Summary
A pheochromocytoma is a catecholamine-secreting tumor that typically develops in the adrenal medulla. Pheochromocytomas are usually benign (∼ 90% of cases) but may also be malignant. Classic clinical features are due to excess sympathetic nervous system stimulation and involve episodic blood pressure crises with paroxysmal headaches, diaphoresis, heart palpitations, and pallor. However, pheochromocytomas may also be asymptomatic or manifest with persistent hypertension. Elevated catecholamine metabolites in the plasma or urine confirm the diagnosis, while imaging studies in patients with positive biochemistry are used to determine the location of the tumor. Surgical resection is the treatment of choice but is only carried out once alpha-adrenergic blockade with phenoxybenzamine has become effective.
Epidemiology
-
Incidence [1]
- Most common tumor of the adrenal medulla in adults
- Present in up to 1% of all hypertensive patients
- Age: 3rd–5th decades of life [1]
Epidemiological data refers to the US, unless otherwise specified.
Etiology
- 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 [2]
- ∼ 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):
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.
Clinical features
Clinical presentation is related to fluctuating levels of excess epinephrine, norepinephrine, and dopamine secretion, therefore, symptoms are relapsing and remitting (episodic hyperadrenergic syndrome).
-
Episodic hypertension (or persistent hypertension in some cases) ; [3]
- 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 [2]
- 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
- Other features consistent with associated familial disorders:
- MEN 2A: medullary thyroid cancer, pheochromocytoma, and parathyroid hyperplasia
- MEN 2B: medullary thyroid cancer, pheochromocytoma, oral/intestinal neuromas, and marfanoid habitus
- NF1: cutaneous neurofibromas, cafe-au-lait spots, and Lisch nodules
- VHL: renal cell carcinoma, hemangioblastoma, angiomatosis, and pheochromocytoma
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.
Diagnostics
Laboratory tests [1]
Whenever possible, all medications should be put on hold one week prior to testing.
-
Best initial test: plasma free metanephrines test ; [4]
- Examples: homovanillic acid, vanillylmandelic acid
- High sensitivity
- Confirmatory test: : metanephrines and catecholamines in 24-hour urine (high specificity) [5]
-
Clonidine suppression test (rarely used)
- Principle of the test: In healthy patients, clonidine normally significantly decreases plasma catecholamine levels by at least 30%.
- Evaluation of results: If pheochromocytoma is present, catecholamine levels will fail to decrease upon clonidine administration, as the tumor will continue to produce catecholamines.
- Genetic testing: if MEN2A, MEN2B, NF1, or VHL is suspected
- Immunohistochemical staining: positive for chromogranin, synaptophysin, and NSE
Other diagnostic tests [1][2]
- 24-hour ambulatory blood pressure monitoring
- Adrenal/abdominal CT or MRI (after positive biochemistry tests to localize tumor)
- Scintigraphy (MIBG)
- Other imagistic tests: to search for potential additional tumors in patients with pheochromocytoma and MEN2A, MEN2B, NF1, or VHL
Differential diagnoses
Pheochromocytoma is often referred to as “the great mimic” because signs and symptoms are similar to those seen in many other clinical conditions. [6]
Endocrine
Adrenocortical carcinoma [7][8]
- Definition: a rare cancer of the adrenal gland that originates in the adrenal cortex
-
Epidemiology [7]
- 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)
- Signs of excessive hormone production
-
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 (a clinically inapparent adrenal mass > 1 cm in diameter that is detected on imaging performed for other reasons than a suspected adrenal condition). [9]
-
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%) [10]
Other
Cardiovascular
Neurological
Miscellaneous
- Porphyria
- Panic disorder
- Anxiety disorders
- Drug-induced
- Recreational drugs (e.g., cocaine)
- Factitious disorder
The differential diagnoses listed here are not exhaustive.
Treatment
Operable disease
Management consists of preoperative blood pressure management and then surgery.
-
Preoperative blood pressure management: combined alpha-adrenergic and beta-adrenergic blockade
- First, a non-selective irreversible alpha-blocker; is given : Phenoxybenzamine blocks alpha-1 and alpha-2 adrenoceptors equally and irreversibly [11]
- After sufficient alpha-adrenergic blockade, a beta-blocker may be started for additional blood pressure control and control of tachyarrhythmias.
-
Laparoscopic tumor resection (adrenalectomy): treatment of choice
- No-touch technique
- Open surgical resection is reserved for large or invasive tumors.
-
Prognosis and follow-up [1]
- Most patients with benign pheochromocytoma become normotensive after tumor resection. [12]
- Long-term annual biochemical monitoring for recurrence is indicated in all patients.
- Benign pheochromocytoma recurs in ∼ 15% of patients, usually 5–15 years after surgery.
Inoperable disease
- Benign pheochromocytoma: primary therapy with phenoxybenzamine
-
Malignant pheochromocytoma
- Metaiodobenzylguanidine (MIBG) therapy: Because MIBG is similar in structure to norepinephrine, it is taken up by sympathetic nerve cells, including neuroblastoma or pheochromocytoma tumor cells, throughout the body. When MIBG is combined with radioactive iodine, it can be used as a treatment that delivers radiation directly to cancer cells.
- Otherwise, palliative treatment (chemotherapy, tumor embolization)
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. Beta-blockers cancel out the vasodilatory effect of peripheral beta-2 adrenoceptors, potentially leading to unopposed alpha-adrenoceptor stimulation, causing vasoconstriction and ultimately hypertensive crisis.