Pheochromocytoma - Paraganglioma

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

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
  • 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
• 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
• 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

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
  • 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
• 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

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