Pheochromocytoma - Paraganglioma

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.

Quick Answers for Clinicians

Diagnosis

Indications for Testing

  • Symptomatic patient
    • New onset of clinical syndrome of hypertension, diaphoresis, tachycardia, syncope, headache
  • Incidental finding on imaging
    • Adrenal abnormality noted on imaging suggestive of pheochromocytoma
  • Hereditary syndrome
    • Associated hereditary syndrome, especially
      • Neurofibromatosis type 1 (NF1, von Recklinghausen disease)
      • Multiple endocrine neoplasm 2 (MEN2)
      • von Hippel-Lindau (VHL) syndrome
      • Hereditary paraganglioma/pheochromocytoma (PGL/PCC) syndromes – especially SDH gene-associated disorders

Laboratory Testing

  • Initial testing (for symptomatic patient or incidental finding) – can use plasma-free metanephrines alone, urine metanephrines alone, or both together
    • Plasma-free metanephrines (normetanephrine and metanephrine) (National Comprehensive Cancer Network [NCCN], 2017)
      • Preferred in
        • High probability patients
        • Renal insufficiency
        • Children
      • Negative testing has high negative predictive value
      • Results
        • Negative and high suspicion – repeat in 6 months
        • Mild elevation or indeterminate
          • Evaluate for causes for false positive
          • Consider referral to endocrinologist
        • Elevated – repeat testing to confirm, proceed to imaging
    • 24-hour, fractionated urine metanephrines
      • Preferred in patients at low risk for tumor (fewer false positives)
      • Results
        • Negative and high suspicion – repeat in 6 months
        • Mild elevation or indeterminate
          • Evaluate for causes for false positive
          • Consider referral to endocrinologist
        • Elevated – repeat testing to confirm, proceed to imaging
  • Other testing (for symptomatic patient or incidental finding)
    • Dopamine, plasma or urine (reported with Catecholamines, fractionated) – consider for
      • Cervical paraganglioma and asymptomatic adrenal tumor
      • Metastatic disease (metastatic tissue often lacks the enzymes needed to synthesize precursors to catecholamines) (Pappachan, 2014)
    • Homovanillic acid
      • Order if high dopamine concentrations found
    • Methoxytyramine (metabolite of dopamine) (not available at ARUP Laboratories) – consider for
      • Cervical paraganglioma
      • Metastatic disease
    • Fractionated catecholamines
      • May be useful for evaluating clinical symptoms of excess catecholamine secretion
      • No longer recommended testing – plasma or urine metanephrines are tests of choice
  • Genetic testing (for hereditary syndrome)
    • Identified pheochromocytoma or paraganglioma – all patients should be referred for genetic testing (30-40% will have genetic variant) (NCCN, 2017)
      • Referral to genetic counselor to guide appropriate testing is recommended
    • Known family history of associated syndrome or known DNA variant – patients should be tested for appropriate variant (familial mutation targeted sequencing)
    • No known family history of associated syndrome or known DNA variant – testing can be narrowed down based on the clinical symptoms, other tumors, age at diagnosis, etc
      • (See ARUP Genetic testing form for example)
      • Detailed information should be provided with genetic test request
        • Ethnicity
        • Clinical signs and symptoms
          • Tumor location
          • Single/multiple tumor, bilateral tumors
          • Secretory/nonsecretory
        • Other tumors/cancers/conditions
          • Renal cell carcinoma
          • Breast cancer
          • Papillary thyroid cancer
          • Parathyroid hyperplasia
          • Gastrointestinal stromal tumor
          • Other
        • Catecholamine secretion
          • Epinephrine (or metabolite metanephrine)
          • Norepinephrine (or metabolite normetanephrine)
          • Dopamine (or metabolite methoxytyramine)
        • Immunohistochemistry results
          • Normal vs absent SDHB
      • Syndromes – suggest specific testing (see Paraganglioma/Pheochromocytoma Genetic Testing Algorithm for details regarding testing)
        • NF1
        • MEN2 – RET
        • VHL
        • Hereditary PGL/PCC syndrome

Histology

  • Tissue biopsy with chromogranin A staining is diagnostic
  • Other useful immunohistochemistry stains may include SDHB and synaptophysin
    • SDHB presence or absence can help guide genetic testing
  • For detailed descriptions, including recommended tests, refer to ARUP’s Immunohistochemistry Stain Offerings

Imaging Studies

  • Multiphasic computed tomography (CT) abdomen and pelvis – recommended first-line imaging (Lenders, Endocrine Society, 2014)
  • Magnetic resonance imaging (MRI) has similar sensitivity to CT but higher cost (NCCN, 2017),
    • Recommended if CT contraindicated or cases in which MRI would show better imaging (skull base/neck, adjacent surgical clips) (Lenders, Endocrine Society, 2014)
  • Metastasis suspected
    • 123I-metaiodobenzylguanidine (123I-MIBG)
    • 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) or l-3,4-dihydroxy-6-[18F]fluorophenylalanine (18F-FDOPA)
    • Somatostatin receptor-based imaging
    • Bone scan – recommended if bone symptoms present

Differential Diagnosis

  • Clinical signs
    • Essential hypertension
    • Anxiety attack
    • Subarachnoid hemorrhage
    • Diencephalic seizures
  • Tumors
    • Adrenocorticoid carcinoma
    • Neuroendocrine tumor
    • Lymphoma
    • Medulloblastoma
    • Rhabdosarcoma
    • Small cell osteosarcoma

Screening

  • Screen individuals with conditions below
    • High risk
      • Individuals or family member with
        • Neurofibromatosis type 1 (NF1)
        • Multiple endocrine neoplasia (MEN) type 2A or 2B
        • Von Hippel-Lindau (VHL)
        • Hereditary paraganglioma/pheochromocytoma (PGL/PCC) syndromes – especially SDH gene-associated disorders
      • Adrenal incidentaloma
    • Lower risk (<1% or not identified) (Pappachan, 2014)
      • Resistance hypertension
      • Unexplained heart failure
      • Paroxysmal headaches, palpitations, sweating, and panic attacks in association with hypertension
      • Hypertensive crisis developing during surgery or general anaesthesia
      • Hypertension triggered by beta blockers, monoamine oxidase inhibitors, micturition/changes in abdominal pressure
      • Orthostatic hypotension in a hypertensive patient
      • New onset diabetes mellitus in a young, lean individual with hypertension
  • Consider genetic testing for at-risk family members based on syndrome recommendations and clinical symptoms
  • Refer to Paraganglioma/Pheochromocytoma Molecular Testing Algorithm

Monitoring

  • Plasma-free or fractionated urine metanephrines (Kunz, North American Neuroendocrine Tumor Society [NANETS], 2013)
    • Recommended at 6 and 12 months following resection (every 3-6 months for advanced disease), then annually
    • Duration of follow-up not defined
  • Chromogranin A (neuroendocrine marker) – consider if tumor does not produce plasma metanephrines

Background

Epidemiology

  • Incidence – 2-8 per million per year in U.S. (National Institutes of Health [NIH]/National Cancer Institute [NCI], 2015)
  • Age – peaks in 40s; occurs at younger age in hereditary forms and older age in sporadic forms
  • Sex – M:F, equal
  • Occurrence – most are sporadic (80%)

Pathophysiology

  • Paragangliomas – arise from chromaffin cells outside the adrenal gland (extra-adrenal tissue) and are found in the abdomen, thorax, and pelvis
  • Pheochromocytomas – arise from chromaffin cells located within the adrenal glands
  • Both produce catecholamines – epinephrine, norepinephrine, or dopamine, or combinations of these
    • Secretion is increased by stress – baseline plasma and urine concentrations can be quite variable
    • Tumor pattern of catecholamine release may suggest association with genetic disorder
      • Neurofibromatosis type 1 (NF1, von Recklinghausen disease) and multiple endocrine neoplasia type 2 (MEN2)​
        • 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
        • ​Metastatic – associated with low levels of methoxytyramine

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

Familial Genetics

  • Diagnosis of pheochromocytoma should be established prior to any genetic testing
    • All patients with pheochromocytoma or paraganglioma should be referred to genetic counselor due to high rate of familial mutations associated with these tumor types (30-40% in some series) (National Comprehensive Cancer Network [NCCN], 2017)
  • Germline mutations in the following 10 genes are found to be associated with paraganglioma and/or pheochromocytoma
    • NF1 – neurofibromatosis type 1, von Recklinghausen disease
    • RET – MEN2
    • VHL – VHL syndrome
    • SDHA/B/C/D,SDHAF2, TMEM127, MAX – hereditary paraganglioma/pheochromocytoma (PGL/PCC) syndromes (SDHB variants are most frequent; TMEM127, MAX, SDHAF2 are rare)
      Hereditary PGL/PCC Syndromes
      Syndrome/Gene Age of Onset Tumors Inheritancea Risk of Malignant Transformation

      PGL/PCC type 1

      (SDHD)

      Mean – 35 yrs

      Range – 10-96 yrs

      Multiple tumors, especially head and neck

      May have sporadically appearing PCC

      May be associated with risk of RCC

      AD

      Parent-of-origin effect – tumor predisposition generally occurs only when mutations are inherited paternally

      Highly penetrant

      <5%

      PGL/PCC type 2

      (SDHAF2)

      Mean – 32 yrs

      Multiple head and neck tumors

      AD

      Parent-of-origin effect – tumor predisposition generally occurs only when mutations are inherited paternally

      Low

      PGL/PCC type 3

      (SDHC)

      Mean – 38 yrs

      Range – 17-70 yrs

      Typically manifest with single, primary tumors

      Head and neck most common

      May have adrenal or extra-adrenal PGL tumors (rare)

      GISTs reported

      AD

      Unknown penetrance

      Low

      PGL/PCC type 4

      (SDHB)

      Mean – ~30 yrs

      Range – 6-77 yrs

      Sporadic and isolated tumors

      Extra-adrenal chest/abdominal/pelvic sympathetic PGL tumors most common

      GISTs reported

      Early-onset risk of RCC reported

      AD

      Lower penetrance than SDHD

      High – 34-97%

      PGL/PCC type 5

      (SDHA)

       

      Reported tumors

      PGL and PCC (low penetrance)

      GISTs

      AD

      Lower penetrance than SDHD

      AR mutations in SDHA have been associated with Leigh syndrome

      Low

      TMEM127

      Mean – ~40 yrs

      Primarily PCC tumors; often bilateral

      Some PGL tumors, especially head, neck, and extra-adrenal abdominal sites

      AD

      Malignancy reported in 1 individual

      MAX

       

      PCC tumors; often bilateral

      AD

      Parent-of-origin effect – tumor predisposition generally occurs only when mutations are inherited paternally

      High – 25%

      a~30% of individuals diagnosed with PGL/PCC have a detectable germline mutation in one of the genes associated with PGL/PCC susceptibility

      AD, autosomal dominant; AR, autosomal recessive; GISTs, gastrointestinal stromal tumors; PGL/PCC, paraganglioma/pheochromocytoma; RCC, renal cell carcinoma

      • 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)

Pediatrics

Epidemiology

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

Genetics

  • Tumors presenting earlier in life suggest genetic syndromes
  • Refer to Familial Genetics in Background

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

Indications for Testing

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

Laboratory Testing

Initial testing – see Diagnosis.​

Imaging Studies

  • Magnetic resonance imaging (MRI) (computed tomography [CT] avoided due to radiation exposure)
  • Metastatic disease
    • Positron emission tomography (PET) using 18F-fluorodeoxyglucose (18F-FDG)
    • Scintigraphy using 123I- metaiodobenzylguanidine (123I-MIBG)

Differential Diagnosis

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

Screening

ARUP Lab Tests

First-line test in suspected pheochromocytoma

First-line test in suspected pheochromocytoma

24-hour specimen optimal

Smaller increases in metanephrine concentration usually are the result of physiological stimuli, drugs, or improper specimen collection

Higher concentration can be caused by life-threatening illness, intense physical activity, or drug interferences

Significant elevation of 1 or both metanephrines (3 or more times the upper reference limit) is associated with an increased probability of a neuroendocrine tumor

Diagnostic and predictive test for multiple endocrine neoplasia type 2A (MEN2A), multiple endocrine neoplasia type 2B (MEN2B), and familial medullary thyroid carcinoma (FMTC)

Not evaluated: regulatory region mutations, deep intronic mutations, large deletions/duplications, and RET exons other than 5, 8, 10, 11, 13-16 

Diagnostic errors can occur due to rare sequence variations

Preferred initial test when hereditary paraganglioma/ pheochromocytoma (PGL/PCC) is suspected

Not detected or evaluated: variants 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

Confirm a suspected diagnosis of hereditary PGL/PCC when SDHB, SDHC, and SDHD testing is negative

Not detected or evaluated: variants 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

Related Tests

May be beneficial in directing testing algorithms

Aid in histologic diagnosis of pheochromocytoma

Stained and returned to client pathologist; consultation available if needed

May be useful in nonsecretory sympathetic and parasympathetic tumors

Not recommended for evaluation of pheochromocytoma or paraganglioma

Use to evaluate clinical symptoms of excess catecholamine secretion

For the assessment of pheochromocytoma and paraganglioma, refer to fractionated metanephrines in plasma or urine

Not recommended for evaluation of pheochromocytoma or paraganglioma

Use to evaluate clinical symptoms of excess catecholamine secretion

For the assessment of pheochromocytoma and paraganglioma, refer to fractionated metanephrines in plasma or urine

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

Significant elevation of one or more catecholamines is associated with an increased probability of a neuroendocrine tumor

Preferred test to confirm suspected diagnosis of von Hippel-Lindau (VHL) syndrome

Deep intronic or regulatory region variants not detected; large deletion/duplication breakpoints will not be determined

Diagnostic errors can occur due to rare sequence variations

Acceptable initial test to confirm a suspected diagnosis of VHL syndrome

Use when SDHB-related hereditary paraganglioma/ pheochromocytoma (PGL/PCC) is suspected

Preferred test to confirm suspected diagnosis of neurofibromatosis (NF1) in individuals not meeting National Institutes of Health (NIH) clinical criteria

Acceptable test to confirm suspected diagnosis of NF1 in individuals not meeting NIH clinical criteria

Second-tier test; preferred initial test is the sequencing and deletion/duplication test

Useful when a familial large deletion is known

Does not detect sequence variation

Medical Experts

Contributor

Baldwin

Erin Baldwin, MS, LCGC

Genetic Counselor, Molecular Genetics, Cytogenetics, and Maternal Serum Screening at ARUP Laboratories

Contributor
Contributor
Contributor

Frank

Elizabeth L. Frank, PhD, DABCC
Professor of Clinical Pathology, University of Utah
Medical Director, Analytic Biochemistry, Calculi and Manual Chemistry; Co-Medical Director, Mass Spectrometry, ARUP Laboratories
Contributor

Mao

Rong Mao, MD, FACMG
Professor of Clinical Pathology, University of Utah
Section Chief, Molecular Genetics and Genomics, ARUP Laboratories

References

Additional Resources
  • 20833332

    Barontini M, Dahia PLM. VHL disease. Best Pract Res Clin Endocrinol Metab. 2010; 24 (3): 401-13.
    PubMed
  • 21262951

    Eisenhofer G, Lenders JW, Timmers H, Mannelli M, Grebe SK, Hofbauer LC, Bornstein SR, Tiebel O, Adams K, Bratslavsky G, Linehan WM, Pacak K. Measurements of plasma methoxytyramine, normetanephrine, and metanephrine as discriminators of different hereditary forms of pheochromocytoma. Clin Chem. 2011 Mar;57(3):411-20. Epub 2011 Jan 24. PubMed

    Generic
  • 20833333

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

    Generic
  • Resources from the ARUP Institute for Clinical and Experimental Pathology®
  • 22931260

    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 Sep 6;367(10):922-30. PubMed

    Generic