What is pheochromocytoma?

Pheochromocytoma: Definition, Diagnosis, and Management

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

Definition and Origin

Pheochromocytomas are neuroendocrine tumors that develop from:

• Neural crest-derived chromaffin cells in the adrenal medulla
• When located outside the adrenal gland, they are called paragangliomas (PGLs)
• Together they are referred to as PPGLs (Pheochromocytomas and Paragangliomas) 2

These tumors are rare, with an annual incidence of 0.1 to 0.6 per 100,000 population, accounting for approximately 4% of adrenal incidentalomas 2.

Clinical Presentation

Symptoms result primarily from catecholamine excess:

• Sustained or paroxysmal hypertension (hallmark feature)
• Headache (often severe)
• Episodic profuse sweating
• Palpitations
• Pallor
• Anxiety or apprehension 2, 1

In severe cases, pheochromocytoma crisis can lead to:

• Cardiomyopathy
• Pulmonary edema
• Total circulatory collapse requiring intensive intervention 3

Parasympathetic PGLs (typically in head and neck) are usually non-secreting (95%) and present with:

• Symptoms from mass effect (hearing loss, tinnitus, dysphagia)
• Cranial nerve palsies 2

Genetic Considerations

Approximately 35% of pheochromocytomas are hereditary, with autosomal dominant inheritance patterns 2, 1:

Key genetic mutations include:

• SDHx genes (SDHA, SDHB, SDHC, SDHD, SDHAF2)
• VHL (Von Hippel-Lindau)
• RET (Multiple Endocrine Neoplasia type 2)
• NF1 (Neurofibromatosis type 1)
• TMEM127, MAX, and others 2

Important risk factor: SDHB mutations are associated with higher risk of aggressive behavior and metastatic disease, with malignancy risk ranging from 31% to 71% 2.

Diagnostic Approach

Biochemical Testing

• First-line: Plasma or 24-hour urine metanephrines and catecholamines
• Plasma metanephrine levels ≥4 times upper limit of normal strongly suggest pheochromocytoma
• Levels 2-4 times upper limit require repeat testing 1

Imaging

1. Initial imaging: Adrenal protocol CT or MRI of abdomen
2. Functional imaging options:
   • Meta-iodobenzylguanidine (MIBG) scintigraphy
   • FDOPA-PET (superior for hereditary syndromes)
   • FDG-PET (useful for potentially malignant lesions, especially SDHB-related tumors) 1

Important caveat: Imaging should only be pursued after biochemical evidence of pheochromocytoma to avoid unnecessary procedures 1.

Management

Preoperative Medical Management

• Alpha-adrenergic blockade is essential before surgery:

  • Options include phenoxybenzamine (40-80 mg/day) or selective α1-blockers (doxazosin, prazosin, terazosin)
  • Must be started 10-14 days before surgery 1, 4

• Beta-blockers should only be added after adequate alpha-blockade if tachycardia persists

  • Adding beta-blockers before alpha-blockade can worsen hypertension 1

• Metyrosine may be used to inhibit catecholamine synthesis:

  • Blocks tyrosine hydroxylase, reducing catecholamine production by 35-80%
  • Can reduce frequency and severity of hypertensive attacks 4

Surgical Management

• Laparoscopic adrenalectomy is recommended for small tumors (<8 cm)
• Open surgery for larger tumors (>5-6 cm) or with evidence of invasion
• Critical warning: Adequate intravascular volume must be maintained during and after surgery to avoid hypotension 1, 4

Post-Surgical Follow-up

• Plasma/urine metanephrines should be measured 8 weeks post-surgery
• Imaging at 3-6 months post-surgery
• Continued surveillance for at least 10 years (lifelong for genetic cases) 1

Malignant Pheochromocytoma

Treatment options include:

• Radiopharmaceuticals (131I-MIBG)
• Locoregional ablative procedures
• Combination chemotherapy (cyclophosphamide, vincristine, dacarbazine)
• For SDHx-related metastatic disease: temozolomide or tyrosine kinase inhibitors 1

Key Pitfalls to Avoid

1. Never perform fine needle biopsy of suspected pheochromocytoma (risk of hypertensive crisis)
2. Never add beta-blockers before adequate alpha-blockade (can worsen hypertension)
3. Never underestimate the importance of genetic testing, especially in young patients, bilateral disease, or family history
4. Never forget adequate volume replacement during and after surgery to prevent hypotension
5. Never discontinue follow-up too early, as recurrence can occur even years later 1, 4