Pheochromocytoma

Pheochromocytoma is a catecholamine producing tumor (epinephrine, norepinephrine).

Epidemiology

• Incidence – 2-8/1,000,000 in the U.S.
• Age – peak 30-60 years
• Sex – nearly equal male/female distribution
• Occurrence – most are sporadic (90%)

Risk Factors

• Multiple Endocrine Neoplasia 2 (MEN2)
  • RET gene
  • Types
    • 2a – medullary thyroid carcinoma (MTC), pheochromocytoma (multicentric, bilateral), parathyroid adenoma
    • 2b – MTC, pheochromocytoma (multicentric, bilateral) intestinal ganglioneuromatosis
    • Familial medullary thyroid cancer (FMTC) – MTC only
• von Hippel-Lindau (VHL)
  • VHL gene
  • Type 2 (A, B and C)
    • A – retinal and central nervous system (CNS) hemangioblastomas, epididymal cystadenomas, pheochromocytomas (multicentric, adrenal, bilateral) and endolymphatic sac tumors
    • B – renal cell cysts and carcinomas, retinal and CNS pheochromocytomas, epididymal cystadenomas (multicentric, adrenal, bilateral) and endolymphatic sac tumors
    • C – pheochromocytoma only
• Familial paraganglioma syndrome (PGL syndromes)
  • SDHB (PGL4) and SDHD (PGL10) genes
  • Head and neck tumors, pheochromocytoma (adrenal and extra-adrenal), abdominal and thoracic paragangliomas
• Neurofibromatosis type 1 (von Recklinghausen disease)
  • NF-1 gene
  • Multiple fibromas on skin and mucosa, café au lait spots and pheochromocytoma
• Other rare syndromes
  • Ataxia-telangiectasia
  • Sturge-Weber
  • Tuberous sclerosis

Pathophysiology

• Located in adrenal medulla 90% of the time
• May occur where chromaffin cells are present; about 90% are benign
  • Chromaffin tumors produce catecholamines

Clinical Presentation

• Hypertension (HTN)
  • Sustained HTN 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, 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

Diagnosis

• Indications for testing – sudden attacks of hypertension, headache, tachycardia
• Laboratory testing
  • Plasma metanephrine and normetanephrine
    • Metabolic products of catecholamines
    • False-positives do occur
    • Less cumbersome than urine testing
  • Urine metanephrine and normetanephrine
    • 24-hour specimen
    • May be a better test in patients at low risk for tumor (fewer false positives)
  • Urine catecholamines
    • Epinephrine and norepinephrine
  • Plasma catecholamines
    • Epinephrine and norepinephrine
  • Clonidine stimulation test is rarely needed
  • Histology – tissue biopsy with chromogranin A staining is diagnostic
• Imaging studies
  • Following biochemical confirmation – MRI/CT and metaiodobenzylguanidine (MIBG) scan
  • CT has 93-100% sensitivity for detecting intra-adrenal tumors ≥5 cm in diameter and 90% for extra-adrenal tumors; sensitivity for MRI is slightly higher
  • Specificity of CT/MRI ranges from 50-90%
  • If initial MRI/CT is negative, use functional imaging with MIBG scan

Disease Monitoring

• Laboratory testing
  • Chromogranin A  
  • Neuroendocrine marker
    • Nonspecific for pheochromocytoma
    • May be used to monitor response to treatment or relapse since levels have been noted to correlate well with plasma metanephrines and tumor mass

Disease Screening

• Consider genetic testing in family members based on clinical presentation

Differential Diagnosis  

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

Indications for Ordering

• 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
Catecholamines Fractionated, Plasma  0080216 Method: High Performance Liquid Chromatography	Diagnose pheochromocytoma
Catecholamines Fractionated (Epinephrine, Norepinephrine), Plasma 0080957 Method: High Performance Liquid Chromatography
Chromogranin A 0080469 Method: Enzyme Immunoassay

Guidelines

General References

References from the ARUP Institute for Clinical and Experimental Pathology®