Pheochromocytoma

Pheochromocytoma is a catecholamine-secreting tumor derived from chromaffin cells. The majority of tumors originate in the adrenal medulla, but they may also arise from sympathetic ganglia (also referred to as paraganglioma). Symptoms are associated with excessive catecholamine production and commonly include hypertension, tachycardia, headache, and sweating. Pheochromocytomas are frequently familial and associated with genetic syndromes. Approximately 90% of pheochromocytomas are benign and surgical resection is the only curative treatment. Prognosis is generally good for benign, sporadic tumors that have been completely resected. Familial forms are associated with higher recurrence rates and malignant potential.

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Overview

Definition

Pheochromocytoma is a catecholamine-secreting tumor derived from chromaffin cells.

Anatomy

  • 98% intra-abdominal
  • 90% located in adrenal glands
  • Familial cases tend to be bilateral.
  • Extra-adrenal pheochromocytoma is referred to as paraganglioma:
    • Develops in paraganglion chromaffin tissue of sympathetic ganglia
    • Anywhere from base of brain to urinary bladder
    • Most common:
      • Organ of Zuckerkandl (at origin of inferior mesenteric artery)
      • Bladder wall
      • Heart
      • Mediastinum
      • Carotid and glomus jugulare bodies

Epidemiology

  • Most common tumor of adrenal medulla in adults
  • Approximately 1,000 cases diagnosed annually in the United States
  • Estimated 0.8 per 100,000 persons/year in the United States
  • No gender difference
  • Age of onset typically 30–50 years old for sporadic cases
  • Approximately 40% associated with hereditary disorders and younger age of onset

Etiology

  • Chromaffin cell neoplasia (derived from the neural crest)
  • 60% or more are sporadic.
  • 10+ gene mutations have been identified in association with pheochromocytoma.
  • Most common genetic syndromes associated with pheochromocytoma: 
    • Von Hippel-Lindau (VHL)
    • Multiple endocrine neoplasia type 2 (MEN2)
    • Neurofibromatosis type 1 (NF-1)

Mnemonic

The “rule of 10s” for pheochromocytoma characteristics:

  • 10% of cases are malignant.
  • 10% of tumors are bilateral.
  • 10% of tumors have extra-adrenal locations (e.g., bladder wall, organ of Zuckerkandl).
  • 10% of tumors show calcifications on imaging.
  • 10% of cases are pediatric.

Pathophysiology

Excessive catecholamine secretion by tumor

  • Intermittent or continuous
  • Most pheochromocytoma secrete predominantly norepinephrine (normal medulla approximately 85% epinephrine); may also secret dopamine.
  • Secretion is not regulated by neural pathways like the normal medulla.
  • Triggers for secretion may include:
    • Direct pressure
    • Postural changes
    • Medications: inhibitors of catecholamine reuptake (e.g., tricyclic antidepressants)
    • Changes in tumor blood flow
    • Emotional or physiological stress
  • Transient increase in secretion may precipitate hypertensive crisis.

Effects of catecholamine secretion

  • 𝛂-adrenergic stimulation:
    • ↑ Blood pressure
    • ↑ Cardiac contractility
    • ↑ Glycogenolysis
    • ↑ Gluconeogenesis
    • ↑ Intestinal relaxation
  • 𝜷-adrenergic stimulation:
    • ↑ Heart rate
    • ↑ Cardiac contractility

Malignant potential

  • No biochemical or histologic difference between benign and malignant pheochromocytoma
  • Malignancy defined by:
    • Local invasion of surrounding tissues
    • Distant metastasis (may occur as late as 50 years after resection)

Clinical Presentation

  • Classic triad (most patients rarely present with all 3 symptoms):
    1. Headache: 90% of symptomatic patients
    2. Sweating: 60%–70% of symptomatic patients
    3. Tachycardia
  • Sustained or paroxysmal hypertension is the most common symptom.
  • Hyperadrenergic spells (pallor, anxiety, palpitations, tremor)
  • Orthostatic hypotension (from catecholamine-induced volume contraction)
  • Cardiomyopathy (catecholamine-induced)
  • 5%–15% of patients may have normal blood pressure and no other symptoms:
    • Pre-biochemical phase (normal catecholamine levels)
    • Tumor incidentally discovered on imaging
  • Pheochromocytoma crisis (rare):
    • Hyper- or hypotension
    • Hyperthermia (> 40℃)
    • Mental status changes
    • Multiple organ dysfunction

Mnemonic

To recall the most common clinical features of pheochromocytoma or episodic hyperadrenergic spells, remember the “5 Ps“: 

  • Pressure (high blood pressure) 
  • Pain (headache) 
  • Perspiration 
  • Palpitations 
  • Pallor

Diagnosis

History

  • Presence of classic triad
  • Hyperadrenergic spells (pallor, anxiety, palpitations, tremor)
  • Hypertension onset at young age (< 20 years old)
  • Hypertension with poor response to medications
  • Family history of pheochromocytoma
  • Family history of VHL, MEN2, or NF-1
  • Idiopathic dilated cardiomyopathy
  • Carney triad: gastric stromal tumors + pulmonary chondromas + paraganglioma

Physical exam

  • Hypertension
  • Tachycardia
  • Pallor
  • Orthostatic hypotension

Biochemical testing

  • Catecholamine metabolized to metanephrine in chromaffin cells
  • Plasma fractionated metanephrine:
    • High sensitivity (96%–100%), but poor specificity (85%–89%; < 80% for patients > 60 years old)
    • Use as 1st test if suspicion is high (family history or genetic syndromes).
    • Usually preferred test in children for whom 24-hour urine collection may be difficult
  • 24-hour urine fractionated metanephrine, vanillylmandelic acid, and catecholamines:
    • Similar sensitivity, but better specificity than plasma metanephrine
    • Preferred 1st test in low-suspicion cases
  • For patients with spells, testing should ideally be performed at the time of the spell.
  • Medications affecting test results:
    • Tricyclic antidepressants
    • Psychoactive medications
    • Phenoxybenzamine
    • Beta-blockers
    • Levodopa

Imaging

  • Contrast-enhanced CT:
    • Usually 1st test
    • Pheochromocytoma has low lipid content and usually attenuation of > 10 Hounsfield units.
  • MRI:
    • Alternative test
    • 1st test in children and pregnant women
  • Iodine metaiodobenzylguanidine (MIBG) scintigraphy: 
    • Radioactive iodine taken by adrenergic tissues similar to norepinephrine
    • Can detect multiple tumors or tumors not visualized on CT or MRI
  • Image-guided biopsy: contraindicated as it may precipitate catecholamine release and severe hypertensive crisis

Related videos

Management

Surgery

  • Only definitive treatment
  • Laparoscopic adrenalectomy is the standard of care for adrenal pheochromocytoma.
  • Bilateral partial adrenalectomy or cortical-sparing adrenalectomy should be performed for bilateral lesions.
  • Total bilateral adrenalectomy often considered in MEN2 because of high recurrence risk
  • Laparoscopic resection also feasible for some abdominal paragangliomas
  • Open resections reserved for large, difficult to access, or locally invasive tumors

Preoperative preparation

  • Goals:
    • Control hypertension and tachycardia to prevent hypertensive crisis.
    • Volume expansion with IV fluids
  • α-adrenergic blockade:
    • Started at least 7 days preoperatively
    • Preferred drug: phenoxybenzamine, but other α-adrenergic receptor blockers can be used
    • Goal: seated blood pressure < 120/80 mm Hg with standing systolic pressure > 90
  • High-sodium diet:
    • Started on 2nd–3rd day of α-blockade
    • Aids volume expansion
  • 𝛃-adrenergic blockade:
    • Usually started 2–3 days preoperatively after adequate α-adrenergic blockade and volume expansion have been accomplished
    • Should be started cautiously at a low dose for concerns of catecholamine-induced cardiomyopathy
  • Calcium channel blockers: sometimes used in place of α-blockers with similar effectiveness
  • Metyrosine:
    • Inhibitor of catecholamine synthesis
    • Add if α-blockade is not effective enough.

Metastatic pheochromocytoma

  • No curative treatment
  • Resection of primary and metastatic disease should be attempted whenever possible.
  • Other therapies:
    • External beam radiation
    • Ablative therapies:
      • Radiofrequency
      • Cryoablation
      • Percutaneous ethanol injection
    • Chemoembolization (for liver metastasis)
    • Iodine MIBG
    • Chemotherapy:
      • Somatostatin analogs
      • Cytotoxic therapy (cyclophosphamide, dacarbazine, vincristine, doxorubicin)
      • Tyrosine kinase receptor inhibitors (sunitinib)
Pheochromocytoma after resection

Pheochromocytoma of left adrenal gland (post-resection)

Image: “Pre-surgical MR and macroscopic anatomy images” by Non-invasive Cardiac Imaging Laboratory, CMR Unit, Department of Cardiology and Cardiovascular Surgery, Niguarda Ca’Granda Hospital, Milan, Italy. License: CC BY 2.0, cropped by Lecturio.

Prognosis

  • Recurrence is approximately 16% (even for apparently benign tumors).
  • Recurrence is higher for familial forms.
  • Long-term monitoring with annual biochemical screening advised
  • Malignant/metastatic disease:
    • 5-year survival at 12%–84% 
    • Prognosis depends on tumor burden, location of metastasis, and rate of progression.

Differential Diagnosis

  • Malignant hypertension: severely elevated blood pressure that can lead to end organ-damage. Malignant hypertension mostly affects patients with a long-standing history of hypertension associated with renal disease or medication noncompliance. Malignant hypertension needs to be recognized and treated emergently.
  • Hyperthyroidism: a condition caused by excessive secretion of thyroid hormone by the thyroid gland. Presentation can include anxiety, sweating, palpitations, and heat intolerance. The diagnosis is established by measurement of plasma levels of thyroid and thyroid-stimulating hormone.
  • Anxiety disorder: psychiatric disorder often associated with physical manifestations. Presentation can include palpitations, sweating, tremors, and shortness of breath. The diagnosis is established by ruling out other medical conditions.
  • Carcinoid syndrome: constellation of symptoms associated with a hormone-producing carcinoid tumor. Presentation commonly includes flushing, diarrhea, and asthma-like symptoms. Carcinoid syndrome is usually caused by the secretion of serotonin. The diagnosis is established by urinary 5-hydroxyindoleacetic (5-HIAA) levels.
  • Insulinoma: an insulin-secreting tumor. Presentation commonly includes symptoms of hypoglycemia such as weakness, confusion, and palpitations. The diagnosis is suspected based on low blood glucose levels associated with symptoms.
  • Paroxysmal supraventricular tachycardia: episodic condition with abrupt onset of tachyarrhythmia. Paroxysmal supraventricular tachycardia is caused by cardiac conduction abnormalities. Presentation can include palpitations and associated anxiety. The diagnosis is established by electrophysiological studies. 
  • Munchausen’s syndrome: psychiatric disorder in which patients deliberately falsify symptoms of illness. Symptoms can be induced by medication ingestion. The diagnosis may be challenging and requires detailed medical and psychosocial history.

References

  1. Blake M. (2020).Pheochromocytoma. Retrieved January 20, 2021, from https://emedicine.medscape.com/article/124059-overview
  2. Young W.F. (2020). Clinical presentation and diagnosis of pheochromocytoma. Retrieved January 20, 2021, from https://www.uptodate.com/contents/clinical-presentation-and-diagnosis-of-pheochromocytoma
  3. Young W.F., Elfiky A. (2019). Paraganglioma and pheochromocytoma: Management of malignant disease. Retrieved January 20, 2021, from https://www.uptodate.com/contents/paraganglioma-and-pheochromocytoma-management-of-malignant-disease
  4. Young W.F., Kebebew E. (2019). Treatment of pheochromocytoma in adults. Retrieved January 20, 2021, from https://www.uptodate.com/contents/treatment-of-pheochromocytoma-in-adults

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