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
First-line test in suspected pheochromocytoma
Quantitative Liquid Chromatography-Tandem Mass Spectrometry
First-line test in suspected pheochromocytoma
24-hour specimen optimal
Smaller increases in metanephrine concentration usually are the result of physiological stimuli, drugs, or improper specimen collection
Higher concentration can be caused by life-threatening illness, intense physical activity, or drug interferences
Significant elevation of 1 or both metanephrines (3 or more times the upper reference limit) is associated with an increased probability of a neuroendocrine tumor
Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry
Diagnostic and predictive test for multiple endocrine neoplasia type 2A (MEN2A), multiple endocrine neoplasia type 2B (MEN2B), and familial medullary thyroid carcinoma (FMTC)
Massively Parallel Sequencing
Recommended test to confirm a clinical diagnosis or family history of a hereditary paraganglioma-pheochromocytoma syndrome
Massively Parallel Sequencing/Multiplex Ligation-dependent Probe Amplification
Use for germline analysis of genes associated with the most common paraganglioma-pheochromocytoma syndromes
Massively Parallel Sequencing/Multiplex Ligation-Dependent Probe Amplification (MLPA)
May be beneficial in directing testing algorithms
Immunohistochemistry
Aid in histologic diagnosis of pheochromocytoma
Stained and returned to client pathologist; consultation available if needed
Immunohistochemistry
Immunohistochemistry
Immunohistochemistry
May be useful in nonsecretory sympathetic and parasympathetic tumors
Immunofluorescence
Not recommended for evaluation of pheochromocytoma or paraganglioma
Use to evaluate clinical symptoms of excess catecholamine secretion
For the assessment of pheochromocytoma and paraganglioma, refer to fractionated metanephrines in plasma or urine
Quantitative High Performance Liquid Chromatography (HPLC)
Not recommended for evaluation of pheochromocytoma or paraganglioma
Use to evaluate clinical symptoms of excess catecholamine secretion
For the assessment of pheochromocytoma and paraganglioma, refer to fractionated metanephrines in plasma or urine
Smaller increases in concentration may be the result of physiological stimuli, drugs, or improper specimen collection
Significant elevation of one or more catecholamines is associated with an increased probability of a neuroendocrine tumor
Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry
Acceptable initial test to confirm a suspected diagnosis of VHL syndrome
Massively Parallel Sequencing/Sequencing/Multiplex Ligation-dependent Probe Amplification
Use to confirm a suspected diagnosis of neurofibromatosis (NF1) or Legius syndrome
Massively Parallel Sequencing
Useful when a familial large deletion is known
Does not detect sequence variation
Multiplex Ligation-dependent Probe Amplification
Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry
References
ACR Appropriateness Criteria - Incidentally Discovered Adrenal Mass
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Barontini M, Dahia PLM. VHL disease. Best Pract Res Clin Endocrinol Metab. 2010;24(3):401-413.
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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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NCCN - Neuroendocrine Tumors
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Medical Experts
Bayrak-Toydemir

Frank

Mao

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