Pheochromocytoma - Paraganglioma

Indications for Testing

Laboratory testing for PPGLs is appropriate in individuals with   :

• Spontaneous or triggered signs and symptoms of a PPGL (eg, episodic, paroxysmal, or resistant hypertension; headache; palpitations; syncope; tachycardia)
• Cardiovascular events consistent with PPGL in the presence of signs and symptoms
• Suggestive incidental findings on imaging
• A diagnosis or family history of an associated hereditary syndrome (eg, SDH gene-associated disorders, MEN2, VHL, NF1)
• A personal history of PPGLs
• Type 2 diabetes and a body mass index (BMI) <25 kg/m²

Laboratory Testing

Diagnosis

Biochemical Testing

Metanephrines in Plasma or Urine

Testing for metanephrine and normetanephrine (metabolites of epinephrine and norepinephrine) is the recommended first step in the evaluation of suspected PPGL.    In patients with known pathogenic genetic variants, testing should be performed according to the known variant because different hereditary syndromes are associated with different catecholamine secretion patterns. Individuals with NF1 or RET variants should be tested for both metanephrine and normetanephrine, and individuals with SDHx or VHL variants should be tested for normetanephrine alone.  It is reasonable to proceed directly to imaging in individuals who do not produce catecholamines or in individuals with severe symptoms. 

In most situations, either a plasma-free metanephrines or fractionated 24-hour urine metanephrines test may be used.    Saliva testing and urine spot testing are currently being researched.  Liquid chromatography with tandem mass spectrometry (LC-MS/MS) is preferred over other assay methods because it is less likely to underestimate metanephrines concentrations than immunoassays and is less subject to analytic interference than electrochemical or fluorometric testing methods.  

For plasma metanephrines testing, it is recommended that the specimen be collected after the patient has been in the supine position for at least 20 minutes.   Vigorous physical activity should be avoided before specimen collection.  Specimen collection should be performed on ice or cold packs, and hemolysis should be prevented.   If samples cannot be collected under the appropriate conditions, urine testing can be performed as an alternative.  A medication review is recommended because some drugs may interfere with plasma metanephrines testing, including acetaminophen, some antidepressants, monoamine oxidase inhibitors, phenoxybenzamine, and drugs that stimulate the sympathetic nervous system.   

Although both urine and plasma tests have high diagnostic sensitivity for PPGL in individuals at low risk, the urine metanephrines test is not suitable in patients with chronic kidney disease, may be less sensitive than the plasma test in individuals with a hereditary syndrome or a known tumor, and may be inconvenient for other patients.    Both free and conjugated metanephrines are measured by some laboratories, but this is associated with an increased risk of false-positive test results.  Measurement of urinary creatinine is recommended to determine whether the urine collection was complete.  Urine metanephrines testing is also subject to interference from some drugs and foods. 

Results should be interpreted in the context of hereditary risk, pretest probability of a PPGL (eg, based on imaging findings), and the patient’s clinical situation.   Ideally, reference intervals should be as personalized as possible (eg, adjusted for body size).  In practice, however, age- and sex-specific reference intervals (developed from samples obtained from individuals in the supine position for plasma testing) should be used if available.   Plasma metanephrines results that are more than twice the upper limit of the appropriate reference interval or elevated results for more than one analyte may warrant imaging regardless of other factors, whereas smaller elevations in single metabolites may warrant imaging in the appropriate clinical context.   Results greater than three times the upper limit of the appropriate reference interval are considered diagnostic.  If results are mildly elevated or indeterminate, a false-positive result should be considered, as false-positive results may occur relatively frequently.   False-negative results may occur, particularly in individuals at high risk, but are rare in individuals at low risk of a PPGL. 

Common causes of false-positive results include certain medications, foods, and physiologically elevated catecholamine concentrations (potentially a result of inappropriate sampling conditions, stress, or conditions such as heart failure or severe illness).    A repeat metanephrines test under controlled conditions (ie, with the patient fasting, in a supine position, and in a calm and warm setting after a supine rest period >20 minutes for plasma metanephrines testing; avoiding exercise before urine metanephrines testing) should be considered following a potential false-positive result.   A percutaneous cannula instead of venipuncture is recommended for blood collection.  Collection in an inpatient setting should be considered for both blood and urine testing.  Repeat testing after a hiatus from medication is not generally necessary but may be reasonable if safe.   In patients with serious illnesses, sampling after recovery may be useful if feasible, although it may also be reasonable to proceed to imaging without repeat testing.  Simultaneous plasma and urine metanephrines testing or clonidine suppression testing may also be considered.   

3-Methoxytyramine in Plasma

Plasma measurement of 3-methoxytyramine (a metabolite of dopamine) should be considered in the investigation of suspected dopamine-secreting tumors, potential metastatic disease, and hereditary PPGL (particularly in individuals with known SDHx variants and possible metastases).    Some foods may interfere with 3-methoxytyramine testing; therefore, a fasting sample is recommended.  Levodopa may also cause false-positive results. 

Catecholamines in Plasma or Urine

Generally, the measurement of plasma or 24-hour urine catecholamines (including dopamine) instead of their metabolites is no longer recommended in the initial evaluation of PPGLs due to a lack of secretion by some tumors.   However, the measurement of fractionated catecholamines may be considered for suspected head or neck paragangliomas or to evaluate for rare tumors. 

Homovanillic Acid and Vanillylmandelic Acid in Plasma or Urine

Plasma or 24-hour urine homovanillic acid (HVA) and vanillylmandelic acid (VMA) testing may be performed in some situations.  LC-MS/MS is the preferred testing method for these analytes.  These tests have largely been replaced by metanephrines testing in clinical practice. 

Chromogranin A in Serum

Chromogranin A testing may be useful for prognosis and treatment decision-making in neuroendocrine tumors, including PPGLs; however, this testing is becoming less common in this clinical scenario.    Elevated chromogranin A concentrations may be associated with a worse prognosis. 

Immunohistochemistry

A histological and immunohistochemical evaluation of tumor tissue may be useful in the investigation of PPGL.  Informative stains may include chromogranin A, cytokeratins, human melanoma black-45 (HMB45), neuron-specific enolase, synaptophysin, S-100, and vimentin. 

Genetic Testing

It is recommended that genetic consultation and testing be considered for all patients with confirmed PPGL.    Individuals diagnosed with PPGL before 45 years of age or those with bilateral, multifocal, or recurrent PPGLs are more likely to have a heritable germline variant. PPGLs have been linked to MEN2, NF1, VHL, and other disorders, as well as germline pathogenic variants in a number of susceptibility genes.   Additionally, many sporadic PPGLs are the result of somatic variants in genes known to lead to the initiation of tumorigenesis. 

The specific genetic testing strategy for an individual patient should be guided by clinical presentation, biochemical test results, family history, and imaging.  Single-gene testing or multigene panel testing by next generation sequencing (NGS) may be appropriate, depending on the clinical circumstances and any syndromic features.  SDHx testing should be strongly considered in individuals with metastatic PPGL due to the high incidence of SDHx variants in these patients.  Initial use of a tumor specimen to assess for somatic variants, followed by germline testing, may be beneficial to distinguish hereditary and sporadic PPGL, guide the search for pathogenic germline variants, and advance knowledge of variants of unknown significance. 

Targeted familial variant testing is appropriate if there is a family history of an associated syndrome with a known germline variant. Genetic testing for at-risk family members, including asymptomatic children, should be considered.

Other Tests

Imaging is recommended in the evaluation of PPGL following a positive biochemical test, if there is high suspicion for a biochemically silent PPGL, or if there is suspected metastatic disease.    

Surveillance

Regular biochemical testing is recommended for individuals with a known germline variant associated with the development of PPGL.    The National Comprehensive Cancer Network (NCCN) recommends beginning these evaluations at 6-10 years of age or later depending on the specific syndrome,  whereas other guidelines recommend beginning as early as 5 years of age.  The specific testing to perform and its frequency depend on the clinical situation and genetic diagnosis.   

Monitoring

Monitoring may include clinical evaluation and laboratory testing. Recommendations for laboratory testing to monitor for incomplete resection, metastases, and recurrence in PPGL vary: