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

Monitoring

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
    • Pheochromocytomas and paragangliomas may be multifocal and/or recurrent
      • SDHB gene mutations (PGL/PCC type 4)
        • Extra-adrenal sympathetic paragangliomas most frequent
        • Mean age of diagnosis – 30 years
        • High risk of malignant transformation
        • May be associated with risk of RCC
      • SDHC gene mutations (PGL/PCC type 3)
        • Skull base and neck paragangliomas most frequent
      • SDHD gene mutations (PGL/PCC type 1)
        • Multiple tumors may occur, especially in the head and neck
        • Mean age of diagnosis – 35 years
        • Tumor predisposition occurs when mutations are inherited from the father but not from the mother
      • SDHAF2 gene mutations (PGL/PCC type 2)
        • Skull base and neck paragangliomas most frequent
      • SDHA gene mutations (PGL/PCC type 5)
      • TMEM127 gene mutations
        • Primarily pheochromocytoma
      • MAX gene mutations
        • Primarily pheochromocytoma, but extra-adrenal paraganglioma has been reported
        • Risk of malignancy
  • 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

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
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 Clinical sensitivity of 99% for VHL
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 of 28% for VHL
Hereditary Paraganglioma-Pheochromocytoma (SDHB) Sequencing and Deletion/Duplication 2007108 Method: Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification
Hereditary Paraganglioma-Pheochromocytoma (SDHB, SDHC, and SDHD) Deletion/Duplication 2007113 Method: Polymerase Chain Reaction/Multiplex Ligation-dependent Probe Amplification
Hereditary Paraganglioma-Pheochromocytoma (SDHC) Sequencing and Deletion/Duplication 2007117 Method: Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification
Hereditary Paraganglioma-Pheochromocytoma (SDHD) Sequencing and Deletion/Duplication 2007122 Method: Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification
Homovanillic Acid (HVA), Urine 0080422 Method: Quantitative High Performance Liquid Chromatography

Diagnostic Algorithm

  Pheochromocytoma Testing Algorithm

  Paraganglioma Pheochromocytoma Molecular Testing Algorithm