Adrenal gland and paraganglia
Pheochromocytoma / paraganglioma

Editorial Board Member: Debra Zynger, M.D.
Pallav Gupta, M.D.

Topic Completed: 1 January 2014

Revised: 3 October 2019

Copyright: 2002-2019,, Inc.

PubMed Search: pheochromocytoma [title] adrenal

Pallav Gupta, M.D.
Page views in 2019: 31,439
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Cite this page: Gupta P. Pheochromocytoma. website. Accessed January 19th, 2020.
Definition / general
  • Also called paraganglioma of adrenal medulla (extra-adrenal tumors are called extra-adrenal paragangliomas)
  • Rare catecholamine secreting tumor (0.005% to 0.1% of unselected autopsies)
  • Described by Poll in 1905 as having cut surface with dusky [pheo] color [chromo]
  • Probably >10% of cases; usually younger age of onset (10-20 years vs. 40-60 years), bilateral (70% vs. 10% in sporadic), multicentric, associated with other neoplasms, male gender
  • MEN 1:
    • Pituitary tumors, parathyroid hyperplasia or adenoma, pancreatic hyperplasia or adenoma and carcinoid tumors
  • MEN 2a/2:
    • Sipple first described in 1961
    • Autosomal dominant with high penetrance, 30-50% have pheochromocytoma, all have medullary thyroid carcinoma and 10-15% have parathyroid hyperplasia
    • Due to mutation in RET proto-oncogene
  • MEN 2b/3:
    • MEN2a signs / symptoms plus mucosal neuromas and ganglioneuromas
    • Autosomal dominant or sporadic
    • May lack parathyroid hyperplasia
  • Sturge-Weber:
    • Cavernous hemangiomas (port-wine spots) of trigeminal nerve (cranial nerve V), pheochromocytoma
  • von Hippel Lindau:
    • 10-20% of patients
    • Cysts of kidney, liver and epididymis
    • Renal cell carcinoma (clear cell type), pheochromocytoma, angiomas and cerebellar hemangioblastoma
  • von Recklinghausen (neurofibromatosis type 1):
    • 1-5% of patients
    • Neurofibromatosis, schwannoma, meningioma, glioma and pheochromocytoma
    • Composite tumors with neuroblastoma, ganglioneuroma or ganglioneuroblastoma may be associated with neurofibromatosis 1 (Mod Pathol 2002;15:183)
Clinical features
  • Causes surgically correctable hypertension (also aldosterone-secreting tumors, renal artery stenosis)
  • Represents 0.1% of patients with hypertension, but may be fatal
  • Mean age 47 years in one series, range 3-81 years
  • Called 10% tumor: 10% bilateral (probably higher), 10% outside adrenal medulla, 10% metastasize (probably higher), 10% in children
  • Extra-adrenal tumors secrete only norepinephrine, have 20% malignancy rate
  • In children, usually extra-adrenal, bilateral and associated with MEN 2a/2b
  • Metastases usually to lymph nodes, bone (ribs, spine), liver and lung; occasionally to brain, diaphragm, ileum, kidney, pancreas, peritoneum, pleura, spleen, stomach
  • Occasionally associated with melanoma (Arch Pathol Lab Med 1998;122:63); also adrenal cortical tumors, neurofibromatosis, other paragangliomas, renal artery stenosis due to dysplasia, von Hippel-Lindau disease
  • Rarely associated with Cushing or other syndromes
  • Symptoms:
    • Triad of sweating attacks, tachycardia and headaches is relatively specific for pheochromocytoma
    • Related to catecholamine hypersecretion (usually norepinephrine > epinephrine)
    • Usually hypertension (abrupt; with tachycardia, palpitations, headaches, tremor, sense of apprehension and weight loss; unresponsive to treatment; isolated paroxysmal episodes of hypertension in < 50%)
  • Catecholamine cardiomyopathy:
    • Myocardial instability, ventricular arrhythmias
    • Due to ischemic damage from vasoconstriction of coronaries or direct toxicity
    • Cardiac biopsy shows myocytolysis, interstitial fibrosis and mononuclear inflammation
  • Diagnosis:
    • Increased urinary excretion of catecholamines or metabolites (vanilllylmandelic acid-VMA or total metanephrines)
    • Elevated serum chromogranin A levels
  • Most reliable is presence of metastases (lymph nodes, liver, lung, bone)
  • Malignant cases have MIB1 positive cell rate of 2-3% or more (Hum Pathol 1998;29:522, Mod Pathol 1999;12:1107)
  • PASS score (Pheochromocytoma of the Adrenal gland Scaled Score):
    • Benign if 0-3 points, potential for malignancy if 4+ points; each feature present gets points added (Am J Surg Pathol 2002;26:551)
    • 1 point: vascular invasion, capsular invasion, profound nuclear pleomorphism or hyperchromasia
    • 2 points: invasion of periadrenal adipose tissue, large nests or diffuse growth, focal or confluent necrosis, high cellularity, tumor cell spindling, cellular monotony, 4+ mitotic figures per 10 high power fields, atypical mitotic figures
    • Reference: Surgery 2008;143:759
Case reports
  • Surgery after premedication with adrenergic blockers
Gross description
  • Varies from small, circumscribed to large, hemorrhagic and necrotic (1g to 4 kg)
  • Mean 7 cm / 200 g
  • Small tumors have rim of compressed adrenal gland
  • Lobulated, yellow-red-brown
  • Familial tumors are bilateral and multicentric, and adjacent medulla may appear hyperplastic
  • Chromaffin reaction: Fresh tumor turns dark brown if add potassium dichromate at pH 5-6 (Zenkers)
Gross images

Contributed by Debra Zynger, M.D.


Frozen section images

Contributed by Debra Zynger, M.D.

Well circumscribed tumor

Nested with cellular crowding

Permanent section

Microscopic (histologic) description
  • Zellballen (small nests or alveolar pattern), trabecular or solid patterns of polygonal / spindle shaped cells in rich vascular network
  • Cells have finely granular basophilic or amphophilic cytoplasm
  • Intracytoplasmic hyaline globules
  • Round / oval nuclei with prominent nucleolus and variable inclusion-like structures (Hum Pathol 1980;11:205)
  • May have marked pleomorphism
  • Capsular and vascular invasion common in benign behaving tumors
  • Nests outlined by sustentacular cells (cannot see in H&E but S100+)
  • Amyloid also common (Hum Pathol 1992;23:33)
  • Rare / no mitotic figures
  • May be mixed with neuroblastoma, ganglioneuroma, ganglioneuroblastoma, cortical adenoma, spindle cell sarcoma
  • Unusual morphological features:
Microscopic (histologic) images

Contributed by Debra Zynger, M.D.


PASS criteria

Contributed by Semir Vranić, M.D., Ph.D.






Cytology images

Contributed by Debra Zynger, M.D.



Positive stains
  • Chromogranin, synaptophysin (also present in adrenal cortical carcinomas), S100 (sustentacular cells), PAS+ diastase resistant hyaline globules and tenascin (strong in clinically malignant tumors, Am J Surg Pathol 2001;25:1419)
  • Also catecholamines, neuron specific enolase, neurofilament
  • Variable vimentin, bcl2 and focal HMB45 (Arch Pathol Lab Med 1992;116:151)
Negative stains
  • MelanA / Mart1, inhibin, keratin (usually) and calretinin
Electron microscopy description
  • Numerous membrane-bound electron dense granules containing catecholamines, tubulolamellar mitochondria and predominantly rough endoplasmic reticulum
Electron microscopy images

Images hosted on other servers:

Neurosecretory granules

Various images

Molecular / cytogenetics description
  • Loss of heterozygosity (LOH) of 1p34-36 in 45%, VHL gene (3p25) in 45% (Hum Pathol 1997;28:411)
  • Also genetic changes in syndromes above
  • Also mutations in genes for succinate dehydrogenase
Differential diagnosis
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