Adrenal gland & paraganglia

Pheochromocytoma / paraganglioma


Editorial Board Member: Bonnie Choy, M.D.
Deputy Editors-in-Chief: Raul S. Gonzalez, M.D., Maria Tretiakova, M.D., Ph.D.
Katherine A. Lehman, B.S.
Debra L. Zynger, M.D.

Last author update: 3 January 2023
Last staff update: 9 May 2024

Copyright: 2002-2024,, Inc.

PubMed Search: Pheochromocytoma adrenal

Katherine A. Lehman, B.S.
Debra L. Zynger, M.D.
Page views in 2023: 68,091
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Cite this page: Lehman KA, Zynger DL. Pheochromocytoma. website. Accessed May 19th, 2024.
Definition / general
Essential features
  • Paraganglioma of the adrenal medulla composed of chromaffin cells that produce catecholamines
  • Most often sporadic but associated with genetic syndromes in approximately 30 - 40% of cases and pathogenic mutations are identifiable in half of cases; therefore genetic testing in all cases may be warranted (Am J Surg Pathol 2021;45:1155)
  • Malignant in approximately 10% of cases
  • No single biomarker or histologic feature predicts malignancy: pheochromocytoma of the adrenal gland scaled score (PASS) provides prognosis based on histologic features (Am J Surg Pathol 2002;26:551)
  • Positive for chromogranin, synaptophysin and S100
  • Pheochromocytoma may also be referred to as adrenal paraganglioma
    • Distinct from paraganglioma / extra-adrenal pheochromocytoma, which arises from chromaffin cells of sympathetic ganglia
    • Distinct from composite pheochromocytoma, which are tumors composed of pheochromocytoma plus ganglioneuroma, ganglioneuroblastoma, neuroblastoma or peripheral nerve sheath tumors
  • Zellballen: used to describe characteristic nested architecture
  • Pheochromocytoma of the adrenal gland scaled score (PASS): prognostic score based on histologic features (Am J Surg Pathol 2002;26:551)
ICD coding
  • ICD-O: 8700/3 - pheochromocytoma
  • ICD-10:
    • C74.1 - adrenal medulla
    • D35.00 - benign neoplasm of unspecified adrenal gland
    • C74.10 - pheochromocytoma, malignant; pheochromoblastoma
  • Adrenal gland medulla
  • Normal chromaffin cell function relies on:
    • 4 key enzymes: tyrosine hydroxylase (rate limiting), aromatic L amino acid decarboxylase, dopamine ß hydroxylase (makes norepinephrine) and phenylethanolamine N methyltransferase (converts norepinephrine to epinephrine)
    • Storage and vesicular transport of catecholamines via vesicular monoamine transporters
    • Exocytosis of storage vesicles following sympathetic neuronal stimulation and stimulatory paracrine signaling in chromaffin cells in response to stress
      • Tightly regulated by neuronal stimulation (acetylcholine, pituitary adenylate cyclase activating peptide) and multiple peptides thought to participate in negative feedback and autocrine / paracrine regulation
  • Alterations in components of normal catecholamine biosynthesis may drive proliferation of chromaffin cells, oversecretion of catecholamines and dysregulation of chromaffin cell division
    • Chromaffin cells in pheochromocytoma release catecholamines without sympathetic innervation or neuronal stimulation
    • Evidence of differences in levels of certain regulatory molecules/enzymes in normal adrenal medulla versus neoplasms (Table 1)
  • 3 clusters of mutations thought to drive pathophysiology have recently been described: (Cancer Cell 2017;31:181)
    • Cluster 1: induce a hypoxic response from cells in the absence of true hypoxia, resulting in excessive methylation of phenylethanolamine N methyltransferase
      • Primarily germline mutations
      • Phenotype: intra- or extra-adrenal; produce mainly norepinephrine, little epinephrine
      • Examples: dysregulation of the TCA cycle (SDH mutations) or VHL related tumors
    • Cluster 2: increased MAP kinase and P13K / AKT pathway activity, which increases cell proliferation and catecholamine synthesis
      • Approximately 20% germline; primarily somatic mutations
      • Phenotype: intra-adrenal, typically produce epinephrine
      • Examples: RET, NF1, TMEM-127, MAX, HRAS
    • Cluster 3: alter Wnt pathway signaling; little is known but attenuate phenylethanolamine N methyltransferase expression
      • All known mutations are somatic
      • Phenotype: intra-adrenal; produce epinephrine in quantities intermediate between cluster 1 and cluster 2
      • Examples: CSDE1, MAML3

    Table 1. Elements of normal catecholamine biosynthesis potentially involved in the pathophysiology of pheochromocytoma (Cancers (Basel) 2019;11:E1121)
    Element Role in normal catecholamine biosynthesis Alterations in pheochromocytoma versus normal adrenal medulla
    Neuropeptide Y Increases tyrosine hydroxylase expression, intracellular calcium and neoangiogenesis Increased plasma levels, increased adrenal mRNA expression
    Adrenomedullin Increases adrenal blood flow and catecholamine release Increased plasma levels
    Pituitary adenylate cyclase activating peptide Increases transcription, stimulates activity of synthetic enzymes, increased expression of regulatory peptides High mRNA expression
    Chromogranin Protein sorting, vesicle stability and hormone storage Increased plasma levels, increased mRNA expression
    Tyrosine hydroxylase (rate limiting), aromatic L amino acid decarboxylase, dopamine β hydroxylase Enzymes required for catecholamine synthesis Upregulation and increased activity
    Carboxypeptidase E Peptide sorting, activation of prosurvival genes and increased survival of chromaffin cells in hypoxia and nutrient deprivation Increased mRNA expression, correlation with rapid growth and malignancy
    Galanin Stimulates catecholamine and glucocorticoid secretion Increased levels
  • Approximately 30% are hereditary and include the following autosomal dominant disorders:
  • Suspect hereditary etiology when:
    • Family history or symptoms of a syndrome
    • Bilateral tumors
    • Presentation of tumor < 45 years of age
    • Paraganglioma concurrent with pheochromocytoma
Clinical features
  • Clinical suspicion with laboratory testing and imaging for confirmation
  • Rarely may be detected in a needle core needle biopsy
    • Histologic appearance overlaps with normal adrenal medulla
    • Diagnose or raise the consideration to prevent severe surgical complications associated with unsuspected pheochromocytoma for which patient does not receive adrenergic blockade
Radiology description
Radiology images

Images hosted on other servers:

CT and scintigraphy


PET / CT and scintigraphy

Prognostic factors

Table 2. Clinical and pathologic features of pheochromocytoma associated with malignancy
Clinical features Younger age
Secretion of norepinephrine
Gross features Tumor size
Tumor weight
Histologic features Periadrenal adipose tissue invasion
Mitotic rate
Atypical mitoses
Cellular spindling
Marked nuclear pleomorphism
Cellular monotony
Large nests or diffuse growth
High cellularity
Capsular invasion
Vascular invasion
Ancillary studies Higher Ki67
SDHB, VHL, RET mutations
Case reports
  • Surgical resection via total adrenalectomy unless bilateral tumors
    • For bilateral tumors: cortical sparing adrenalectomy to reduce complications related to lifelong glucocorticoid replacement (JAMA Netw Open 2019;2:e198898)
    • Preoperative considerations: administer alpha adrenergic blockers prior to surgery to prevent intraoperative hypertensive crisis, volume expansion to counter catecholamine mediated volume contraction
  • Metastatic tumor also treated with surgical resection if possible
  • Chemotherapy for unresectable tumor: cyclophosphamide, vincristine and dacarbazine
Clinical images

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Café au lait spots and axillary freckling in NF1

images of giant

Gross description
Gross images

Contributed by Debra L. Zynger, M.D. (Case #319)
Well circumscribed tan mass Well circumscribed tan mass

Well circumscribed tan mass

Well circumscribed tan mass Well circumscribed tan mass

Well circumscribed tan mass

Renal invasion

Renal invasion

Composite pheochromocytoma


Frozen section description
  • Vaguely nested architecture
  • Cellular crowding
  • Vesicular, overlapping nuclei
Frozen section images

Contributed by Debra L. Zynger, M.D.

Well circumscribed tumor

Nested with cellular crowding

Permanent section

Microscopic (histologic) description
  • Nested (zellballen), trabecular or solid arrangement
    • Nests outlined with sustentacular cells best visualized with S100 immunostain
  • Cells: large, polygonal, uniform or extensively vacuolated
  • Cytoplasm: abundant fine, granular red-purple cytoplasm
    • Pigmented granules containing hemosiderin, melanin, neuromelanin and lipofuscin may be seen
  • Nuclei: may be uniform or exhibit extensive variation in size, round to oval nuclei, nucleoli prominent
  • Pheochromocytoma of the adrenal gland scaled score (PASS) and grading system for adrenal pheochromocytoma and paraganglioma (GAPP) can be used to assess for malignant potential (see Table 3 and Table 4)
  • Composite pheochromocytoma: pheochromocytoma with ganglioneuroma, ganglioneuroblastoma, neuroblastoma or peripheral nerve sheath tumors

Table 3. Pheochromocytoma of the adrenal gland scaled score (Am J Surg Pathol 2002;26:551)
Histologic feature Score
(total ≥ 4 is concerning for malignancy)
Periadrenal adipose invasion +2
> 3 mitoses/10 high power fields +2
Atypical mitoses +2
Necrosis +2
Cellular spindling +2
Marked nuclear pleomorphism +1
Cellular monotony +2
Large nests or diffuse growth +2
High cellularity +2
Capsular invasion +1
Vascular invasion +1
Hyperchromasia +1

Table 4. Grading system for adrenal pheochromocytoma and paraganglioma (GAPP) (Endocr Relat Cancer 2014;21:405)
Feature Score (well differentiated, 0 - 2; moderately differentiated,  
3 - 6; poorly differentiated, 7 - 10)
Histological pattern Zellballen, 0
Large and irregular cell nests, +1
Pseudorosette, +1
Cellularity (number of tumor cells in 10 mm x  
10 mm square at high power magnification)
Low, < 150, 0
Moderate, 150 - 250, +1
High, > 250, +2
Comedonecrosis +2
Capsular / vascular invasion +1
Ki67 % < 1%, 0
1 - 3%, +1
> 3%, +2
Catecholamine type Nonfunctional, 0
Epinephrine or epinephrine + norepinephrine, 0
Norepinephrine or norepinephrine + dopamine , +1
Microscopic (histologic) images

Contributed by Debra L. Zynger, M.D. (Case #319), Brian Werstein, M.D. and Nicole K. Andeen, M.D. (Case #489)

Nested architecture

Sheets of cells

Abundant cytoplasm

Capsular invasion

Adipose invasion

Vascular invasion

Cellular spindling

Nuclear pleomorphism

Mitotic activity


Large nests

Lymph node metastasis






Composite pheochromocytoma with ganglioneuroma

Virtual slides

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Cytology images

Contributed by Debra L. Zynger, M.D.


Touch preparation

Positive stains
Electron microscopy description
  • Numerous dense cytoplasmic secretory granules 200 - 300 nm containing catecholamines
  • Most have norepinephrine granules
    • Epinephrine granules: centrally placed dense core that lacks a halo
    • Norepinephrine granules: eccentrically placed dense core surrounded by an empty halo
Electron microscopy images

Contributed by Debra L. Zynger, M.D. and Edward Calomeni, B.S.

Numerous epinephrine granules

Norepinephrine granules

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Neurosecretory granules

Molecular / cytogenetics description
  • Genetic testing is recommended for all patients with pheochromocytoma
  • Germline mutations include:
    • Von Hippel-Lindau syndrome: autosomal dominant truncation, deletion or missense mutation of VHL tumor suppressor gene on 3p25-26
      • Pheochromocytoma in 10 - 20%
      • Also hemangioblastomas of the central nervous system, renal cysts, clear cell renal cell carcinoma, pancreatic cysts and pancreatic neuroendocrine tumors, endolymphatic sac tumors and epididymal cystadenomas (Cancer Genet 2012;205:1)
    • Multiple endocrine neoplasia type 2 (MEN 2): autosomal dominant activating mutations in RET proto oncogene on 10q11.2
      • Pheochromocytoma in 50%
      • Also medullary thyroid carcinoma (Endocr Relat Cancer 2018;25:T15)
      • MEN 2a: may also present with hyperparathyroidism
      • MEN 2b: may also present with Marfanoid habitus and multiple mucosal ganglioneuromas
    • Neurofibromatosis type 1 (NF1): autosomal dominant inactivating mutations in NF1 tumor suppressor gene on 17q11.2 (J Clin Oncol 2005;23:8812)
      • Pheochromocytoma in 5 - 7%
      • Also café au lait spots, iris hamartomas, axillary or inguinal freckling, osseous dysplasia and optic pathway glioma (Cancer Genet 2012;205:1)
    • Familial paraganglioma: inactivating mutations in succinate dehydrogenase tumor suppressor gene
    • Others: mutations in TMEM127 and MYC associated factor X (MAX) (familial), HRAS (somatic) (Cancer Genet 2012;205:1, Genes Chromosomes Cancer 2016;55:452)
Molecular / cytogenetics images

Images hosted on other servers:

NF1 mutation

TMEM127 mutation

Sample pathology report
  • Left adrenal, adrenalectomy
    • Pheochromocytoma, 5.1 cm (see synoptic report)
Differential diagnosis
Board review style question #1

    A 38 year old woman presents to clinic complaining of intermittent episodes of headaches and sweating. Her family history is significant for VHL gene mutation in her father. On exam, she has mild hypertension and elevated plasma metanephrines. A noncontrast CT of the abdomen reveals an attenuating 8 cm tumor in the adrenal medulla. An adrenalectomy was done and is shown in the photo. Which immunostains should be expressed?

  1. AE1 / AE3, CK7, TTF1
  2. AE1 / AE3, CK7, ER
  3. MelanA, inhibin A, calretinin
  4. PAX8, PAX2, CAIX
  5. Synaptophysin, chromogranin, S100
Board review style answer #1
E. Synaptophysin, chromogranin, S100. The clinical presentation and image are diagnostic of a pheochromocytoma. Synaptophysin, chromogranin and S100 are positive in pheochromocytoma. AE1 / AE3, CK7 and TTF1 are consistent with metastatic lung adenocarcinoma. AE1 / AE3, CK7 and ER are consistent with metastatic breast carcinoma. MelanA, inhibin A are calretinin are seen in adrenal cortical adenoma / carcinoma. PAX8, PAX2 and CAIX are associated with renal cell carcinoma, clear cell type.

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Reference: Pheochromocytoma
Board review style question #2

A 65 year old man presents with acute worsening of previously well controlled hypertension. Further investigation reveals elevated plasma metanephrines and a right sided adrenal mass. Adrenalectomy reveals a 3 cm, 120 g pheochromocytoma with large, uniform, polygonal cells and 4 mitotic figures per 10 high power fields (HPF). It is positive for chromogranin and synaptophysin. Which of the following features is associated with a more aggressive course?

  1. > 3 mitoses per HPF
  2. Age of diagnosis ≥ 45 years
  3. Positive for synaptophysin
  4. Tumor size < 5 cm
  5. Tumor weight < 130 g
Board review style answer #2
A. > 3 mitoses per HPF. > 3 mitoses per HPF increases risk for malignant pheochromocytoma. It is part of the pheochromocytoma of the adrenal gland scaled score (PASS). A score of ≥ 4 is concerning for malignancy, and scores are based on the presence of the following features: periadrenal adipose invasion (+2), > 3 mitosis per 10 high powered fields (+2), atypical mitoses (+2), necrosis (+2), cellular spindling (+2), marked nuclear pleomorphism (+1), cellular monotony (+2), large nests or diffuse growth (+2), high cellularity (+2), capsular invasion (+1), vascular invasion (+1), hyperchromasia (+1). Age of diagnosis < 45 years is associated with more aggressive disease, rather than older age. Staining with synaptophysin is a characteristic feature of pheochromocytoma and does not predict a more aggressive disease course. Larger and heavier tumors are associated with more aggressive disease, rather than smaller and lighter tumors.

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Reference: Pheochromocytoma
Board review style question #3

The adrenal tumor shown above was found to express chromogranin and GATA3 and was negative for AE1 / AE3. Which is the correct diagnosis?

  1. Adrenal cortical adenoma
  2. Adrenal cortical carcinoma
  3. Lung adenocarcinoma
  4. Pheochromocytoma
  5. Urothelial carcinoma
Board review style answer #3
D. Pheochromocytoma

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Reference: Pheochromocytoma
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