Pheochromocytoma

Aka: Pheochromocytoma, Paroxysmal Hypertension

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II. Definitions

  1. Pheochromocytoma
    1. CatecholamineSecreting tumor of the Adrenal Gland

III. Epidemiology

  1. Incidence: Rare
    1. Prevalence in general population: 0.05%
    2. Accounts for <1% of Hypertension cases
    3. Accounts for 5-7% of incidental Adrenal Masses on CT
  2. Peak ages: 30-60 years
  3. Equal male and female predominance

IV. Pathophysiology

  1. Pheochromocytoma distribution
    1. Adrenal (90%)
    2. Extra-adrenal (e.g. chest, Abdomen, Pelvis, head or neck)

V. Presentation: Classic Episodes

  1. Predominant Symptoms
    1. Headache
    2. Diaphoresis or Sweating
    3. Palpitations
  2. Associated Symptoms
    1. Anxiety
    2. Tremor
    3. Pallor
    4. Chest Pain
    5. Epigastric Pain
    6. Flushing (rare)
    7. Painless Hematuria (rare)
    8. Orthostatic Hypotension and Syncope
    9. Labile Blood Pressure
  3. Timing of episodes
    1. Duration: One hour or less
    2. Frequency: daily to once every few months

VI. Presentation: Other

  1. Hyperadrenergic spells (see classic episodes above)
  2. Resistant Hypertension
  3. Malignant or intra-operative Hypertension
  4. Family History of Pheochromocytoma or predisposing syndromes (e.g. MEN 2, NF1, VHL. SDH)
  5. Premature Hypertension (age under 20 years)
  6. Idiopathic Dilated Cardiomyopathy

VII. Diagnostic Clues

  1. Six "H's"
    1. Hypertension
    2. Headache - throbbing (90%)
    3. Hyperhidrosis or excessive sweating (69%)
    4. Heart consciousness or Palpitations (73%)
    5. Hypermetabolism
    6. Hyperglycemia
  2. Rule of 10
    1. Familial (10%, e.g. Multiple Endocrine Neoplasia)
    2. Malignant (10%)
    3. Multiple or Bilateral (10%)
    4. Extra-adrenal (10%)
    5. Childhood onset (10%)
    6. Recurrence after Surgery (10%)

VIII. Differential Diagnosis

  1. Primary Aldosteronism
  2. Carcinoid
  3. Accelerated or Malignant Hypertension
  4. Illicit, OTC or prescribed Sympathomimetic medications
  5. Chemodectoma
  6. Ganglioneuroma
  7. Thyrotoxicosis
  8. Menopause
  9. Panic Disorder
  10. Antihypertensive withdrawal (e.g. Clonidine Withdrawal)

IX. Labs: Preparation

  1. Stop any interfering medications
    1. Labetalol (stop for 1 week)
    2. Tricyclic Antidepressant (stop for 2 weeks)
    3. Psychoactive medications (stop for weeks)
    4. Levodopa or Methyldopa
    5. Decongestants
    6. Benzodiazepines
    7. Muscle relaxants (mephenasin, Methocarbamol)
    8. Avoid Tylenol for 48 hours
    9. Avoid Aspirin
  2. Stop other interfering agents
    1. No Caffeine, Alcohol or Tobacco for 4 hours
    2. Tomatoes
    3. Walnuts
    4. Pineapple
    5. Banana
    6. Eggplant
    7. Avocado
    8. Plums

X. Labs: Available Tests

  1. Best studies
    1. Urine Metanephrines (24 hour collections)
      1. Use as first line screening
      2. Test Sensitivity: 76%
      3. Test Specificity: 94%
    2. Plasma Free Metanephrines
      1. Very high False Positive Rate (Pheochromocytoma is rare)
      2. Use only for confirmation, not for screening
      3. Test Sensitivity: 99%
      4. Test Specificity: 89%
  2. Tests with lower efficacy
    1. Urinary VMA
      1. Normal value under 6.5 mg/day
      2. Imprecise test
      3. Drugs and food interfere with test
      4. Test Sensitivity: 63%
      5. Test Specificity: 94%
    2. Plasma Catecholamines (Norepinephrine, Epinephrine)
      1. Test Sensitivity: 85%
      2. Test Specificity: 80%

XI. Labs: Protocol

  1. First: 24-hour Urine Metanephrine and Urine VMA
  2. Next: Plasma Free Metanephrines
  3. Next: Plasma Catecholamines (equivocal metanephrines)
  4. Final: Clonidine Suppression (positive Catecholamines)

XII. Imaging: Tumor localization

  1. Abdominal CT with and without contrast
    1. Precautions
      1. Ionic Iodinated contrast is a risk for Hypertensive Emergency, but nonionic contrast is safe
        1. Bessell-Browne (2007) AJR Am J Roentgenol 188:970-4 [PubMed]
    2. Interpretation
      1. Incidental non-contrast CT Adrenal Mass with hounsfield density <10 excludes Pheochromocytoma
        1. Test Sensitivity: 99.6%
        2. Buitenwerf (2018) Eur J Endocrinol 178:431-7 [PubMed]
    3. Efficacy
      1. Test Sensitivity: 90%
      2. Test Specificity: 93%
  2. Adrenal MRI
    1. Test Sensitivity: 93%
    2. Test Specificity: 93%
  3. SPECT I-123 MIBG Scan (single photon emission, Iodine-131 metaiodobenzyl-guanidine)
    1. Test Sensitivity: 77 to 91%
    2. Test Specificity: 95 to 100%
    3. Good for looking for tumors in unusual sites
    4. Injection of radioisotope is 1-3 days before imaging

XIII. Management

  1. Preoperative Medical Management
    1. Alpha Adrenergic ReceptorAntagonist (2 weeks pre-op)
      1. Phenoxybenzamine (alpha blocker) orally twice daily
      2. Phentolamine IV prn
    2. Beta Blocker (only start after alpha blockade)
      1. Propranolol orally four times daily
      2. Precaution
        1. Only use if already on alpha-adrenergic blocker
        2. Otherwise, risk of worsening Hypertension from unopposed alpha stimulation
  2. Surgical Management
    1. Laparoscopic adrenalectomy Indications
      1. Single, small adrenal tumors
      2. Hypertension controlled
    2. Open Adrenalectomy
      1. Adrenal tumor size over 7 cm
  3. Intra-Operative Management
    1. Continuous Arterial-line Blood Pressure Monitoring
    2. Treat Hypotension
      1. Fluid management
      2. Consider pressor support
    3. Treat Hypertension
      1. Phentolamine
      2. Nitroprusside
    4. Treat Tachycardia or ectopy
      1. Beta Blocker
  4. Adjunctive treatment for malignant Pheochromocytoma
    1. Chemotherapy
      1. Cyclophosphamide
      2. Dacarbazine
      3. Vincristine
    2. MIGB (metaiodobenzyl-guanidine I-131)
    3. Metyrosine 1 gram every 6 hours
      1. Depletes tumor Catecholamine stores

XIV. Course

  1. Persistent Hypertension in 25% of treated patients

XV. Monitoring

  1. Screen Urine Metanephrines annually
  2. Screen Urine Catecholamines annually

XVI. References

  1. Bailey (2001) CMEA Medicine Lecture, San Diego
  2. Broder (2020) Crit Dec Emerg Med 34(12): 14
  3. (Feb 2001) Ann Intern Med

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