What is the initial workup for a patient suspected of having an extraadrenal paraganglioma?

Workup for Extraadrenal Paraganglioma

All patients with suspected extraadrenal paraganglioma require biochemical confirmation with plasma free metanephrines (or 24-hour urinary fractionated metanephrines) plus plasma methoxytyramine, followed by whole-body anatomical imaging (CT or MRI) combined with functional imaging using PET with radiolabeled somatostatin analogs. 1

Biochemical Testing

• Measure plasma free metanephrines or 24-hour urinary fractionated metanephrines as the initial test, which provides 98% diagnostic sensitivity for pheochromocytomas and paragangliomas (PPGLs). 2, 3

• Add plasma methoxytyramine measurement to the initial workup, as up to 30% of extraadrenal paragangliomas produce dopamine, and elevated methoxytyramine (>3 times upper limit) indicates higher malignancy risk. 1, 4

• Plasma normetanephrine levels more than double the upper reference limit are rare (2.3%) in head/neck paragangliomas but suggest the presence of paraganglioma outside the head and neck region. 1

• Do not rely on urine methoxytyramine, as it is not a useful biomarker since urinary dopamine derives almost exclusively from renal uptake and decarboxylation of circulating DOPA. 1

Anatomical Imaging

• For head and neck paragangliomas, perform MRI with angiography sequences (MRA) as the first-line modality to assess multifocality and tumor extension, with sensitivity of 88.7% and specificity of 93.7%. 1

• For skull base head/neck paragangliomas, add temporal bone CT to evaluate bone involvement. 1

• For abdominal/retroperitoneal paragangliomas, perform CT or MRI of the abdomen and pelvis as initial anatomical imaging. 1, 4

• CT with intravenous contrast is less costly and time-consuming than MRI and is particularly useful for perioperative planning, making it often preferred at initial evaluation except in pediatric cases or pregnancy. 1

Functional Imaging

• Perform whole-body PET imaging with radiolabeled somatostatin analogs (e.g., 68Ga-DOTATATE) as the first-choice functional imaging, as extraadrenal paragangliomas typically exhibit strong somatostatin receptor subtype 2 expression with sensitivity approaching 100% for head/neck parasympathetic lesions. 1

• Alternative functional imaging options include FDG-PET/CT or 123I-MIBG scintigraphy, though somatostatin receptor imaging is preferred. 1

• Imaging should encompass from the base of the skull to the pelvis to detect multifocal disease and metastases. 1

• Functional imaging is crucial for extraadrenal paragangliomas regardless of size, as pretreatment imaging provides accurate disease staging and nuclear imaging plays a leading role. 1

Additional Staging Workup

• Obtain chest CT (or include chest in whole-body PET/CT) to evaluate for thoracic metastases. 1

• Perform cerebral MRI if there is concern for brain metastases based on symptoms or high-risk features. 1

• Consider bone imaging (bone scan, bone CT, bone MRI, or as part of FDG-PET/CT or DOTATATE-PET/CT) to detect bone metastases, particularly in patients with large tumors (>5 cm) or SDHB mutations. 1

Genetic Testing Considerations

• Consider genetic testing in all patients with paragangliomas, as mutations in succinate dehydrogenase subunit genes (SDHx) are associated with extraadrenal locations and higher malignancy risk. 1, 2

• SDHB mutations carry 31-71% malignancy risk and warrant extended lifelong monitoring. 1

• Genetic testing should be performed by accredited laboratories and is particularly important in patients with extraadrenal location, young age, family history, or multifocal disease. 2

Critical Pitfalls to Avoid

• Never perform biopsy before ruling out paraganglioma biochemically, as biopsy carries high risk of hypertensive crisis and tachyarrhythmia in functional tumors. 1

• Do not skip biochemical testing even if imaging is highly suggestive, as functional imaging is usually not performed before biochemical confirmation. 1

• Recognize that extraadrenal paragangliomas have higher malignancy rates (21-36%) compared to adrenal pheochromocytomas, with tumor size >5 cm being a strong predictor of malignant behavior. 5, 6

• All extraadrenal paragangliomas should be managed by an expert interdisciplinary team familiar with PPGL disease to ensure favorable outcomes. 1

• Malignancy can only be definitively diagnosed by presence of metastases at sites where chromaffin tissue is normally absent (liver, bone, lungs, lymph nodes). 1