomas than for pheochromocytomas.
Proteinuria
MedGen UID:
10976
Concept ID:
C0033687
Finding
Increased levels of protein in the urine.
Elevated urinary norepinephrine level
MedGen UID:
1841548
Concept ID:
C5826344
Finding
The concentration of noradrenaline in the urine, normalized for urine concentration, is above the upper limit of normal.
Congestive heart failure
MedGen UID:
9169
Concept ID:
C0018802
Disease or Syndrome
The presence of an abnormality of cardiac function that is responsible for the failure of the heart to pump blood at a rate that is commensurate with the needs of the tissues or a state in which abnormally elevated filling pressures are required for the heart to do so. Heart failure is frequently related to a defect in myocardial contraction.
Renal artery stenosis
MedGen UID:
19727
Concept ID:
C0035067
Disease or Syndrome
The presence of stenosis of the renal artery.
Tachycardia
MedGen UID:
21453
Concept ID:
C0039231
Finding
A rapid heartrate that exceeds the range of the normal resting heartrate for age.
Episodic hypertension
MedGen UID:
347389
Concept ID:
C1857175
Finding
Cerebral hemorrhage
MedGen UID:
423648
Concept ID:
C2937358
Pathologic Function
Hemorrhage into the parenchyma of the brain.
Positive regitine blocking test
MedGen UID:
871125
Concept ID:
C4025594
Finding
A positive response to the regitine blocking test consisting of a substantial reduction in blood pressure following administration of regitine, indicative of the presence of increased levels of epinephrine and norepinephrine in the circulation, which is seen in pheochromocytoma-associated hypertension.
Hypercalcemia
MedGen UID:
5686
Concept ID:
C0020437
Disease or Syndrome
An abnormally increased calcium concentration in the blood.
Hyperhidrosis
MedGen UID:
5690
Concept ID:
C0020458
Finding
Abnormal excessive perspiration (sweating) despite the lack of appropriate stimuli like hot and humid weather.
Cafe-au-lait spot
MedGen UID:
113157
Concept ID:
C0221263
Finding
Cafe-au-lait spots are hyperpigmented lesions that can vary in color from light brown to dark brown with smooth borders and having a size of 1.5 cm or more in adults and 0.5 cm or more in children.
Developmental cataract
MedGen UID:
3202
Concept ID:
C0009691
Congenital Abnormality
A cataract that occurs congenitally as the result of a developmental defect, in contrast to the majority of cataracts that occur in adulthood as the result of degenerative changes of the lens.
Hypertensive retinopathy
MedGen UID:
101819
Concept ID:
C0152132
Disease or Syndrome
Retinopathy due to hypertension.

Conditions with this feature

Von Hippel-Lindau syndrome
MedGen UID:
42458
Concept ID:
C0019562
Disease or Syndrome
Von Hippel-Lindau (VHL) syndrome is characterized by hemangioblastomas of the brain, spinal cord, and retina; renal cysts and clear cell renal cell carcinoma; pheochromocytoma, pancreatic cysts, and neuroendocrine tumors; endolymphatic sac tumors; and epididymal and broad ligament cysts. Cerebellar hemangioblastomas may be associated with headache, vomiting, gait disturbances, or ataxia. Spinal hemangioblastomas and related syrinx usually present with pain. Sensory and motor loss may develop with cord compression. Retinal hemangioblastomas may be the initial manifestation of VHL syndrome and can cause vision loss. Renal cell carcinoma occurs in about 70% of individuals with VHL and is the leading cause of mortality. Pheochromocytomas can be asymptomatic but may cause sustained or episodic hypertension. Pancreatic lesions often remain asymptomatic and rarely cause endocrine or exocrine insufficiency. Endolymphatic sac tumors can cause hearing loss of varying severity, which can be a presenting symptom. Cystadenomas of the epididymis are relatively common. They rarely cause problems, unless bilateral, in which case they may result in infertility.
Multiple endocrine neoplasia type 2A
MedGen UID:
9958
Concept ID:
C0025268
Neoplastic Process
Multiple endocrine neoplasia type 2 (MEN2) includes the following phenotypes: MEN2A, FMTC (familial medullary thyroid carcinoma, which may be a variant of MEN2A), and MEN2B. All three phenotypes involve high risk for development of medullary carcinoma of the thyroid (MTC); MEN2A and MEN2B involve an increased risk for pheochromocytoma; MEN2A involves an increased risk for parathyroid adenoma or hyperplasia. Additional features in MEN2B include mucosal neuromas of the lips and tongue, distinctive facies with enlarged lips, ganglioneuromatosis of the gastrointestinal tract, and a marfanoid habitus. MTC typically occurs in early childhood in MEN2B, early adulthood in MEN2A, and middle age in FMTC.
Multiple endocrine neoplasia type 2B
MedGen UID:
9959
Concept ID:
C0025269
Neoplastic Process
Multiple endocrine neoplasia type 2 (MEN2) includes the following phenotypes: MEN2A, FMTC (familial medullary thyroid carcinoma, which may be a variant of MEN2A), and MEN2B. All three phenotypes involve high risk for development of medullary carcinoma of the thyroid (MTC); MEN2A and MEN2B involve an increased risk for pheochromocytoma; MEN2A involves an increased risk for parathyroid adenoma or hyperplasia. Additional features in MEN2B include mucosal neuromas of the lips and tongue, distinctive facies with enlarged lips, ganglioneuromatosis of the gastrointestinal tract, and a marfanoid habitus. MTC typically occurs in early childhood in MEN2B, early adulthood in MEN2A, and middle age in FMTC.
Neurofibromatosis, type 1
MedGen UID:
18013
Concept ID:
C0027831
Neoplastic Process
Neurofibromatosis 1 (NF1) is a multisystem disorder characterized by multiple café au lait macules, intertriginous freckling, multiple cutaneous neurofibromas, and learning disability or behavior problems. About half of people with NF1 have plexiform neurofibromas, but most are internal and not suspected clinically. Plexiform neurofibromas can cause pain, neurologic deficits, and abnormalities of involved or adjacent structures. Less common but potentially more serious manifestations include optic nerve and other central nervous system gliomas, malignant peripheral nerve sheath tumors, scoliosis, tibial dysplasia, vasculopathy, and gastrointestinal, endocrine, or pulmonary disease.
Pheochromocytoma
MedGen UID:
18419
Concept ID:
C0031511
Neoplastic Process
Hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes are characterized by paragangliomas (tumors that arise from neuroendocrine tissues distributed along the paravertebral axis from the base of the skull to the pelvis) and pheochromocytomas (paragangliomas that are confined to the adrenal medulla). Sympathetic paragangliomas cause catecholamine excess; parasympathetic paragangliomas are most often nonsecretory. Extra-adrenal parasympathetic paragangliomas are located predominantly in the skull base and neck (referred to as head and neck PGL [HNPGL]) and sometimes in the upper mediastinum; approximately 95% of such tumors are nonsecretory. In contrast, sympathetic extra-adrenal paragangliomas are generally confined to the lower mediastinum, abdomen, and pelvis, and are typically secretory. Pheochromocytomas, which arise from the adrenal medulla, typically lead to catecholamine excess. Symptoms of PGL/PCC result from either mass effects or catecholamine hypersecretion (e.g., sustained or paroxysmal elevations in blood pressure, headache, episodic profuse sweating, forceful palpitations, pallor, and apprehension or anxiety). The risk for developing metastatic disease is greater for extra-adrenal sympathetic paragangliomas than for pheochromocytomas.
Pheochromocytoma-islet cell tumor syndrome
MedGen UID:
401431
Concept ID:
C1868392
Neoplastic Process
Carney complex, type 1
MedGen UID:
388559
Concept ID:
C2607929
Disease or Syndrome
Carney complex (CNC) is characterized by skin pigmentary abnormalities, myxomas, endocrine tumors or overactivity, and schwannomas. Pale brown to black lentigines are the most common presenting feature of CNC and typically increase in number at puberty. Cardiac myxomas occur at a young age, may occur in any or all cardiac chambers, and can manifest as intracardiac obstruction of blood flow, embolic phenomenon, and/or heart failure. Other sites for myxomas include the skin, breast, oropharynx, and female genital tract. Primary pigmented nodular adrenocortical disease (PPNAD), which causes Cushing syndrome, is the most frequently observed endocrine tumor in CNC, occurring in approximately 25% of affected individuals. Large-cell calcifying Sertoli cell tumors (LCCSCTs) are observed in one third of affected males within the first decade and in most adult males. Up to 75% of individuals with CNC have multiple thyroid nodules, most of which are nonfunctioning thyroid follicular adenomas. Clinically evident acromegaly from a growth hormone (GH)-producing adenoma is evident in approximately 10% of adults. Psammomatous melanotic schwannoma (PMS), a rare tumor of the nerve sheath, occurs in an estimated 10% of affected individuals. The median age of diagnosis is 20 years.
Paragangliomas 7
MedGen UID:
1673088
Concept ID:
C5193116
Disease or Syndrome
Pheochromocytoma/paraganglioma syndrome-7 (PPGL7) is an autosomal dominant tumor predisposition syndrome in which affected individuals develop adult-onset neuroendocrine neoplasms, known as paragangliomas. Most tumors arise in the abdomen, secrete normetanephrine, and follow a benign disease course (summary by Remacha et al., 2019). For a discussion of genetic heterogeneity of pheochromocytoma/paraganglioma syndrome, see PPGL1 (168000).

Professional guidelines

PubMed

Fassnacht M, Tsagarakis S, Terzolo M, Tabarin A, Sahdev A, Newell-Price J, Pelsma I, Marina L, Lorenz K, Bancos I, Arlt W, Dekkers OM
Eur J Endocrinol 2023 Jul 20;189(1):G1-G42. doi: 10.1093/ejendo/lvad066. PMID: 37318239
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Rossi GP, Bisogni V, Rossitto G, Maiolino G, Cesari M, Zhu R, Seccia TM
High Blood Press Cardiovasc Prev 2020 Dec;27(6):547-560. Epub 2020 Nov 7 doi: 10.1007/s40292-020-00415-9. PMID: 33159664Free PMC Article

Curated

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®), Neuroendocrine and Adrenal Tumors, 2023

Recent clinical studies

Etiology

Sharma S, Fishbein L
Endocr Pract 2023 Dec;29(12):999-1006. Epub 2023 Aug 15 doi: 10.1016/j.eprac.2023.07.027. PMID: 37586639
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Thompson LD
Am J Surg Pathol 2002 May;26(5):551-66. doi: 10.1097/00000478-200205000-00002. PMID: 11979086

Diagnosis

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Therapy

Kalra S, Bhattacharya S, Dhingra A, Khare J, Jindal S
J Pak Med Assoc 2024 May;74(5):998-999. doi: 10.47391/JPMA.24-36. PMID: 38783456
Wang K, Crona J, Beuschlein F, Grossman AB, Pacak K, Nölting S
J Clin Endocrinol Metab 2022 Nov 23;107(11):2963-2972. doi: 10.1210/clinem/dgac471. PMID: 35973976Free PMC Article
Farrugia FA, Martikos G, Tzanetis P, Charalampopoulos A, Misiakos E, Zavras N, Sotiropoulos D
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Carrasquillo JA, Pandit-Taskar N, Chen CC
Semin Nucl Med 2016 May;46(3):203-14. doi: 10.1053/j.semnuclmed.2016.01.011. PMID: 27067501
Vöö S, Bucerius J, Mottaghy FM
Methods 2011 Nov;55(3):238-45. Epub 2011 Oct 25 doi: 10.1016/j.ymeth.2011.10.006. PMID: 22056346

Prognosis

Wachtel H, Hutchens T, Baraban E, Schwartz LE, Montone K, Baloch Z, LiVolsi V, Krumeich L, Fraker DL, Nathanson KL, Cohen DL, Fishbein L
J Clin Endocrinol Metab 2020 Dec 1;105(12):e4661-70. doi: 10.1210/clinem/dgaa608. PMID: 32877928Free PMC Article
Fassnacht M, Assie G, Baudin E, Eisenhofer G, de la Fouchardiere C, Haak HR, de Krijger R, Porpiglia F, Terzolo M, Berruti A; ESMO Guidelines Committee. Electronic address: clinicalguidelines@esmo.org
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Kimura N, Takayanagi R, Takizawa N, Itagaki E, Katabami T, Kakoi N, Rakugi H, Ikeda Y, Tanabe A, Nigawara T, Ito S, Kimura I, Naruse M; Phaeochromocytoma Study Group in Japan
Endocr Relat Cancer 2014 Jun;21(3):405-14. Epub 2014 May 6 doi: 10.1530/ERC-13-0494. PMID: 24521857
Moalem J, Suh I, Duh QY
Cancer Treat Res 2010;153:119-34. doi: 10.1007/978-1-4419-0857-5_8. PMID: 19957223

Clinical prediction guides

Mete O, Asa SL, Gill AJ, Kimura N, de Krijger RR, Tischler A
Endocr Pathol 2022 Mar;33(1):90-114. Epub 2022 Mar 13 doi: 10.1007/s12022-022-09704-6. PMID: 35285002
Rossi GP, Bisogni V, Rossitto G, Maiolino G, Cesari M, Zhu R, Seccia TM
High Blood Press Cardiovasc Prev 2020 Dec;27(6):547-560. Epub 2020 Nov 7 doi: 10.1007/s40292-020-00415-9. PMID: 33159664Free PMC Article
Wachtel H, Hutchens T, Baraban E, Schwartz LE, Montone K, Baloch Z, LiVolsi V, Krumeich L, Fraker DL, Nathanson KL, Cohen DL, Fishbein L
J Clin Endocrinol Metab 2020 Dec 1;105(12):e4661-70. doi: 10.1210/clinem/dgaa608. PMID: 32877928Free PMC Article
Kimura N, Takayanagi R, Takizawa N, Itagaki E, Katabami T, Kakoi N, Rakugi H, Ikeda Y, Tanabe A, Nigawara T, Ito S, Kimura I, Naruse M; Phaeochromocytoma Study Group in Japan
Endocr Relat Cancer 2014 Jun;21(3):405-14. Epub 2014 May 6 doi: 10.1530/ERC-13-0494. PMID: 24521857
Thompson LD
Am J Surg Pathol 2002 May;26(5):551-66. doi: 10.1097/00000478-200205000-00002. PMID: 11979086

Recent systematic reviews

Bancos I, Atkinson E, Eng C, Young WF Jr, Neumann HPH; International Pheochromocytoma and Pregnancy Study Group
Lancet Diabetes Endocrinol 2021 Jan;9(1):13-21. Epub 2020 Nov 26 doi: 10.1016/S2213-8587(20)30363-6. PMID: 33248478Free PMC Article
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