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.
Diagnosis
Indications for Testing
- Symptomatic patient
- New onset of clinical syndrome of hypertension, diaphoresis, tachycardia, syncope, headache
- Incidental finding on imaging
- Adrenal abnormality noted on imaging suggestive of pheochromocytoma
- Hereditary syndrome
- Associated hereditary syndrome, especially
- Neurofibromatosis type 1 (NF1, von Recklinghausen disease)
- Multiple endocrine neoplasm 2 (MEN2)
- von Hippel-Lindau (VHL) syndrome
- Hereditary paraganglioma/pheochromocytoma (PGL/PCC) syndromes – especially SDH gene-associated disorders
- Associated hereditary syndrome, especially
Laboratory Testing
- Initial testing (for symptomatic patient or incidental finding) – can use plasma-free metanephrines alone, urine metanephrines alone, or both together
- Plasma-free metanephrines (normetanephrine and metanephrine) (National Comprehensive Cancer Network [NCCN], 2017)
- Preferred in
- High probability patients
- Renal insufficiency
- Children
- Negative testing has high negative predictive value
- Results
- Negative and high suspicion – repeat in 6 months
- Mild elevation or indeterminate
- Evaluate for causes for false positive
- Consider referral to endocrinologist
- Elevated – repeat testing to confirm, proceed to imaging
- Preferred in
- 24-hour, fractionated urine metanephrines
- Preferred in patients at low risk for tumor (fewer false positives)
- Results
- Negative and high suspicion – repeat in 6 months
- Mild elevation or indeterminate
- Evaluate for causes for false positive
- Consider referral to endocrinologist
- Elevated – repeat testing to confirm, proceed to imaging
- Plasma-free metanephrines (normetanephrine and metanephrine) (National Comprehensive Cancer Network [NCCN], 2017)
- Other testing (for symptomatic patient or incidental finding)
- Dopamine, plasma or urine (reported with Catecholamines, fractionated) – consider for
- Cervical paraganglioma and asymptomatic adrenal tumor
- Metastatic disease (metastatic tissue often lacks the enzymes needed to synthesize precursors to catecholamines) (Pappachan, 2014)
- Homovanillic acid
- Order if high dopamine concentrations found
- Methoxytyramine (metabolite of dopamine) (not available at ARUP Laboratories) – consider for
- Cervical paraganglioma
- Metastatic disease
- Fractionated catecholamines
- May be useful for evaluating clinical symptoms of excess catecholamine secretion
- No longer recommended testing – plasma or urine metanephrines are tests of choice
- Dopamine, plasma or urine (reported with Catecholamines, fractionated) – consider for
- Genetic testing (for hereditary syndrome)
- Identified pheochromocytoma or paraganglioma – all patients should be referred for genetic testing (30-40% will have genetic variant) (NCCN, 2017)
- Referral to genetic counselor to guide appropriate testing is recommended
- Known family history of associated syndrome or known DNA variant – patients should be tested for appropriate variant (familial mutation targeted sequencing)
- No known family history of associated syndrome or known DNA variant – testing can be narrowed down based on the clinical symptoms, other tumors, age at diagnosis, etc
- (See ARUP Genetic testing form for example)
- Detailed information should be provided with genetic test request
- Ethnicity
- Clinical signs and symptoms
- Tumor location
- Single/multiple tumor, bilateral tumors
- Secretory/nonsecretory
- Other tumors/cancers/conditions
- Renal cell carcinoma
- Breast cancer
- Papillary thyroid cancer
- Parathyroid hyperplasia
- Gastrointestinal stromal tumor
- Other
- Catecholamine secretion
- Epinephrine (or metabolite metanephrine)
- Norepinephrine (or metabolite normetanephrine)
- Dopamine (or metabolite methoxytyramine)
- Immunohistochemistry results
- Normal vs absent SDHB
- Syndromes – suggest specific testing (see Paraganglioma/Pheochromocytoma Genetic Testing Algorithm for details regarding testing)
- NF1
- MEN2 – RET
- VHL
- Hereditary PGL/PCC syndrome
- Identified pheochromocytoma or paraganglioma – all patients should be referred for genetic testing (30-40% will have genetic variant) (NCCN, 2017)
Histology
- Tissue biopsy with chromogranin A staining is diagnostic
- Other useful immunohistochemistry stains may include SDHB and synaptophysin
- SDHB presence or absence can help guide genetic testing
- For detailed descriptions, including recommended tests, refer to ARUP’s Immunohistochemistry Stain Offerings
Imaging Studies
- Multiphasic computed tomography (CT) abdomen and pelvis – recommended first-line imaging (Lenders, Endocrine Society, 2014)
- Magnetic resonance imaging (MRI) has similar sensitivity to CT but higher cost (NCCN, 2017),
- Recommended if CT contraindicated or cases in which MRI would show better imaging (skull base/neck, adjacent surgical clips) (Lenders, Endocrine Society, 2014)
- Metastasis suspected
- 123I-metaiodobenzylguanidine (123I-MIBG)
- 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) or l-3,4-dihydroxy-6-[18F]fluorophenylalanine (18F-FDOPA)
- Somatostatin receptor-based imaging
- Bone scan – recommended if bone symptoms present
Differential Diagnosis
- Clinical signs
- Essential hypertension
- Anxiety attack
- Subarachnoid hemorrhage
- Diencephalic seizures
- Tumors
- Adrenocorticoid carcinoma
- Neuroendocrine tumor
- Lymphoma
- Medulloblastoma
- Rhabdosarcoma
- Small cell osteosarcoma
Screening
- Screen individuals with conditions below
- High risk
- Individuals or family member with
- Neurofibromatosis type 1 (NF1)
- Multiple endocrine neoplasia (MEN) type 2A or 2B
- Von Hippel-Lindau (VHL)
- Hereditary paraganglioma/pheochromocytoma (PGL/PCC) syndromes – especially SDH gene-associated disorders
- Adrenal incidentaloma
- Individuals or family member with
- Lower risk (<1% or not identified) (Pappachan, 2014)
- Resistance hypertension
- Unexplained heart failure
- Paroxysmal headaches, palpitations, sweating, and panic attacks in association with hypertension
- Hypertensive crisis developing during surgery or general anaesthesia
- Hypertension triggered by beta blockers, monoamine oxidase inhibitors, micturition/changes in abdominal pressure
- Orthostatic hypotension in a hypertensive patient
- New onset diabetes mellitus in a young, lean individual with hypertension
- High risk
- Consider genetic testing for at-risk family members based on syndrome recommendations and clinical symptoms
- Refer to Paraganglioma/Pheochromocytoma Molecular Testing Algorithm
Monitoring
- Plasma-free or fractionated urine metanephrines (Kunz, North American Neuroendocrine Tumor Society [NANETS], 2013)
- Recommended at 6 and 12 months following resection (every 3-6 months for advanced disease), then annually
- Duration of follow-up not defined
- Chromogranin A (neuroendocrine marker) – consider if tumor does not produce plasma metanephrines
Background
Epidemiology
- Incidence – 2-8 per million per year in U.S. (National Institutes of Health [NIH]/National Cancer Institute [NCI], 2015)
- Age – peaks in 40s; occurs at younger age in hereditary forms and older age in sporadic forms
- Sex – M:F, equal
- Occurrence – most are sporadic (80%)
Pathophysiology
- Paragangliomas – arise from chromaffin cells outside the adrenal gland (extra-adrenal tissue) and are found in the abdomen, thorax, and pelvis
- Pheochromocytomas – arise from chromaffin cells located within the adrenal glands
- Both produce catecholamines – epinephrine, norepinephrine, or dopamine, or combinations of these
- Secretion is increased by stress – baseline plasma and urine concentrations can be quite variable
- Tumor pattern of catecholamine release may suggest association with genetic disorder
- Neurofibromatosis type 1 (NF1, von Recklinghausen disease) and multiple endocrine neoplasia type 2 (MEN2)
- Increase in plasma concentration of metanephrine
- von Hippel-Lindau (VHL) syndrome
- Low level of epinephrine
- No increase in plasma concentration of metanephrine
- Rarely shows increases in plasma or urinary epinephrine and metanephrine
- SDH gene-associated disorders
- Plasma concentration and urinary output of dopamine more often increased in SDH gene-associated disorders than in other conditions
- Plasma methoxytyramine provides sensitive biomarker for indicating tumor dopamine production
- Increased dopamine production leads to increased plasma methoxytyramine
- Rare increase in plasma or urinary epinephrine and metanephrine
- Metastatic – associated with low levels of methoxytyramine
- Neurofibromatosis type 1 (NF1, von Recklinghausen disease) and multiple endocrine neoplasia type 2 (MEN2)
Clinical Presentation
- Hypertension
- Sustained hypertension in large proportion 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 are lung, lymph nodes, bones, liver
Familial Genetics
- Diagnosis of pheochromocytoma should be established prior to any genetic testing
- All patients with pheochromocytoma or paraganglioma should be referred to genetic counselor due to high rate of familial mutations associated with these tumor types (30-40% in some series) (National Comprehensive Cancer Network [NCCN], 2017)
- Germline mutations in the following 10 genes are found to be associated with paraganglioma and/or pheochromocytoma
- NF1 – neurofibromatosis type 1, von Recklinghausen disease
- RET – MEN2
- VHL – VHL syndrome
- SDHA/B/C/D,SDHAF2, TMEM127, MAX – hereditary paraganglioma/pheochromocytoma (PGL/PCC) syndromes (SDHB variants are most frequent; TMEM127, MAX, SDHAF2 are rare)
Hereditary PGL/PCC Syndromes Syndrome/Gene Age of Onset Tumors Inheritancea Risk of Malignant Transformation PGL/PCC type 1
(SDHD)
Mean – 35 yrs
Range – 10-96 yrs
Multiple tumors, especially head and neck
May have sporadically appearing PCC
May be associated with risk of RCC
AD
Parent-of-origin effect – tumor predisposition generally occurs only when mutations are inherited paternally
Highly penetrant
<5%
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
Low
PGL/PCC type 3
(SDHC)
Mean – 38 yrs
Range – 17-70 yrs
Typically manifest with single, primary tumors
Head and neck most common
May have adrenal or extra-adrenal PGL tumors (rare)
GISTs reported
AD
Unknown penetrance
Low
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
Lower penetrance than SDHD
High – 34-97%
PGL/PCC type 5
(SDHA)
Reported tumors
PGL and PCC (low penetrance)
GISTs
AD
Lower penetrance than SDHD
AR mutations in SDHA have been associated with Leigh syndrome
Low
TMEM127
Mean – ~40 yrs
Primarily 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 – 25%
a~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; GISTs, gastrointestinal stromal tumors; PGL/PCC, paraganglioma/pheochromocytoma; RCC, renal cell carcinoma
- Neuroendocrine tumors of the autonomic nervous system
- Sympathetic nervous system tumors
- Secrete catecholamines
- Usually in retroperitoneal space, abdomen, or thorax
- Paroxysmal tachycardia/palpitations
- Hypertension
- Headache
- Hyperglycemia
- Pallor/weight loss
- Parasympathetic nervous system tumors
- Usually in head and neck region, or aortic root
- Tumors are usually nonsecreting
- Symptoms are due to compression or infiltration of adjacent structures (including cranial nerves)
Pediatrics
Epidemiology
- Incidence – rare, but the most common pediatric endocrine tumor
- Age – average onset is 11 years
Genetics
- Tumors presenting earlier in life suggest genetic syndromes
- Refer to Familial Genetics in Background
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
Indications for Testing
New onset hypertension, diaphoresis, adrenal abnormality, tachycardia, or an associated hereditary syndrome.
Laboratory Testing
Initial testing – see Diagnosis.
Imaging Studies
- Magnetic resonance imaging (MRI) (computed tomography [CT] avoided due to radiation exposure)
- Metastatic disease
- Positron emission tomography (PET) using 18F-fluorodeoxyglucose (18F-FDG)
- Scintigraphy using 123I- metaiodobenzylguanidine (123I-MIBG)
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 Genetic Testing Algorithm
ARUP Laboratory Tests
Quantitative Liquid Chromatography-Tandem Mass Spectrometry
Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry
Massively Parallel Sequencing
Massively Parallel Sequencing
Massively Parallel Sequencing/Multiplex Ligation-Dependent Probe Amplification (MLPA)
Immunohistochemistry
Immunohistochemistry
Immunohistochemistry
Immunohistochemistry
Immunofluorescence
Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry
Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry
DMassively Parallel Sequencing/Sequencing/Multiplex Ligation-Dependent Probe Amplification (MLPA)
Massively Parallel Sequencing
Multiplex Ligation-Dependent Probe Amplification (MLPA)
Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry
References
ACR Appropriateness Criteria - Incidentally Discovered Adrenal Mass
ACR Appropriateness Criteria. American College of Radiology. [Last reviewed: 2012; Accessed: Jan 2018]
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Adler JT, Meyer-Rochow GY, Chen H, et al. Pheochromocytoma: current approaches and future directions. Oncologist. 2008;13(7):779-793.
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Brito JP, Asi N, Bancos I, et al. Testing for germline mutations in sporadic pheochromocytoma/paraganglioma: a systematic review. Clin Endocrinol (Oxf). 2015;82(3):338-345.
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Eisenhofer G, Lenders JW, Timmers H, et al. Measurements of plasma methoxytyramine, normetanephrine, and metanephrine as discriminators of different hereditary forms of pheochromocytoma. Clin Chem. 2011;57(3):411-420.
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Eisenhofer G, Peitzsch M. Laboratory evaluation of pheochromocytoma and paraganglioma. Clin Chem. 2014;60(12):1486-1499.
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Fishbein L, Merrill S, Fraker DL, et al. Inherited mutations in pheochromocytoma and paraganglioma: why all patients should be offered genetic testing. Ann Surg Oncol. 2013;20(5):1444-1450.
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Lenders JWM, Duh QY, Eisenhofer G, et al. Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014;99(6):1915-1942.
NCCN - Neuroendocrine Tumors
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Pacak K, Eisenhofer G, Ahlman H, et al. Pheochromocytoma: recommendations for clinical practice from the First International Symposium. October 2005. Nat Clin Pract Endocrinol Metab. 2007;3(2):92-102.
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Pappachan JM, Raskauskiene D, Sriraman R, et al. Diagnosis and management of pheochromocytoma: a practical guide to clinicians. Curr Hypertens Rep. 2014;16(7):442.
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Tischler AS. Pheochromocytoma and extra-adrenal paraganglioma: updates. Arch Pathol Lab Med. 2008;132(8):1272-1284.
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van Berkel A, Lenders JWM, Timmers HJLM. Diagnosis of endocrine disease: Biochemical diagnosis of phaeochromocytoma and paraganglioma. Eur J Endocrinol. 2014;170(3):R109-119.
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Medical Experts
Bayrak-Toydemir

Frank

Mao

For additional test information, refer to the Hereditary Paraganglioma-Pheochromocytoma Panel Test Fact Sheet