Pheochromocytoma

  • Diagnosis
  • Algorithms
  • Screening
  • Monitoring
  • Background
  • Pediatrics
  • Lab Tests
  • References
  • Related Topics
  • Videos

Indications for Testing

  • New onset of hypertension, diaphoresis, adrenal abnormality, tachycardia, or an associated hereditary syndrome

Laboratory Testing

  • Initial testing – plasma free or urine metanephrines (normetanephrine and metanephrine) (Lenders, 2014); urine may be preferred in patients at low risk for tumor (fewer false positives)
    • Plasma test preferable in patients with renal insufficiency and in children
    • Not elevated – pheochromocytoma unlikely
      • If high suspicion exists, repeat testing in 3-6 months
      • Negative testing has high negative predictive value
    • Mildly elevated or indeterminate – evaluate potential false positives (influence of diet, medications, inappropriate sampling conditions)
      • If suspicion still exists for pheochromocytoma, consider additional evaluation – follow up with endocrinologist (clonidine suppression testing)
    • Moderately to highly elevated – if high suspicion of pheochromocytoma, repeat metanephrines testing
      • Elevated – pheochromocytoma likely; proceed with CT/MRI of abdomen and pelvis (refer to Imaging Studies)
      • Not elevated – pheochromocytoma unlikely; if high suspicion exists, repeat testing in 6-12 months
  • Other testing
    • Tumors that produce only dopamine are not detected by screening with plasma metanephrines – use measurement of dopamine in plasma or urine.
      • These tumors are rare
    • Chromogranin A in concert with above testing may improve sensitivity of diagnostic and long-term follow-up testing
      • Nonspecific testing for pheochromocytoma
    • Fractionated catecholamines – may be useful to confirm results from metanephrine tests
    • If tumor is coincidentally found in asymptomatic patient who is not being familially screened, consider dopamine testing
      • If high, order homovanillic acid test
  • Genetic testing
    • Diagnosis of pheochromocytoma should be established prior to any genetic testing
    •  The following tumor settings suggest possibility of genetic mutation (NCCN, 2014)
      • Paraganglioma (PGL)
      • Bilateral, recurrent, or multifocal adrenal pheochromocytoma (PCC)
      • Unilateral PCC and family history of PGL/PCC
      • Unilateral PCC onset <45 years
    • ~30-40% of pheochromocytomas are associated with a known genetic syndrome
      • Multiple endocrine neoplasia type 2 (MEN2)
      • von Hippel-Lindau (VHL) syndrome
      • Neurofibromatosis type 1 (NF1, von Recklinghausen disease)
      • Hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes
    • Refer to Paraganglioma/Pheochromocytoma Molecular Testing Algorithm

Histology

  • Immunohistochemistry
    • Tissue biopsy with chromogranin A staining is diagnostic
      • Other stains – cytokeratin 8,18 low molecular weight (CAM 5.2), protein gene product (PGP) 9.5, and synaptophysin

Imaging Studies

  • Magnetic resonance imaging (MRI) or multiphasic computed tomography (CT) of abdomen and pelvis following biochemical confirmation
    • MRI – slightly more sensitive than CT; variable specificity
    • CT – high sensitivity for intra-adrenal tumors ≥5 cm in diameter and for extra-adrenal tumors; same specificity as MRI
    • Imaging results
      • Tumor visualized – consider genetic testing (eg, MEN2 gene)
      • No tumor visualized – proceed to scintigraphy using 123I- metaiodobenzylguanidine (MIBG) or positron emission tomography (PET) using either 18F-fluorodeoxyglucose (FDG) or L-3,4-dihydroxy-6-[18F]fluorophenylalanine (18F-FDOPA)
        • Negative – consider technetium bone scan if bone symptoms are present
        • Positive – consider genetic testing (eg, MEN2 gene mutation analysis)

Differential Diagnosis

  • Essential hypertension
  • Anxiety attack
  • Subarachnoid hemorrhage
  • Diencephalic seizures
  • Chromogranin A (neuroendocrine marker)
    • Nonspecific for pheochromocytoma
      • May be used to monitor response to treatment or disease relapse
      • Concentration has been noted to correlate well with plasma metanephrines and tumor mass

Paragangliomas are neuroendocrine tumors of the autonomic nervous system. Sympathetic paragangliomas generally secrete catecholamines (epinephrine, norepinephrine) and are usually located in the retroperitoneal space, abdomen, or thorax; paragangliomas of the adrenal medulla are commonly called pheochromocytomas. Parasympathetic paragangliomas are usually in the head and neck region and are generally nonsecreting.

Epidemiology

  • Incidence – 8/million in U.S. (Brito, 2015)
  • Age – peaks in 40s; may occur at a younger age in hereditary forms and older age in sporadic forms
  • Sex – M:F, equal
  • Occurrence – most are sporadic (80%)

Pathophysiology

  • Most paragangliomas are found in the adrenal medulla and are benign in histology
    • Derived from chromaffin cells (chromaffin tumors produce catecholamines)
  • Tumor pattern of catecholamine release may suggest association with genetic disorder
    • Multiple endocrine neoplasia type 2 (MEN2) and neurofibromatosis type 1 (NF1, von Recklinghausen disease)
      • Increase in plasma concentration of metanephrine
    • von Hippel-Lindau (VHL) syndrome
      • Low level of epinephrine
      • No increase in plasma concentration of metanephrine
      • Rarely shows increases in plasma or urinary epinephrine and metanephrine
    • SDH gene-associated disorders
      • Plasma concentration and urinary output of dopamine more often increased in SDH gene-associated disorders than in other conditions
      • Plasma methoxytyramine provides sensitive biomarker for indicating tumor dopamine production
        • Increased dopamine production leads to increased plasma methoxytyramine
      • Rare increase in plasma or urinary epinephrine and metanephrine

Clinical Presentation

  • Hypertension
    • Sustained hypertension in large proportion of patients
    • May be severe
  • Paroxysmal attacks
    • Sudden onset
    • Duration – several minutes to hours
    • Headache, diaphoresis, chest pain, pallor, tachycardia, nausea
  • May be induced by certain drugs – opiates, anesthetics, glucagon, monoamine oxidase (MAO) inhibitors
  • Cardiac signs
    • Tachycardia, arrhythmia, bradycardia
    • Heart failure
    • Hypertensive encephalopathy
    • Myocardial infarction
    • Sudden death
  • Metastatic disease
    • Most common sites are lung, lymph nodes, bones, liver
  • Associated hereditary syndromes
    • MEN2
      • RET gene mutations
        • MEN2A – medullary thyroid carcinoma (MTC), pheochromocytoma (multicentric, bilateral), parathyroid adenoma
        • MEN2B – MTC (onset in early childhood), pheochromocytoma (multicentric, bilateral), mucosal neuroma, intestinal ganglioneuromatosis
        • Familial medullary thyroid carcinoma (FMTC) – MTC only
    • VHL syndrome
      • VHL gene mutations
        • Retinal, cerebellar, and spinal hemangioblastoma; renal cell carcinoma (RCC); pheochromocytoma; pancreatic neuroendocrine tumors; endolymphatic sac tumors; renal, pancreatic, and epididymal cysts
        • Different VHL subtypes based on specific mutation
          • Type 1 – low risk for pheochromocytoma
          • Type 2A – low risk for RCC
          • Type 2B – risk for pheochromocytoma and RCC
          • Type 2C – risk for pheochromocytoma only
    • Hereditary paraganglioma/pheochromocytoma (PGL/PCC) syndromes
      • Paragangliomas – neuroendocrine tumors of the autonomic nervous system
      • Sympathetic nervous system tumors
        • Secrete catecholamines
        • Usually in retroperitoneal space, abdomen, or thorax
        • Paroxysmal tachycardia/palpitations
        • Hypertension
        • Headache
        • Hyperglycemia
        • Pallor/weight loss
      • Parasympathetic nervous system tumors
        • Usually in head and neck region, or aortic root
        • Tumors are usually nonsecreting
        • Symptoms are due to compression or infiltration of adjacent structures (including cranial nerves)
    • NF1
      • NF1 gene mutations
      • Multiple café au lait spots, neurofibromas, axillary and inguinal freckling, optic glioma, pheochromocytoma

Clinical Background

Epidemiology

  • Incidence – rare, but the most common pediatric endocrine tumor
  • Age – average onset is 11 years

Genetics

  • Pheochromocytomas may be associated with a known genetic syndrome
    • Multiple endocrine neoplasia type 2 (MEN2)
      • RET gene mutations
      • Type 2B – early-onset medullary thyroid carcinoma
    • von Hippel-Lindau (VHL) syndrome
      • VHL gene mutations
      • Pheochromocytoma may be first presentation of VHL
    • Hereditary paraganglioma/pheochromocytoma (PGL/PCC) syndromes
      • SDHBSDHCSDHDSDHAF2SDHATMEM127, and MAX gene mutations
    • Neurofibromatosis type 1 (NF1, von Recklinghausen disease)
      • NF1 gene mutations
      • Multiple café au lait spots, neurofibromas, axillary and inguinal freckling, optic glioma, pheochromocytoma
  • Refer to Paraganglioma/Pheochromocytoma Molecular Testing Algorithm

Clinical Presentation

  • Sustained hypertension – 60-90% of cases
  • Palpitations, headaches, sweating, pallor
  • Malignant tumors rare
    • Highest risk with SDHB germline mutations
  • Complications
    • Hypertensive crisis
    • Cardiomyopathy
    • Seizures, stroke
    • Pancreatitis

Diagnosis

Indications for Testing

  • New onset hypertension, diaphoresis, adrenal abnormality, tachycardia, or an associated hereditary syndrome

Laboratory Testing

  • Initial testing – see Diagnosis section
  • Clonidine suppression test not validated in children
  • Genetic testing
    • Diagnosis of a pheochromocytoma or paraganglioma should be confirmed prior to genetic testing
    • Should be performed for all children who present with tumor regardless of family history
    • Specific genetic tests
    • Testing for associated syndromes
      • VHL and RET genes
        • Consider in children with pheochromocytoma
      • SDHB gene
        • Consider in malignant paragangliomas
      • NF1 gene
        • Not recommended
        • Testing has very low yield since NF1 is usually a clinical diagnosis
    • Refer to Paraganglioma/Pheochromocytoma Molecular Testing Algorithm

Imaging Studies

  • Magnetic resonance imaging (MRI) to avoid computed tomography (CT) due to radiation exposure – may also use abdominal ultrasound if expertise is available
  • Scintigraphy using 123I- metaiodobenzylguanidine (123I-MIBG) – use to confirm malignant disease, assess patient for multiple tumors, or use if MRI is negative
  • Positron emission tomography (PET) using 18F-fluorodeoxyglucose (18F-FDG) may be superior in pheochromocytomas that are found in SDH carriers

Differential Diagnosis

  • Essential hypertension
  • Anxiety attack
  • Subarachnoid hemorrhage
  • Diencephalic seizures

Screening

  • Consider genetic testing for at-risk family members, including asymptomatic children
  • Refer to Paraganglioma/Pheochromocytoma Molecular Testing Algorithm

Tests generally appear in the order most useful for common clinical situations. Click on number for test-specific information in the ARUP Laboratory Test Directory.

Metanephrines, Plasma (Free) 0050184
Method: Quantitative Liquid Chromatography-Tandem Mass Spectrometry

Limitations

False positives may occur

Follow Up

If indeterminate, order urine metanephrines

Metanephrines Fractionated by HPLC-MS/MS, Urine 2007996
Method: Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry

Limitations

24-hour specimen required

Smaller increases in metanephrine concentration may be the result of physiological stimuli, drugs, or improper specimen collection; higher concentration can be caused by improper specimen collection, life-threatening illness, intense physical activity, or neuroendocrine tumors

Catecholamines Fractionated by LC-MS/MS, Urine Free 0080407
Method: Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry

Limitations

Smaller increases in concentration may be the result of physiological stimuli, drugs, or improper specimen collection

Moderately elevated concentration may be caused by essential hypertension, intense anxiety, intense physical exercise, or drug interactions (including some over-the-counter medications and herbal products)

Multiple Endocrine Neoplasia Type 2 (MEN2), RET Gene Mutations by Sequencing 0051390
Method: Polymerase Chain Reaction/Sequencing

Limitations

Mutations in regulatory regions or exons not targeted for sequencing are not identified

SDHB with Interpretation by Immunohistochemistry 2006948
Method: Immunohistochemistry

Hereditary Paraganglioma-Pheochromocytoma (SDHB, SDHC, and SDHD) Sequencing and Deletion/Duplication Panel 2007167
Method: Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification

Limitations

Not detected or evaluated – mutations in genes other than those listed; deep intronic and regulatory region mutations

Breakpoints of large deletions/duplications will not be determined

Rare diagnostic errors may occur due to primer- or probe-site mutations

Hereditary Paraganglioma-Pheochromocytoma (SDHA) Sequencing 2011461
Method: Polymerase Chain Reaction/Sequencing

Limitations

Not detected or evaluated – mutations in genes other than those listed; deep intronic and regulatory region mutations

Breakpoints of large deletions/duplications will not be determined

Rare diagnostic errors may occur due to primer- or probe-site mutations

In some cases, results may be uninterpretable due to technical limitations in the presence of pseudogenes

Cytokeratin 8,18 Low Molecular Weight (CAM 5.2) by Immunohistochemistry 2003493
Method: Immunohistochemistry

Chromogranin A by Immunohistochemistry 2003830
Method: Immunohistochemistry

Protein Gene Product (PGP) 9.5 by Immunohistochemistry 2004091
Method: Immunohistochemistry

Synaptophysin by Immunohistochemistry 2004139
Method: Immunohistochemistry

Related Tests

Guidelines

Chen H, Sippel RS, O'Dorisio S, Vinik AI, Lloyd RV, Pacak K, North American Neuroendocrine Tumor Society (NANETS). The North American Neuroendocrine Tumor Society consensus guideline for the diagnosis and management of neuroendocrine tumors: pheochromocytoma, paraganglioma, and medullary thyroid cancer. Pancreas. 2010; 39(6): 775-83. PubMed

Lenders JW M, Duh Q, Eisenhofer G, Gimenez-Roqueplo A, Grebe SK G, Murad MHassan, Naruse M, Pacak K, Young WF, Endocrine Society. Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014; 99(6): 1915-42. PubMed

NCCN Clinical Practice Guidelines in Oncology, Neuroendocrine Tumors. National Comprehensive Cancer Network. Fort Washington, PA [Accessed: Mar 2016]

Pacak K, Eisenhofer G, Ahlman H, Bornstein SR, Gimenez-Roqueplo A, Grossman AB, Kimura N, Mannelli M, McNicol AMarie, Tischler AS, International Symposium on Pheochromocytoma. Pheochromocytoma: recommendations for clinical practice from the First International Symposium. October 2005. Nat Clin Pract Endocrinol Metab. 2007; 3(2): 92-102. PubMed

General References

Adler JT, Meyer-Rochow GY, Chen H, Benn DE, Robinson BG, Sippel RS, Sidhu SB. Pheochromocytoma: current approaches and future directions. Oncologist. 2008; 13(7): 779-93. PubMed

Barontini M, Dahia PL M. VHL disease. Best Pract Res Clin Endocrinol Metab. 2010; 24(3): 401-13. PubMed

Barron J. Phaeochromocytoma: diagnostic challenges for biochemical screening and diagnosis. J Clin Pathol. 2010; 63(8): 669-74. PubMed

Brito JP, Asi N, Bancos I, Gionfriddo MR, Zeballos-Palacios CL, Leppin AL, Undavalli C, Wang Z, Domecq JP, Prustsky G, Elraiyah TA, Prokop LJ, Montori VM, Murad MH. Testing for germline mutations in sporadic pheochromocytoma/paraganglioma: a systematic review. Clin Endocrinol (Oxf). 2015; 82(3): 338-45. PubMed

Donckier JE, Michel L. Phaeochromocytoma: state-of-the-art. Acta Chir Belg. 2010; 110(2): 140-8. PubMed

Eisenhofer G, Lenders JW M, Timmers H, Mannelli M, Grebe SK, Hofbauer LC, Bornstein SR, Tiebel O, Adams K, Bratslavsky G, Linehan M, Pacak K. Measurements of plasma methoxytyramine, normetanephrine, and metanephrine as discriminators of different hereditary forms of pheochromocytoma. Clin Chem. 2011; 57(3): 411-20. PubMed

Eisenhofer G, Peitzsch M. Laboratory evaluation of pheochromocytoma and paraganglioma. Clin Chem. 2014; 60(12): 1486-99. PubMed

Kantorovich V, King KS, Pacak K. SDH-related pheochromocytoma and paraganglioma. Best Pract Res Clin Endocrinol Metab. 2010; 24(3): 415-24. PubMed

Pappachan JM, Raskauskiene D, Sriraman R, Edavalath M, Hanna FW. Diagnosis and management of pheochromocytoma: a practical guide to clinicians. Curr Hypertens Rep. 2014; 16(7): 442. PubMed

Tischler AS. Pheochromocytoma and extra-adrenal paraganglioma: updates. Arch Pathol Lab Med. 2008; 132(8): 1272-84. PubMed

van Berkel A, Lenders JW M, Timmers HJ L M. Diagnosis of endocrine disease: Biochemical diagnosis of phaeochromocytoma and paraganglioma. Eur J Endocrinol. 2014; 170(3): R109-19. PubMed

Waguespack SG, Rich T, Grubbs E, Ying AK, Perrier ND, Ayala-Ramirez M, Jimenez C. A current review of the etiology, diagnosis, and treatment of pediatric pheochromocytoma and paraganglioma. J Clin Endocrinol Metab. 2010; 95(5): 2023-37. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Clark ZD, Frank EL. Urinary metanephrines by liquid chromatography tandem mass spectrometry: using multiple quantification methods to minimize interferences in a high throughput method. J Chromatogr B Analyt Technol Biomed Life Sci. 2011; 879(31): 3673-80. PubMed

Comstock JM, Willmore-Payne C, Holden JA, Coffin CM. Composite pheochromocytoma: a clinicopathologic and molecular comparison with ordinary pheochromocytoma and neuroblastoma. Am J Clin Pathol. 2009; 132(1): 69-73. PubMed

Heider EC, Davis BG, Frank EL. Nonparametric determination of reference intervals for plasma metanephrine and normetanephrine. Clin Chem. 2004; 50(12): 2381-4. PubMed

Kushnir MM, Urry FM, Frank EL, Roberts WL, Shushan B. Analysis of catecholamines in urine by positive-ion electrospray tandem mass spectrometry. Clin Chem. 2002; 48(2): 323-31. PubMed

Lanikova L, Lorenzo F, Yang C, Vankayalapati H, Drachtman R, Divoky V, Prchal JT. Novel homozygous VHL mutation in exon 2 is associated with congenital polycythemia but not with cancer. Blood. 2013; 121(19): 3918-24. PubMed

Lorenzo FR, Yang C, Fui MNg Tang, Vankayalapati H, Zhuang Z, Huynh T, Grossmann M, Pacak K, Prchal JT. A novel EPAS1/HIF2A germline mutation in a congenital polycythemia with paraganglioma. J Mol Med (Berl). 2013; 91(4): 507-12. PubMed

Margraf RL, Calderon FR O, Mao R, Wittwer CT. RET mutation scanning update: exon 15. Clin Chem. 2009; 55(11): 2059-61. PubMed

Margraf RL, Mao R, Highsmith E, Holtegaard LM, Wittwer CT. Mutation scanning of the RET protooncogene using high-resolution melting analysis. Clin Chem. 2006; 52(1): 138-41. PubMed

Pacak K, Jochmanova I, Prodanov T, Yang C, Merino MJ, Fojo T, Prchal JT, Tischler AS, Lechan RM, Zhuang Z. New syndrome of paraganglioma and somatostatinoma associated with polycythemia. J Clin Oncol. 2013; 31(13): 1690-8. PubMed

Petteys BJ, Graham KS, Parnás L, Holt C, Frank EL. Performance characteristics of an LC-MS/MS method for the determination of plasma metanephrines. Clin Chim Acta. 2012; 413(19-20): 1459-65. PubMed

Singh RJ, Grebe SK, Yue B, Rockwood AL, Cramer JC, Gombos Z, Eisenhofer G. Precisely wrong? Urinary fractionated metanephrines and peer-based laboratory proficiency testing. Clin Chem. 2005; 51(2): 472-3; discussion 473-4. PubMed

Yang C, Sun MG, Matro J, Huynh TT, Rahimpour S, Prchal JT, Lechan R, Lonser R, Pacak K, Zhuang Z. Novel HIF2A mutations disrupt oxygen sensing, leading to polycythemia, paragangliomas, and somatostatinomas. Blood. 2013; 121(13): 2563-6. PubMed

Zhuang Z, Yang C, Lorenzo F, Merino M, Fojo T, Kebebew E, Popovic V, Stratakis CA, Prchal JT, Pacak K. Somatic HIF2A gain-of-function mutations in paraganglioma with polycythemia. N Engl J Med. 2012; 367(10): 922-30. PubMed

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Last Update: April 2016