Indications for Testing

• Sudden attacks of hypertension, headache, tachycardia

Laboratory Testing

• Fractionated plasma free metanephrines (normetanephrine and metanephrine)
  • Initial test recommended for diagnosing pheochromocytoma
  • Metabolic products of catecholamines
  • False positives occur
• Fractionated urine metanephrines, total (normetanephrine and metanephrine)
  • Alternative to recommended initial test
  • 24-hour specimen required
  • May be a better test in patients at low risk for tumor (fewer false positives)
• Fractionated urine catecholamines
  • Confirm either of the two above tests
  • Measure norepinephrine and epinephrine
• Others
  • Chromogranin A in concert with above testing may improve sensitivity of diagnostic and long-term follow-up testing – nonspecific
  • If tumor is coincidentally found and asymptomatic in patient not being familially screened, consider dopamine testing
    • If high, order homovanillic acid and methoxytyramine
• Clonidine suppression test rarely needed
  • Suppressed plasma normetanephrine ≥40% below reference excludes pheochromocytoma
• After diagnosis of pheochromocytoma is established, consider molecular testing for a hereditary disorder associated with pheochromocytoma
  • Approximately 25% of individuals with pheochromocytoma and no known family history of pheochromocytoma may have an inherited mutation in either RET, VHL, SDHD or SDHB

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

• Perform MRI/multiphasic CT following biochemical confirmation; perform metaiodobenzylguanidine scan if needed
  • Scanning
    • Sensitivity – 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 – CT/MRI specificity 50-90%
  • If initial MRI/CT is negative, perform functional imaging with ¹²³I-MIBG scan
• Technetium bone scan if bone symptoms are present and ¹²³I-MIBG is negative

Differential Diagnosis  

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

• Consider genetic testing for family members based on clinical presentation

• 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

Pheochromocytoma is a catecholamine-producing tumor (epinephrine, norepinephrine) and is currently a term reserved for paragangliomas located in the adrenal glands. If the paraganglioma is located in an extra-adrenal site, it is referred to as an extra-adrenal paraganglioma.

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%)

Associated Hereditary Syndromes

• Multiple endocrine neoplasia 2 (MEN2)
  • RET gene mutations
  • Types
    • 2A – medullary thyroid carcinoma (MTC) (onset in early adulthood), pheochromocytoma (multicentric, bilateral), parathyroid adenoma
    • 2B – MTC (onset in childhood), pheochromocytoma (multicentric, bilateral), mucosal neuromas, intestinal ganglioneuromatosis
    • Familial medullary thyroid carcinoma – MTC only in adult onset
• von Hippel-Lindau syndrome (VHL)
  • VHL gene mutations
  • Type 1
    • Cerebellar hemangioblastomas, retinal angioma, pheochromocytoma, renal cell carcinoma, neuroendocrine tumors of the pancreas
  • Type 2 (A, B, C)
    • 2A – retinal and cerebellar hemangioblastomas, epididymal cystadenomas, pheochromocytomas (multicentric, adrenal, bilateral) and endolymphatic sac tumors
    • 2B – renal cell cysts and carcinomas, retinal and CNS paragangliomas, epididymal cystadenomas (multicentric, adrenal, bilateral) and endolymphatic sac tumors
    • 2C – pheochromocytoma only
• Familial pheochromocytoma susceptibility
  • TMEM127 gene mutations
• Familial paraganglioma syndrome (PGL syndrome)
  • SDHB (PGL4), SDHC (PGL3), and SDHD (PGL10) gene mutations
  • Pheochromocytomas and/or paragangliomas may be multifocal and/or recurrent
• Neurofibromatosis type 1 (von Recklinghausen disease)
  • NF1 gene mutations
  • Multiple café au lait spots, neurofibromas, axillary and inguinal freckling, optic glioma, pheochromocytoma

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 give a hint to genetic association
  • MEN2 (RET) 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
    • Plasma concentrations and urinary outputs of dopamine more often increased in SDH genes than in other mutations
    • 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, 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

Clinical Background

Epidemiology

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

Genetics

• 40% of pheochromocytomas are associated with a known genetic syndrome
  • Multiple endocrine neoplasia 2 (MEN2)
    • RET gene mutations
    • 2B – medullary thyroid carcinoma
  • von Hippel-Lindau syndrome (VHL)
    • VHL gene mutations
    • Pheochromocytoma may be first presentation of VHL
  • Familial paraganglioma syndrome
    • SDH gene mutations
  • Neurofibromatosis type 1 (von Recklinghausen)
    • NF1 gene mutations

Clinical Presentation

• Sustained hypertension (60-90% of cases)
  • Palpitations, headaches, sweating, pallor
  • Malignant tumors rare
    • Highest risk with SDHB genetic mutation and paragangliomas
    • Risk of malignant transformation also highest with paragangliomas
  • Complications
    • Hypertensive crisis
    • Cardiomyopathy
    • Seizures, stroke
    • Pancreatitis

Diagnosis

Indications for Testing

• Sudden attacks of hypertension, headache, tachycardia

Laboratory Testing

• Fractionated plasma free metanephrines (normetanephrine and metanephrine)
  • Initial test recommended for diagnosing pheochromocytoma
  • Metabolic products of catecholamines
  • False positives occur
• Fractionated urine metanephrines, total (normetanephrine and metanephrine)
  • Alternative to recommended initial test
  • 24-hour specimen required
  • May be a better test in patients at low risk for tumor (fewer false positives)
• Fractionated urine catecholamines
  • Confirm either of the two above tests
  • Measure norepinephrine and epinephrine
• Chromogranin A
  • Nonspecific
  • May be useful in nonsecreting tumors
  • May be useful marker in rare SDHB-related paraganglioma that is biochemically silent
• Genetic testing
  • Should be performed for all children who present with tumor regardless of family history
  • VHL– gene of interest in children with pheochromocytoma
  • SDHB– gene of interest in children with paraganglioma or malignant disease
  • NF1 testing has very low yield since it is usually a clinical diagnosis – not recommended
• Clonidine suppression test or glucagon rarely needed – not validated in children

Imaging Studies

• MRI; 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

Tests generally appear in the order most useful for common clinical situations

Guidelines

• Chen H, Sippel RS, O'Dorisio MS, Vinik AI, Lloyd RV, Pacak K. The North American Neuroendocrine Tumor Society consensus guideline for the diagnosis and management of neuroendocrine tumors: pheochromocytoma, paraganglioma, and medullary thyroid cancer. Pancreas. 2010; 39 (6) :775-783.PubMed
• NCCN Clinical Practice Guidelines in Oncology, Neuroendocrine Tumors. National Comprehensive Cancer Network. Fort Washington: Pennsylvania [Accessed: 22 Jun 2011] 
• Pacak K, Eisenhofer G, Ahlman H, Bornstein SR, Gimenez-Roqueplo AP, Grossman AB, Kimura N, Mannelli M, McNicol AM, Tischler AS. Pheochromocytoma: recommendations for clinical practice from the First International Symposium. October 2005. Nat Clin Pract Endocrinol Metab. 2007; 3 (2) :92-102.PubMed

General

• Adler JT, Meyer-Rochow GY, Chen H, Benn DE, Robinson BG, Sippel RS, Sidhu SB. Pheochromocytoma: current approaches and future directions. Oncologist. 2008; 13 (7) :779-793.PubMed
• Barontini M, Dahia PL. VHL disease. Best Pract Res Clin Endocrinol Metab. 2010; 24 (3) :401-413.PubMed
• Barron J. Phaeochromocytoma: diagnostic challenges for biochemical screening and diagnosis. J Clin Pathol. 2010; 63 (8) :669-674.PubMed
• Donckier JE, Michel L. Phaeochromocytoma: state-of-the-art. Acta Chir Belg. 2010; 110 (2) :140-148.PubMed
• 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; 57 (3) :411-420.PubMed
• Havekes B, Romijn JA, Eisenhofer G, Adams K, Pacak K. Update on pediatric pheochromocytoma. Pediatr Nephrol. 2009; 24 (5) :943-950.PubMed
• Kantorovich V, King KS, Pacak K. SDH-related pheochromocytoma and paraganglioma. Best Pract Res Clin Endocrinol Metab. 2010; 24 (3) :415-424.PubMed
• Scholz T, Schulz C, Klose S, Lehnert H. Diagnostic management of benign and malignant pheochromocytoma. Exp Clin Endocrinol Diabetes. 2007; 115 (3) :155-159.PubMed
• Tischler AS. Pheochromocytoma and extra-adrenal paraganglioma: updates. Arch Pathol Lab Med. 2008; 132 (8) :1272-1284.PubMed
• Waguespack SG, Rich T, Grubbs E, Ying AK, Perrier ND, yala-Ramirez M, Jimenez C. A current review of the etiology, diagnosis, and treatment of pediatric pheochromocytoma and paraganglioma. J Clin Endocrinol Metab. 2010; 95 (5) :2023-2037.PubMed

ARUP Institute for Clinical and Experimental Pathology®

• Comstock JM, Willmore-Payne C, Holden JA, Coffin CM. Composite pheochromocytoma: a clinicopathologic and molecular comparison with ordinary pheochromocytoma and neuroblastoma. Am J Clin Pathol. 2009; 132 (1) :69-73.PubMed
• Crockett DK, Frank EL, Roberts WL. Rapid analysis of metanephrine and normetanephrine in urine by gas chromatography-mass spectrometry. Clin Chem. 2002; 48 (2) :332-337.PubMed
• Heider EC, Davis BG, Frank EL. Nonparametric determination of reference intervals for plasma metanephrine and normetanephrine. Clin Chem. 2004; 50 (12) :2381-2384.PubMed
• Kushnir MM, Urry FM, Frank EL, Roberts WL, Shushan B. Analysis of catecholamines in urine by positive-ion electrospray tandem mass spectrometry. Clin Chem. 2002; 48 (2) :323-331.PubMed
• Margraf RL, Calderon FR, Mao R, Wittwer CT. RET mutation scanning update: exon 15. Clin Chem. 2009; 55 (11) :2059-2061.PubMed
• Margraf RL, Mao R, Highsmith WE, Holtegaard LM, Wittwer CT. Mutation scanning of the RET protooncogene using high-resolution melting analysis. Clin Chem. 2006; 52 (1) :138-141.PubMed
• Singh RJ, Grebe SK, Yue B, Rockwood AL, Cramer JC, Gombos Z, Eisenhofer G. Precisely wrong? Urinary fractionated metanephrines and peer-based laboratory proficiency testing. Clin Chem. 2005; 51 (2) :472-473.PubMed

Aldosteronism
Hypercalcemia
Multiple Endocrine Neoplasias
Thyroid Cancer
Tumor Markers