What is pheochromocytoma?

Pheochromocytoma: Definition, Clinical Features, and Management

Pheochromocytoma is a rare catecholamine-producing neuroendocrine tumor that originates from chromaffin cells of the adrenal medulla, causing potentially life-threatening hypertension and other symptoms due to excessive hormone secretion. 1

Pathophysiology and Epidemiology

• Pheochromocytomas develop from neuroendocrine cells derived from pluripotent neural crest stem cells associated with the autonomic nervous system 1
• These rare tumors have an annual incidence of 0.1 to 0.6 per 100,000 population and account for approximately 4% of adrenal incidentalomas 1
• Approximately 35% of pheochromocytomas are hereditary, showing autosomal dominant inheritance patterns, often with reduced penetrance 1

Clinical Presentation

• Symptoms typically result from catecholamine excess, including:

  • Sustained or paroxysmal elevations in blood pressure
  • Severe headaches
  • Episodic profuse sweating
  • Palpitations
  • Pallor
  • Apprehension or anxiety 1, 2

• The classic symptomatic triad consists of:

  • Headache
  • Palpitations
  • Sweating 3

• In severe cases, patients may develop:

  • Cardiovascular and cerebrovascular incidents
  • Myocardial disorders
  • Gastrointestinal issues
  • Pheochromocytoma crisis (multi-organ involvement) 3

• Some patients may be asymptomatic with only abnormal imaging and biochemical findings 3

Genetic Associations

• Hereditary pheochromocytomas are associated with multiple genetic syndromes:

  • SDHx genes (SDHA, SDHB, SDHC, SDHD, SDHAF2) - collectively associated with distinct PGL syndromes 1
  • VHL (Von Hippel-Lindau syndrome) 1
  • RET (Multiple Endocrine Neoplasia type 2) 1
  • NF1 (Neurofibromatosis type 1) 1
  • TMEM127 (transmembrane protein 127) 1
  • MAX (MYC associated factor X) 1
  • Recently identified genes: HIF2a, EGLN1, and KIF1b 1

• SDHB mutations are particularly concerning as they are associated with:

  • Higher risk of aggressive behavior
  • Development of metastatic disease
  • Ultimately death 1
  • Malignancy risk ranging from 31% to 71% 1

Diagnostic Evaluation

• Biochemical testing is the first step in diagnosis:

  • Plasma free metanephrines is the most sensitive and specific single test 2
  • If plasma testing is equivocal, 24-hour urine collection for catecholamines and metanephrines should be performed 2
  • Plasma methoxytyramine measurement helps assess malignancy likelihood 2

• Imaging studies for localization:

  • CT or MRI of the abdomen after positive biochemical testing 2
  • Chest CT to evaluate for metastatic disease 2
  • Functional imaging (MIBG scintigraphy) to detect multifocal disease 2

• Genetic testing should be considered, particularly in patients with:

  • Family history of pheochromocytoma/paraganglioma
  • Young age at diagnosis
  • Bilateral or multifocal disease
  • Extra-adrenal location 2

Treatment Approach

• Complete surgical excision (R0 resection) is the mainstay of potentially curative treatment 2

• Preoperative preparation:

  • Alpha-blockade is essential before surgical intervention to prevent hypertensive crisis 4, 5
  • This pharmacologic preparation is crucial for successful outcomes 5

• Surgical options:

  • Laparoscopic adrenalectomy is preferred over open surgery when feasible 3
  • Adrenal-sparing approaches may be considered in appropriate cases 4

• For malignant pheochromocytoma:

  • Cytoreductive surgery might be considered 2
  • Disease and symptom control is the main treatment goal for inoperable cases 2
  • Radiopharmaceuticals (131I-MIBG) for patients with sufficient MIBG uptake 2
  • Palliative options include radiotherapy and chemotherapy 4

Risk Factors for Malignancy

• Malignancy is defined only by the presence of metastatic lesions at sites where chromaffin cells are normally absent 2
• Risk factors for malignancy include:
  • Tumor size ≥5 cm
  • Extra-adrenal paraganglioma
  • SDHB germline mutation
  • Elevated plasma methoxytyramine (>3x upper limit) 2

Follow-up Protocol

• Biochemical testing approximately 14 days following surgery to check for remaining disease 2
• Long-term follow-up includes:
  • Clinical evaluation
  • Biochemical testing
  • Imaging with CT of thorax and abdomen as clinically indicated 2

Clinical Pearls and Pitfalls

• The most important clinical consideration is to include pheochromocytoma in the differential diagnosis of hypertension, especially when paroxysmal or resistant to treatment 4
• Failure to diagnose can lead to life-threatening complications during procedures or anesthesia due to catecholamine surges 4, 5
• Maternal imprinting with silencing of the maternal allele occurs for SDHD and SDHAF2, meaning only mutations inherited from the father will cause disease 1