Pheochromocytoma - Paraganglioma

Content Review: June 2017 Last Update: September 2023

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.


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


  • 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


  • 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


  • 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



  • 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%)


  • 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


      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


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

      Highly penetrant


      PGL/PCC type 2


      Mean – 32 yrs

      Multiple head and neck tumors


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


      PGL/PCC type 3


      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


      Unknown penetrance


      PGL/PCC type 4


      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


      Lower penetrance than SDHD

      High – 34-97%

      PGL/PCC type 5



      Reported tumors

      PGL and PCC (low penetrance)



      Lower penetrance than SDHD

      AR mutations in SDHA have been associated with Leigh syndrome



      Mean – ~40 yrs

      Primarily PCC tumors; often bilateral

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


      Malignancy reported in 1 individual



      PCC tumors; often bilateral


      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)



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


  • 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


ARUP Laboratory Tests

Related Tests


Additional Resources
  • 20833332

    Barontini M, Dahia PLM. VHL disease. Best Pract Res Clin Endocrinol Metab. 2010;24(3):401-413.

  • Medical Experts



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


    Rong Mao, MD, FACMG
    Professor of Pathology (Clinical), and Co-Director of Laboratory Genetics and Genomics Fellowship, University of Utah
    Medical Director, Molecular Genetics and Genomics, ARUP Laboratories