What is paraganglioma?

Paraganglioma: Clinical Overview and Management

Paragangliomas are rare neuroendocrine tumors that arise from extra-adrenal paraganglia of the autonomic nervous system, which can cause significant morbidity and mortality through catecholamine hypersecretion or mass effect. 1

Definition and Classification

Paragangliomas develop from neuroendocrine cells derived from neural crest stem cells associated with the autonomic nervous system. They can be classified based on their location:

• Sympathetic paragangliomas: Arise from chromaffin cells in the:

  • Organ of Zuckerkandl
  • Para-aortic sympathetic chain
  • Urinary bladder wall
  • Sympathetic chain in neck or mediastinum
  • Lower mediastinum, abdomen, and pelvis 1

• Parasympathetic paragangliomas: Predominantly found in:

  • Head and neck region (skull base, middle ear, carotid body)
  • Upper mediastinum 1

Clinical Presentation

Paragangliomas present in several ways depending on their location and functional status:

• Catecholamine-secreting tumors (typically sympathetic):

  • Hypertension (sustained or paroxysmal)
  • Headaches
  • Palpitations
  • Profuse sweating (diaphoresis)
  • Pallor
  • Anxiety 1, 2

• Non-secreting tumors (typically parasympathetic, especially head and neck):

  • Usually asymptomatic until they grow large
  • Mass effect symptoms (dysphagia, hearing loss, tinnitus)
  • Cranial nerve palsies 1

• Incidental finding on imaging studies 2

• Family screening for hereditary paraganglioma syndromes 2

Genetics and Hereditary Syndromes

Up to 35-50% of paragangliomas are hereditary, making genetic testing essential 1, 2:

• SDHx genes (SDHA, SDHB, SDHC, SDHD, SDHAF2): Associated with distinct paraganglioma syndromes

  • SDHB mutations carry higher risk of malignancy and metastatic disease 1

• Other genes: VHL, RET, NF1, MAX, TMEM127, HIF2a, EGLN1, KIF1b, FH 1

• Associated syndromes:

  • Multiple Endocrine Neoplasia type 2
  • Von Hippel-Lindau disease
  • Neurofibromatosis type 1
  • Carney triad 2

Diagnostic Approach

1. Biochemical testing (for suspected catecholamine-secreting tumors):

   • Plasma or 24-hour urine fractionated metanephrines
   • Should precede imaging studies 1, 2

2. Imaging studies:

   • CT or MRI for initial localization
   • Functional imaging:
     • 123I-MIBG scintigraphy
     • PET scanning 1, 3

3. Genetic testing:

   • Should be considered in all patients with paraganglioma
   • Especially important in young patients, multiple tumors, or family history 4

Prognosis and Malignancy Risk

The prognosis of paragangliomas varies by location and genetic background:

• Most paragangliomas are histologically benign but can cause significant morbidity

• Malignancy risk factors:

  • SDHB mutation (highest risk)
  • Retroperitoneal location
  • Large tumor size at diagnosis 1

• Carotid body paragangliomas: Low malignancy rate (2-3%, up to 12% in some studies)

• Retroperitoneal paragangliomas: Higher incidence of malignant behavior 1

Management

1. Surgical resection is the treatment of choice 2:

   • Preoperative preparation with alpha-blockade is essential for catecholamine-secreting tumors
   • Complete resection is curative for benign tumors

2. Perioperative management:

   • Alpha-adrenergic blockade followed by beta-blockade
   • Close monitoring for cardiovascular complications
   • Watch for post-resection hypotension 5, 4

3. Post-surgical follow-up:

   • Annual biochemical testing to assess for recurrence or metastatic disease
   • Surveillance imaging based on genetic status and risk factors 2

Important Considerations and Pitfalls

• Misdiagnosis: Paragangliomas can be misdiagnosed as other conditions, particularly when non-functional
• Perioperative complications: Sudden catecholamine release during surgery can cause hypertensive crisis
• Post-resection hypotension: Abrupt decline in catecholamines after tumor removal can cause severe hypotension
• Multifocal disease: Common in hereditary cases, requiring thorough imaging
• Delayed recurrence: Can occur many years after initial resection, necessitating long-term follow-up 5, 4

Patients with paragangliomas require a multidisciplinary approach involving endocrinologists, surgeons, radiologists, geneticists, and pathologists to ensure optimal outcomes and reduce morbidity and mortality.