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Pheochromocytoma

Chapter 399 | Part 12: Endocrinology · Part 12 – Endocrinology & Metabolism · Chapter 399

Key Clinical Points

  1. Pheochromocytomas (PPGLs) are catecholamine-producing tumors of the sympathetic or parasympathetic nervous system.
  2. The 'rule of tens' states that ~10% of cases are bilateral, ~10% extra-adrenal, and ~10% metastatic.
  3. Approximately 25–33% of patients have inherited conditions (e.g., RET, VHL, NF1, SDHx).
  4. The classic triad is palpitations, headache, and profuse sweating (seen in ~1/3 of patients).
  5. Diagnosis requires biochemical confirmation (metanephrines/catecholamines) and imaging (CT/MRI).
  6. Preoperative alpha-adrenergic blockade (phenoxybenzamine) is mandatory before beta-blockade to prevent hypertensive crisis.
  7. Metastatic disease is defined by distant metastases (lung, bone, liver), not just histologic atypia.
  8. Genetic screening: Universal germline panel testing is the gold standard for characterization.
  9. Surgery is the definitive treatment; minimally invasive techniques are now the standard.
  10. Nuclear medicine (e.g., 131I-MIBG) is the preferred treatment for scintigraphically documented metastases.

DEFINITION & CLASSIFICATION

• Definition (Harrison's 22e): The name pheochromocytoma reflects the formerly used black-colored staining caused by chromaffin oxidation of catecholamines. • General Description: Catecholamine-producing tumors derived from the sympathetic or parasympathetic nervous system. • Classification: • Pheochromocytoma: Adrenal tumors (usually secreting). • Paraganglioma: Tumors at all other sites including head and neck, thoracic, extra-adrenal retroperitoneal, and pelvic sites. • Rule of Tens: • ~10% are bilateral • ~10% are extra-adrenal • ~10% are metastatic

EPIDEMIOLOGY

• Incidence: 0.04 to 0.95 cases per 100,000 per year. • Prevalence in Hypertension: ~0.1% of hypertensive patients. • Age at Diagnosis: Mean age ~40 years; however, inherited cases are diagnosed significantly earlier (mean of ~15 years younger than sporadic cases).

ETIOLOGY & PATHOPHYSIOLOGY

• Inheritance: 25–33% have an inherited condition. • Genetic Clusters: • Cluster 1 (Pseudohypoxia): SDHx, FH, VHL, HIF2A • Cluster 2 (Kinase Signaling): RET, NF1, TMEM127, MAX, HRAS, KIF1Bβ, PDH • Cluster 3 (Wnt Signaling): CSDE1, MAML3 • Specific Syndromes: • MEN 2A: RET mutation → Medullary thyroid carcinoma + Pheochromocytoma + Hyperparathyroidism. • MEN 2B: RET mutation → Aggressive MTC + Pheochromocytoma + Mucosal neuromas + Marfanoid habitus. • VHL Disease: Retinal/cerebellar hemangioblastomas, renal cell carcinoma, and pheochromocytoma. • NF1: Tumor suppressor (Ras signaling) → Neurofibromas, café au lait spots, Lisch nodules.

CLINICAL FEATURES

• The Great Masquerader: Highly variable presentation. • Classic Triad: Palpitations, headache, and profuse sweating (seen in ~1/3 of patients). • Primary Sign: Hypertension (can be sustained or paroxysmal). • Paroxysms: Last <1 h; triggered by surgery, positional changes, exercise, pregnancy, urination, or medications. • Associated Symptoms: • Anxiety and panic attacks • Pallor • Nausea and abdominal pain • Weight loss • Orthostatic hypotension (in some cases) • Hypercalcemia, Erythrocytosis, Elevated blood sugar • Table 399-1: Lists 18 clinical features including tachycardia, dilated cardiomyopathy, and paradoxical response to antihypertensives.

DIFFERENTIAL DIAGNOSIS

• Clinical Mimickers: • Essential hypertension • Anxiety attacks • Cocaine or amphetamine use • Mastocytosis or carcinoid syndrome (usually without hypertension) • Intracranial lesions • Clonidine withdrawal • Autonomic epilepsy • Factitious crises (sympathomimetic amines) • Asymptomatic Adrenal Mass Mimickers: • Nonfunctioning adrenal adenoma • Aldosteronoma • Cortisol-producing adenoma (Cushing's syndrome)

DIAGNOSTIC APPROACH

  1. Clinical Suspicion: Based on triad (headache, palpitations, sweating) + hypertension.
  2. Biochemical Testing: Measure metanephrines and catecholamines (plasma or 24-h urine). • Rule of Three: If results are ≥ 3x upper limit of normal, diagnosis is highly likely. • Interference Check: If borderline, exclude drugs (levodopa, sympathomimetics, diuretics, tricyclic antidepressants, opiates) and diet.
  3. Imaging: Perform CT or MRI if biochemical tests are positive. • CT Note: Presence of pheochromocytoma is unlikely if unenhanced CT shows ≤ 95% attenuation.
  4. Advanced Imaging (if needed): If imaging is negative but biochemistry is positive, use MIBG scintigraphy or PET (68Gallium-DOTATATE/DOTATE or 18Fluoro-DOPA).
  5. Histology: • Morphology: 'Zellballen' pattern (neuroendocrine cells with peripheral sustentacular cells). • IHC: Positive for chromogranin, synaptophysin, and S-100. • SDHB Staining: Used to identify germline mutations; loss of staining indicates mutation.

MANAGEMENT & TREATMENT

  1. Preoperative Preparation: • Goal: Blood pressure <160/90 mmHg. • Alpha-blockade: Phenoxybenzamine (0.5–4 mg/kg) is mandatory before beta-blockers. • Supportive Care: Liberal salt intake and hydration to counter volume contraction. • Acute Paroxysms: Prazosin or IV phentolamine while awaiting alpha-blockade effect.
  2. Surgical Management: • Standard: Minimally invasive (laparoscopy/retroperitoneoscopy). • Intraoperative Crisis: Nitroprusside infusion for hypertension; volume infusion for hypotension. • Adrenal Sparing: Consider in extra-adrenal cases to preserve cortex.
  3. Metastatic Disease Treatment: • Nuclear Medicine (Preferred): • 131I-MIBG: 100–300 mCi over 3–6 cycles. • Somatostatin receptor ligands (e.g., DOTATOC with Y-90 or Lu-177). • Chemotherapy: Averbuch's protocol (dacarbazine, cyclophosphamide, vincristine). • Targeted Therapy: Sunitinib and temozolomide (under investigation).

COMPLICATIONS & PROGNOSIS

• Malignancy Definition: Defined as 'metastatic pheochromocytoma' (distant metastases to lungs, bone, or liver). • Prognosis: 5-year survival for metastatic disease is 30–60%. • Risk Factors for Recurrence: Size >5 cm, high PASS score, GAPP score, and SDHB-positive status.

SPECIAL POPULATIONS

• Pregnancy: • Pathophysiology: hCG-induced stimulation of epinephrine production. • Management: Endoscopic removal (ideally 4th–6th month) → safe delivery. • Genetic Screening: • Standard: Universal germline panel is the gold standard. • High Risk Indicators: Early age of onset, extra-adrenal location, multiple tumors, or family history.

KEY PEARLS & HIGH-YIELD POINTS

• Rule of Tens: 10% bilateral, 10% extra-adrenal, 10% metastatic. • Alpha-Blockade First: Never start a beta-blocker before adequate alpha-blockade (risk of hypertensive crisis). • Metanephrines: High sensitivity/specificity for biochemical diagnosis. • SDHB Mutation: Loss of SDHB staining on IHC indicates germline mutation and higher risk of malignancy. • Adrenal Incidentaloma: Only ~5% of these are pheochromocytomas.

Reference Tables

TABLE 399-2 Biochemical and Imaging Methods Used for Diagnosis of Pheochromocytoma and Paraganglioma

Harrison's 22e, p.3074

1. Headaches
2. Profuse sweating
3. Palpitations and tachycardia
4. Hypertension, sustained or
paroxysmal
5. Anxiety and panic attacks
6. Pallor
7. Nausea
8. Abdominal pain
9. Weakness		 10. Weight loss
11. Paradoxical response to
antihypertensive drugs
12. Polyuria and polydipsia
13. Constipation
14. Orthostatic hypotension
15. Dilated cardiomyopathy
16. Erythrocytosis
17. Elevated blood sugar
18. Hypercalcemia

TABLE 399-2 Biochemical and Imaging Methods Used for Diagnosis of Pheochromocytoma and Paraganglioma

DIAGNOSTIC METHOD SENSITIVITY SPECIFICITY
24-h urinary tests
Catecholamines +++ +++
Fractionated metanephrines ++++ ++
Total metanephrines +++ ++++
+++
++++
Imaging
CT ++++ +++
MRI ++++ +++
++
Somatostatin receptor scintigraphya ++ ++
++++
68Gallium-DOTATOC or DOTATATE PET/CT ++++ ++++