Algorithm(s)
PDF algorithm(s) available at www.arupconsult.com.
Pheochromocytoma Testing Algorithm
Clinical Background
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-Landau (VHL)
- VHL gene
- Type 2
- A - retinal and 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
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
See Also
Algorithm(s)
PDF algorithm(s) available at www.arupconsult.com.
Pheochromocytoma Testing Algorithm
Diagnosis
Diagnosis
- Laboratory testing
- Plasma metanephrine and normetanephrine
- Metabolic products of catecholamines
- False-positives do occur
- 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
- Imaging studies
- Following biochemical confirmation - MRI/CT and metaiodobenzylguanidine (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
Differential Diagnosis
- Essential hypertension
- Anxiety attack
- Subarachnoid hemorrhage
- Diencephalic seizures
Algorithm(s)
PDF algorithm(s) available at www.arupconsult.com.
Pheochromocytoma Testing Algorithm
Tests generally appear in the order most useful for common clinical situations
| Test name: Metanephrines, Plasma (Free)
|
| ARUP #: 0050184 |
| Methodology: High Performance Liquid Chromatography
|
| Use: Diagnose pheochromocytoma |
| Limitations: |
| Follow-up: If indeterminate, order urine metanephrines |
| Test name: Metanephrines, Urine
|
| ARUP #: 0080436 |
| Methodology: Gas Chromatography/Mass Spectrometry
|
| Use: Diagnose pheochromocytoma |
Limitations: Causes of higher concentrations include improper collection of specimens, life threatening illness, intense physical activity and neuroendocrine tumors |
| Follow-up: |
| Test name: Catecholamines Fractionated by LC-MS/MS, Urine Free
|
| ARUP #: 0080407 |
| Methodology: Tandem Mass Spectrometry
|
| Use: Diagnose pheochromocytoma |
| Limitations: Moderately elevated concentration are caused by essential hypertension, intense anxiety, intense physical exercise and drug interactions (including some over-the-counter medications and herbal products) |
| Follow-up:
|
| Test name: Chromosome Analysis, FISH-Metaphase
|
| ARUP #: 0097615 |
| Methodology: Fluorescence in situ Hybridization
|
| Use: |
| Test name: Immunohistochemistry Stain Offering
|
| ARUP #: arup005 |
| Methodology: Immunohistochemistry
|
| Use: For fixed tissue samples, consultative services as well as immunohistochemical staining for CAM5.2 (LMW), Chromogranin A, PGP9.5 and synaptophysin are available |
Additional Tests Available
| Test name: Catecholamines Fractionated, Plasma
|
| ARUP #: 0080216 |
| Methodology: High Performance Liquid Chromatography
|
| Comments: Diagnose pheochromocytoma |
| Test name: Catecholamines Fractionated (Epinephrine, Norepinephrine), Plasma
|
| ARUP #: 0080957 |
| Methodology: High Performance Liquid Chromatography
|
| Comments: |
| Test name: Chromogranin A
|
| ARUP #: 0080469 |
| Methodology: Enzyme Immunoassay
|
| Comments: |
References
Guidelines
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.
General References
Chrisoulidou A, Kaltsas G, Ilias I, Grossman AB. The diagnosis and management of malignant phaeochromocytoma and paraganglioma. Endocr Relat Cancer.
2007;
14(
3):
569-585.
Grossman A, Pacak K, Sawka A, Lenders JW, Harlander D, Peaston RT, Reznek R, Sisson J, Eisenhofer G. Biochemical diagnosis and localization of pheochromocytoma: can we reach a consensus?. Ann N Y Acad Sci.
2006;
1073:
332-347.
Karagiannis A, Mikhailidis DP, Athyros VG, Harsoulis F. Pheochromocytoma: an update on genetics and management. Endocr Relat Cancer.
2007;
14(
4):
935-956.
Lenders JW, Eisenhofer G, Mannelli M, Pacak K. Phaeochromocytoma . Lancet.
2005;
366(
9486):
665-675.
Mittendorf EA, Evans DB, Lee JE, Perrier ND. Pheochromocytoma: advances in genetics, diagnosis, localization, and treatment. Hematol Oncol Clin North Am.
2007;
21(
3):
509-525.
Scholz T, Schulz C, Klose S, Lehnert H. Diagnostic management of benign and malignant pheochromocytoma. Exp Clin Endocrinol Diabetes.
2007;
115(
3):
155-159.
Zapanti E, Ilias I. Pheochromocytoma: physiopathologic implications and diagnostic evaluation. Ann N Y Acad Sci.
2006;
1088:
346-360.
References from the ARUP Institute for Clinical and Experimental Pathology Research®
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.
Heider EC, Davis BG, Frank EL. Nonparametric determination of reference intervals for plasma metanephrine and normetanephrine. Clin Chem.
2004;
50(
12):
2381-2384.
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.
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.
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.
Medical Reviewers
Frank, Elizabeth L. , Ph.D. Medical Director, Analytic Biochemistry and Calculi at ARUP Laboratories; Associate Professor, Clinical Pathology, University of Utah
Meikle, A. Wayne, M.D. Medical Director, RIA and Endocrinology at ARUP Laboratories; Professor of Internal Medicine and Pathology, University of Utah
Comprehensive Review: May 2008
Last Update: September 2008
