Pheochromocytoma

Diagnosis

Indications for Testing

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

Laboratory Testing

  • Initial testing – plasma free or urine metanephrines (normetanephrine and metanephrine); urine may be preferred in patients at low risk for tumor (fewer false positives)
    • Not elevated – pheochromocytoma unlikely
      • If high suspicion exists, repeat testing in 3-6 months
    • Mildly elevated or indeterminate – evaluate potential false positives (influence of diet, medications, inappropriate sampling conditions)
      • If suspicion still exists for pheochromocytoma, consider additional evaluation
    • Moderate to very 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
    • Chromogranin A in concert with above testing may improve sensitivity of diagnostic and long-term follow-up testing – nonspecific
    • Fractionated catecholamines – may be useful to confirm results from metanephrine tests
    • If tumor is coincidentally found and asymptomatic in patient not being familially screened, consider dopamine testing
      • If high, order homovanillic acid and methoxytyramine
  • Genetic testing
    • ~30% of pheochromocytomas are associated with a known genetic syndrome
      • Multiple endocrine neoplasia type 2 (MEN2)
      • von Hippel-Lindau (VHL) syndrome
      • Neurofibromatosis type 1 (NF1)
      • Hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndrome
    • Diagnosis of pheochromocytoma should be established prior to testing
    • 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

  • MRI or multiphasic CT of abdomen and pelvis following biochemical confirmation
    • MRI – slightly more sensitive than CT; 50-90% specificity
    • CT – 90% 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)
      • No tumor visualized – proceed to metaiodobenzylguanidine (123I-MIBG) or PET using 18F-FDG or 18F-FDOPA
        • Negative MIBG/PET – consider technetium bone scan if bone symptoms are present
        • Positive MIBG/PET – consider genetic testing (eg, MEN2)

Differential Diagnosis  

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

Screening

  • Consider genetic testing for family members based on clinical presentation
  • Refer to Paraganglioma/Pheochromocytoma Molecular Testing Algorithm

Monitoring

  • Chromogranin A (neuroendocrine marker)
    • Nonspecific for pheochromocytoma
      • May be used to monitor response to treatment or disease relapse
      • Concentrations have been noted to correlate well with plasma metanephrines and tumor mass

Clinical Background

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 – 2-8/1,000,000 in the U.S.
  • Age – peaks in 30s-50s; 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

  • 90% of paragangliomas are found in the adrenal medulla; most are benign in histology
    • Derived from chromaffin cells (chromaffin tumors produce catecholamines)
  • Tumor pattern of catecholamine release may suggest genetic association
    • MEN2 and NF1
      • Increases in plasma concentrations of metanephrine 
    • VHL
      • Low levels of epinephrine
      • Lack of increase in plasma concentrations of metanephrine
      • Rarely shows increases in plasma or urinary epinephrine and metanephrine
    • SDH gene-associated disorders
      • Plasma concentrations and urinary outputs of dopamine more often increased in SDH gene-associated disorders than in other conditions
      • Plasma methoxytyramine provides sensitive biomarker for indicating tumoral dopamine production
        • Increased dopamine production leads to increased plasma methoxytyramine
      • Rare increases in plasma or urinary epinephrine and metanephrine

Clinical Presentation

  • Hypertension
    • Sustained hypertension in ~50% 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 of metastases – lung, lymph nodes, bones, liver
  • Associated hereditary syndromes
    • Multiple endocrine neoplasia type 2 (MEN2)
      • RET gene mutations
        • MEN2A – medullary thyroid carcinoma (MTC), pheochromocytoma (multicentric, bilateral), parathyroid adenoma
        • MEN2B – MTC (onset in early childhood), pheochromocytoma (multicentric, bilateral), mucosal neuromas, intestinal ganglioneuromatosis
        • Familial medullary thyroid carcinoma (FMTC) – MTC only
    • von Hippel-Lindau (VHL) syndrome
      • VHL gene mutations
      • Retinal, cerebellar, and spinal hemangioblastomas; 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

      Syndrome/gene

      Age of onset

      Tumors

      Inheritance*

      Risk of malignant transformation

      PGL/PCC type 1

      (SDHD)

      • Mean –35 yrs
      • Range –10-96 yrs
      • Multiple tumors, especially head and neck
      • May have sporadic appearing PCC
      • May be associated with risk of RCC

      AD**

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

      High

      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

      Unclear; only reported in a few families

      PGL/PCC type 3

      (SDHC)

       
      • Typically manifest with single, primary tumors
      • Head and neck most common
      • May have adrenal or extra-adrenal PGL tumors
      • GISTs reported

      AD

      Unclear; only reported in a few families

      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

      High

      PGL/PCC type 5

      (SDHA)

       
      • Reported tumors
        •  PGL and PCC (low penetrance)
        • GISTs

      AD

      AR** mutations in SDHA have been associated with Leigh syndrome

      Unclear; only reported in a few families

      TMEM127

      • Mean –~40 yrs
      • Primary 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

      *~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

    • Neurofibromatosis type 1 (von Recklinghausen disease)
      • NF1 gene mutations
      • Multiple café au lait spots, neurofibromas, axillary and inguinal freckling, optic glioma, pheochromocytoma

Pediatrics

Clinical Background

Epidemiology

  • Incidence – rare, but the most common pediatric endocrine tumor (0.02/1,000,000)
  • Age – average onset is 11 years

Genetics

  • ~30% of pheochromocytomas are 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
      • SDHB, SDHC, SDHD, SDHAF2, SDHA, TMEM127, and MAX gene mutations
    • Neurofibromatosis type 1 (von Recklinghausen)
      • 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 metanephrine, catecholamine, and chromogranin tests in Diagnosis tab
  • Clonidine suppression test rarely used
    • Not validated in children
  • Genetic testing
    • ~30% of pheochromocytomas are associated with a known genetic syndrome
      • May help determine the risks of having multiple tumors or developing malignant tumors
    • 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
    • Associated syndromes
      • VHL and RET – genes of interest in children with pheochromocytoma
      • SDHB – gene of interest in malignant paragangliomas
      • NF1
        • Testing has very low yield since it is usually a clinical diagnosis
        • Not recommended
    • Refer to Paraganglioma/Pheochromocytoma Molecular Testing Algorithm

Imaging Studies

  • MRI to avoid CT due to radiation exposure; may also use abdominal ultrasound if expertise is available
  • 123I-MIBG – confirm malignant disease, look for multiple tumors, or use if MRI is negative
  • 18F-FDG PET 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

Indications for Laboratory Testing

  • 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
Test Name and Number Recommended Use Limitations Follow Up
Metanephrines, Plasma (Free) 0050184
Method: Quantitative Liquid Chromatography-Tandem Mass Spectrometry

Recommended initial test for diagnosis of pheochromocytoma

False positives may occur

If indeterminate, order urine metanephrines

Metanephrines Fractionated by HPLC-MS/MS, Urine 2007996
Method: Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry
Alternative to recommended initial test for diagnosis of pheochromocytoma

24-hour specimen required

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

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

Confirm results from metanephrine tests

Measures dopamine, epinephrine, and norepinephrine

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

Moderately elevated concentrations may be caused by essential hypertension, intense anxiety, intense physical exercise, and 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

Diagnostic test for MEN2

Detects mutations most commonly causal for MEN2A, FMTC, and MEN2B

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

 
SDHB with Interpretation by Immunohistochemistry 2006948
Method: Immunohistochemistry

May be beneficial in directing testing algorithms

Weak diffuse staining for SDHB correlates well with the presence of a germline mutation in the genes of the succinate dehydrogenase complex: SDHB, SDHC, and SDHD

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

Preferred initial test for those with clinical evidence of PGL/PCC syndrome; positive family history; multiple tumors/multifocal or extra-adrenal tumors; malignancy associated with PGL/PCC tumor; or age onset <45 years

Presymptomatic testing for relatives of an individual with hereditary PGL/PCC syndrome

Clinical sensitivity – combined sequencing and deletion/duplication analysis

  • SDHB – 7-11%
  • SDHC – 4%
  • SDHD – 15%

Mutations outside of genes listed are not detected

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

Regulatory region and deep intronic mutations are not detected

Breakpoints of large deletions/duplications will not be detected

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

Aid in histologic diagnosis of pheochromocytoma

Stained and returned to client pathologist; consultation available if needed

   
Chromogranin A by Immunohistochemistry 2003830
Method: Immunohistochemistry

Aid in histologic diagnosis of pheochromocytoma

Stained and returned to client pathologist; consultation available if needed

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

Aid in histologic diagnosis of pheochromocytoma

Stained and returned to client pathologist; consultation available if needed

   
Synaptophysin by Immunohistochemistry 2004139
Method: Immunohistochemistry

Aid in histologic diagnosis of pheochromocytoma

Stained and returned to client pathologist; consultation available if needed

   
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Chromogranin A 0080469
Method: Quantitative Enzyme Immunoassay

May be useful in nonsecretory sympathetic and parasympathetic tumors

Catecholamines Fractionated, Plasma 0080216
Method: Quantitative High Performance Liquid Chromatography

Not recommended

von Hippel-Lindau (VHL) Sequencing and Deletion/Duplication 2002965
Method: Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification

Preferred test for confirmation of VHL syndrome

Clinical sensitivity – 99% 

von Hippel-Lindau (VHL) Sequencing 2002970
Method: Polymerase Chain Reaction/Sequencing

Preferred test for evaluation of VHL-associated polycythemia

von Hippel-Lindau (VHL) Deletion/Duplication 2002988
Method: Polymerase Chain Reaction/Multiplex Ligation-dependent Probe Amplification

Useful if large familial deletion is known

Clinical sensitivity – 28% for VHL

Hereditary Paraganglioma-Pheochromocytoma (SDHB) Sequencing and Deletion/Duplication 2007108
Method: Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification

Use when hereditary PGL/PCC type 4 is suspected

Hereditary Paraganglioma-Pheochromocytoma (SDHB, SDHC, and SDHD) Deletion/Duplication 2007113
Method: Polymerase Chain Reaction/Multiplex Ligation-dependent Probe Amplification

Use if no mutations detected by sequencing or when a familial deletion is known

Hereditary Paraganglioma-Pheochromocytoma (SDHC) Sequencing and Deletion/Duplication 2007117
Method: Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification

Use when hereditary PGL/PCC type 3 is suspected

Hereditary Paraganglioma-Pheochromocytoma (SDHD) Sequencing and Deletion/Duplication 2007122
Method: Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification

Use when hereditary PGL/PCC type 1 is suspected

Homovanillic Acid (HVA), Urine 0080422
Method: Quantitative High Performance Liquid Chromatography