Adrenal gland & paraganglia
Pheochromocytoma / paraganglioma
Pheochromocytoma


Topic Completed: 28 January 2020

Minor changes: 11 March 2020

Copyright: 2002-2020, PathologyOutlines.com, Inc.

PubMed Search: Pheochromocytoma[TI] adrenal[TI] pathology free full text[sb]

Katherine A. Lehman, M.D. Candidate
Debra Zynger, M.D.
Page views in 2019: 31,439
Page views in 2020 to date: 19,271
Cite this page: Lehman K, Zynger D. Pheochromocytoma. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/adrenalpheochromocytoma.html. Accessed August 8th, 2020.
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% of cases
  • Malignant in approximately 10% of cases: treatment is total adrenalectomy if unilateral and cortical sparing adrenalectomy if bilateral
  • 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
Terminology
  • 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
  • ICD-10: D35.00 - benign neoplasm of unspecified adrenal gland
  • ICD-10: C74.10 - pheochromocytoma, malignant; pheochromoblastoma
Epidemiology
Sites
  • Adrenal gland medulla
Pathophysiology
  • 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
Etiology
  • 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
Diagnosis
  • 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
Laboratory
Radiology description
Radiology images

Images hosted on other servers:

CT and scintigraphy

MRI

PET / CT and scintigraphy

Prognostic factors
  • No specific histologic or molecular markers to differentiate benign from malignant
    • See Table 2 for clinical and pathologic features associated with malignancy
  • There is a TNM staging system for which pT is based on tumor size (≤ 5 cm or > 5cm) and depth of invasion
  • Worse prognosis for larger (metastatic mean diameter ~ 7 - 9 cm) and heavier (metastatic mean 280 g) tumors
  • Presence of metastases defines malignancy: most commonly to lymph nodes, bone, liver and lung (Endocr Relat Cancer 2007;14:569)
  • ~ 10% of pheochromocytomas are metastatic (Endocr Relat Cancer 2007;14:569, J Surg Oncol 2015;112:815)
  • 5 year and 10 year survival ~ 65% and 35%, respectively (J Surg Oncol 2015;112:815)
  • 6 - 9% of excised tumors have local recurrence (Surgery 2014;156:1523)

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
Necrosis
Cellular spindling
Marked nuclear pleomorphism
Cellular monotony
Large nests or diffuse growth
High cellularity
Capsular invasion
Vascular invasion
Hyperchromasia
Ancillary studies Ki67
SDHB, VHL, RET mutations
Case reports
Treatment
  • 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

Images hosted on other servers:

Café au lait spots and axillary freckling in NF1

Intraoperative images of giant pheochromocytoma

Gross description
Gross images

Contributed by Debra Zynger, M.D.

Well circumscribed tan mass

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

Contributed by Debra 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) can be used to assess for malignant potential (see Table 3)
    • Features to assess: periadrenal adipose invasion, > 3 mitoses / 10 high power fields, atypical mitoses, necrosis, cellular spindling, marked nuclear pleomorphism, cellular monotony, large nests or diffuse growth, high cellularity, capsular invasion, vascular invasion
    • Score ≥ 4 is concerning for malignancy (Am J Surg Pathol 2002;26:551)
  • Composite pheochromocytoma: pheochromocytoma with ganglioneuroma, ganglioneuroblastoma, neuroblastoma or peripheral nerve sheath tumors

Table 3 Pheochromocytoma of the Adrenal Gland Scaled Score
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 +2
Cellular monotony +2
Large nests or diffuse growth +2
High cellularity +2
Capsular invasion +1
Vascular invasion +1
Hyperchromasia +1
Microscopic (histologic) images

Contributed by Debra Zynger, M.D., Brian Werstein, M.D. and Nicole K. Andeen, M.D.

Nested architecture

Sheets of cells

Abundant cytoplasm

Chromogranin

S100

GATA3


PASS criteria


Low power

Medium power

High power

Lymph node

S100

Synaptophysin

Virtual slides

Images hosted on other servers:

Pheochromocytoma

Cytology images

Contributed by Debra Zynger, M.D.

Diff-Quik

H&E

Positive stains
Negative 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 Zynger, M.D. and Edward Calomeni, B.S.

Numerous epinephrine granules

Norepinephrine granules



Images hosted on other servers:

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
  • Adrenal cortical carcinoma
    • Typically large and produce steroids; irregular mass with noncontrast CT attenuation ≥ 10 HU and inhomogeneous contrast enhancement with delayed washout
    • Solid growth pattern, abundant eosinophilic cytoplasm with focal clear areas, variable mitoses and nuclear polymorphism depending on grade (Endocr Rev 2014;35:282)
    • MelanA, inhibin A and calretinin positive; Ki67 usually high
    • Chromogranin and S100 negative
    • Synaptophysin variable
  • Adrenal medulla or adrenal medullary hyperplasia
    • Normal adrenal medulla can mimic on needle core biopsy
    • Generally considered neoplastic if radiologically or grossly a discrete tumor
    • IHC cannot differentiate
  • Metastases
    • Metastatic renal cell carcinoma, melanoma, lung, colon, breast
    • History, morphology and immunohistochemistry vary according to origin but typically lack chromogranin and S100 (unless melanoma)
    • Rule out carcinoma with broad spectrum keratin such as AE1/AE3 plus CK7 and CK20
  • Adrenal cortical adenoma
    • May be nonfunctional (clinically silent) or secrete steroids; non contrast CT shows small, round, homogeneous mass with smooth borders and attenuation typically ≤ 10 HU; contrast CT has rapid contrast washout
    • Clear, compact cells without abnormal mitoses or dysplasia arranged in nests, cords or trabecular shapes within a fibrous capsule (Onco Targets Ther 2015;8:1251)
    • MelanA, inhibin A and calretinin positive
    • Chromogranin and S100 negative
    • Synaptophysin weak to negative
  • Composite pheochromocytoma
    • Also has a component of ganglioneuroma, ganglioneuroblastoma, neuroblastoma or peripheral nerve sheath tumors
Board review style question #1

    A 38 year old female 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 non contrast 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 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.

Reference: Pheochromocytoma

Comment Here
Board review style question #2
    A 65 year old male 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 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 (+2), 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.

Reference: Pheochromocytoma

Comment Here
Board review style question #3
    Which of the following genes are NOT associated with hereditary pheochromocytoma?

  1. NF1
  2. VHL
  3. RET
  4. MEN1
  5. MAX
Board review answer #3
D. MEN1
Inherited mutations in the MEN1 gene are associated with multiple endocrine neoplasia (MEN) type 1. MEN type 1 is associated with tumors of the parathyroid glands, the pituitary gland and the pancreas, but there is no significant association with pheochromocytoma. Mutations in the rest of the listed genes are associated with hereditary pheochromocytoma (Endocr Pract 2017;23:690).

Reference: Pheochromocytoma

Comment Here
Back to top