Pheochromocytoma

A pheochromocytoma is a catecholamine-secreting tumor that develops in the adrenal medulla. Pheochromocytomas are malignant in approximately 10% of cases. Excess sympathetic nervous system stimulation in individuals with pheochromocytoma leads to episodic blood pressure crises with paroxysmal headaches, diaphoresis, heart palpitations, and pallor. Pheochromocytomas may also be asymptomatic or manifest with persistent hypertension. Elevated catecholamine metabolites in the plasma or urine confirm the diagnosis, and imaging studies are used to determine the location of the tumor. Surgical resection is the treatment of choice. Preoperative alpha-adrenergic blockade (e.g., phenoxybenzamine) is indicated to prevent intraoperative complications such as hypertensive crises.

• Paraganglioma: a neuroendocrine neoplasm that originates from neural crest cells in the autonomic ganglia or adrenal medulla ^[1][2]
• Pheochromocytoma: an intra-adrenal paraganglioma that arises from chromaffin cells in the adrenal medulla and typically secretes catecholamines ^[1][2][3]

Sympathetic paragangliomas (including pheochromocytomas) typically produce catecholamines, while parasympathetic paragangliomas (rare) are usually nonfunctional. ^[4]

• Incidence ^[5]
  • Most common tumor of the adrenal medulla in adults
  • Present in up to 1% of all hypertensive patients
• Age: 3^rd–5^th decades of life ^[5]

Epidemiological data refers to the US, unless otherwise specified.

• The majority of pheochromocytomas are benign, unilateral, catecholamine-producing tumors, that rarely produce other hormones such as EPO.
• Tumors arise from chromaffin cells, which are derived from the neural crest.
• Localization ^[6]
  • ∼ 90% adrenal medulla (physiologically activated by acetylcholine)
  • ∼ 10% extra-adrenal in the sympathetic ganglia
  • ∼ 10% at multiple locations
• 25% of pheochromocytomas are hereditary (germline mutations):
  • Multiple endocrine neoplasia type 2 (MEN 2A, MEN 2B)
  • Neurofibromatosis type 1 (NF1)
  • Von Hippel-Lindau disease (VHL)

MAry P. sang “superCALi-fragilistic-EXpiali-DOcious” to the children 10 times: 10% of pheochromocytomas are MAlignant; 10% show CALcifications; 10% are EXtra-adrenal; 10% are DUal sided, i.e., bilateral; and 10% affect children. ^[7][8]

Clinical presentation is related to fluctuating levels of excess epinephrine, norepinephrine, and dopamine secretion, so symptoms are characterized by patterns of relapse and remitting (episodic hyperadrenergic syndrome).

• Episodic hypertension (or persistent hypertension in some cases) ; ^[9]
  • Triggers for paroxysmal elevations in blood pressure: foods and beverages high in tyramine; (e.g., red wine, aged cheese), surgery, pressure on the tumor (e.g., during massage), or certain drugs (e.g., beta blockers, MAOIs)
• Paroxysmal ^[6]
  • Throbbing headache
  • Diaphoresis
  • Heart palpitations, tachycardia
  • Pallor
  • Abdominal pain and nausea
  • Anxiety
• Weight loss due to increased basal metabolism
• Hyperglycemia
• Signs of polycythemia, if EPO is secreted
• Additional features of hereditary disorders associated with pheochromocytoma
  • Medullary thyroid cancer and parathyroid hyperplasia (MEN 2A)
  • Medullary thyroid cancer, oral/intestinal neuromas, and marfanoid habitus (MEN 2B)
  • Cutaneous neurofibromas, cafe-au-lait spots, and Lisch nodules (NF1)
  • Renal cell carcinoma, hemangioblastoma, angiomatosis (VHL)

Patients can show typical clinical features (e.g., secondary hypertension) but may also be asymptomatic.

5 most important Problems (5 P’s) of Pheochromocytoma: increased blood Pressure, head Pain (headache), Perspiration, Palpitations, and Pallor

Hypertensive crises can be triggered by palpation of the tumor on abdominal exam.

Approach ^[1][10][11]

• Consult a specialist early.
• Obtain biochemical testing to prove catecholamine excess.
• Obtain imaging to locate the tumor.
• Consider indications for genetic testing on an individual basis.

Biochemical testing ^[1][2][10]

Screening for catecholamine excess ^[1]

• Indications
  • Characteristic features of pheochromocytoma
  • Adrenal incidentaloma
  • Known or suspected hereditary disorders associated with pheochromocytoma
• Preferred modalities (highly sensitive): plasma free metanephrines (taken in supine position ), OR urinary fractionated metanephrines (24-hour urine collection)
  • Significantly elevated metanephrines: Diagnosis is likely.
  • Normal metanephrines: Diagnosis is unlikely.
  • Moderately elevated metanephrines (inconclusive results)
    • Repeat the initial test after removal of interfering factors. ^[2][12]
    • If results remain inconclusive after repeat testing: Obtain a clonidine suppression test.
• Other modalities (lower diagnostic accuracy): no longer routinely recommended
  • Fractionated catecholamines (plasma or 24-hour urine collection) ^[2]
  • Homovanillic acid and vanillylmandelic acid

Inconclusive test results should prompt further testing. False positives are common because of low pretest probability, suboptimal specificity, and the possibility of interfering factors.

Clonidine suppression test ^[1]

• Indication (not routinely recommended): inconclusive results from catecholamine excess testing
• Method: normetanephrine is measured in plasma at baseline and 3 hours after oral administration of clonidine.
• Interpretation
  • Inadequate normetanephrine suppression : Diagnosis is likely.
  • Adequate normetanephrine suppression : Diagnosis is unlikely.

Imaging ^[1][2][10]

Obtain imaging studies only after catecholamine excess has been confirmed.

• CT abdomen and pelvis with contrast: preferred initial modality
• MRI: preferred in patients with known metastatic disease
• Functional imaging studies: Consider in select patients under specialist consultation.
  • PET-CT
  • Scintigraphy (MIBG)

Additional diagnostics

• Genetic testing: Practice shared decision-making under specialist guidance. ^[1][2]
  • Includes testing for MEN 2A, MEN 2B, von Hippel Lindau, NF1, and familial paraganglioma syndrome
  • Indications include
    • Extra-adrenal paraganglioma
    • Features consistent with hereditary disorders associated with pheochromocytoma
    • First-degree relatives of individuals who carry mutations
• Histopathology ^[11][13]
  • Biopsies are not indicated for diagnostic purposes.
  • Histopathological studies may be performed postoperatively.
  • Immunohistochemical staining is typically positive for chromogranin, synaptophysin, and NSE.

Pheochromocytoma is often referred to as “the great mimic” because signs and symptoms are similar to those seen in many other clinical conditions. ^[14]

Endocrine

Adrenocortical carcinoma ^[15][16]

• Definition: a rare cancer of the adrenal gland that originates in the adrenal cortex
• Epidemiology ^[15]
  • Rare disease; estimated annual incidence 1–2:1,000,000
  • Median age at diagnosis: 50–60 years
• Etiology
  • Mostly sporadic
  • Some cases are associated with hereditary cancer syndromes (e.g., Li-Fraumeni syndrome, Beckwith-Wiedemann syndrome, MEN 1).
• Clinical features
  • Signs of excessive hormone production
    • Hypercortisolism (e.g., muscle weakness, plethora, osteoporosis, impaired glucose tolerance)
    • Hyperandrogenism (e.g., increased growth of facial hair, deepening of the voice, and male pattern baldness)
    • In rare cases: autonomous aldosterone secretion (e.g., hypertension)
  • Nonspecific symptoms caused by tumor growth (e.g., flank pain)
• Diagnostics
  • Physical examination and patient history
  • 24-hour urine test: ↑ free cortisol
  • Blood tests
    • Dexamethasone suppression test
    • Dehydroepiandrosterone sulfate
    • Aldosterone, renin
    • Metanephrine, normetanephrine
  • Imaging
    • MRI or CT usually shows a large (> 6 cm in diameter) tumor that may contain necrosis, calcifications, and/or hemorrhage and may have heterogeneous enhancement.
    • Adrenocortical carcinomas are frequently detected as adrenal incidentalomas ^[17]
• Treatment
  • Curative: adrenalectomy and, if, necessary, removal of lymph nodes
  • Palliative: can include chemotherapy, radiation therapy, surgery, and/or a clinical trial of targeted therapy or immunotherapy
• Prognosis: depends on the stage but is generally poor (overall 5-year survival is ∼ 50%) ^[18]

Other

• Hyperthyroidism
• Carcinoid syndrome
• Hypoglycemia
• Medullary thyroid carcinoma
• Menopause
• Mastocytosis

Cardiovascular

• Heart failure
• Arrhythmias
• Ischemic heart disease
• Baroreflex failure

Neurological

• Migraine
• Stroke
• Diencephalic epilepsy
• Meningioma
• Postural orthostatic tachycardia syndrome

Miscellaneous

• Porphyria
• Panic disorder
• Anxiety disorders
• Drug-induced
  • Monoamine oxidase inhibitors
  • Sympathomimetic drugs
  • Clonidine withdrawal
• Recreational drugs (e.g., cocaine)
• Factitious disorder

The differential diagnoses listed here are not exhaustive.

General principles ^[1][2][10]

Multidisciplinary care at a specialized center is recommended.

• Surgical tumor resection is the only curative treatment.
• Preoperative blood pressure management and postoperative monitoring for adrenal crisis are essential.
• Management of advanced nonoperable disease (e.g., metastatic disease) is palliative and may include: ^[11]
  • Cytoreductive therapies (e.g., cytoreductive surgery, radiotherapy, chemotherapy)
  • Symptomatic therapy (e.g., alpha blockers)
• Patients with germline mutations should be included in surveillance programs led by endocrinologists.

Treat hypertensive crisis due to pheochromocytoma with IV antihypertensives that target catecholamine excess (e.g., phentolamine, clevidipine, or nicardipine) and avoid beta blockers. ^[19][20][21]

Surgical resection ^[1][2][10]

• Adrenalectomy: treatment of choice for pheochromocytoma
  • Subtotal (organ sparing) adrenalectomy: removal of the part of the gland containing the tumor
  • Total (radical) adrenalectomy: removal of the entire adrenal gland
  • Techniques
    • Laparoscopic resection: preferred for most tumors
    • Open resection: preferred for large; (> 6 cm) or invasive tumors
• Removal of extra-adrenal paragangliomas: Open resection is preferred. ^[1]

A no-touch technique should be used because contact with the tumor can lead to massive catecholamine release.

Preoperative management ^[1][2][11]

Preoperative management of blood pressure and heart rate is required.

• Treatment target
  • BP < 130/80 mmHg, > 90 mmHg systolic
  • Heart rate 60–80/min while seated
• Pharmacotherapy: Initiate 7–14 days prior to surgery. ^[1]
  • Indicated for all patients with hormonally active pheochromocytoma
  • Start with alpha-adrenergic blockade.
    • Nonselective irreversible: phenoxybenzamine ^[1][2]
    • OR selective alpha-1 blocker: doxazosin (off label) ^[1]
  • Add a beta blocker after effective alpha blockade to control tachycardia, e.g.: ^[2]
    • Metoprolol (off label)
    • OR propranolol
  • Consider the following for additional blood pressure control:
    • Calcium channel blockers, e.g., amlodipine ^[1]
    • Metyrosine ^[1]
• Nonpharmacological therapy: Ensure high sodium and fluid intake to prevent postoperative hypotension. ^[2]

Treat PHEochromocytoma with PHEnoxybenzamine, but remember that Alpha blockers should be given Ahead and Beta blockers Behind.

Starting beta blockers before alpha blockers is contraindicated because doing so can cause life-threatening hypertensive crisis. Beta-blockers cancel out the vasodilatory effect of peripheral beta-2 adrenoceptors, potentially leading to unopposed alpha-adrenoceptor stimulation and thereby causing vasoconstriction and increased blood pressure.

Postoperative management ^[1][2][10]

• Postoperative monitoring
  • Measure blood pressure, heart rate, and blood glucose levels for 24–48 hours.
  • Start management for acute adrenal insufficiency as needed (e.g., glucocorticoids, IV fluids).
• Long-term monitoring
  • May include repeat biochemical testing and imaging studies; see “Diagnostics.”
  • The frequency of monitoring is based on individual risk for persistent, recurrent, and/or metastatic disease. ^[11]

The risk of postoperative acute adrenal insufficiency and subsequent hypoglycemia is especially high in individuals with bilateral adrenalectomy.