PHEOCHROMOCYTOMA

The 5 Minute Urology Consult 3rd Ed.

Shaun G.S. Grewal, MD

Gerald L. Andriole, MD, FACS

BASICS

DESCRIPTION

• Pheochromocytoma is a rare catecholamine-producing tumor arising chromaffin cells in the adrenal medulla

• Paragangliomas refer to lesions found in extra-adrenal sites arising from the sympathetic nervous system

ALERT

Hypertensive crisis and life-threatening complications can be seen with pheochromocytoma.

EPIDEMIOLOGY

Incidence

• 3–4 cases per million population yearly in US (1)

– Average age in sporadic cases: 40–50 yr

– Average age in hereditary cases: <40 yr

Prevalence

• 0.005–0.1% of the general population

– 01–0.2% of adult hypertensive patients

• >50% of catecholamine-producing tumors undiagnosed until death

RISK FACTORS

• Familial tumors associated with MEN multiple endocrine neoplasia (MEN) syndromes:

– MEN IIA (Sipple syndrome): Pheochromocytoma (50%), medullary carcinoma of the thyroid (50%), and parathyroid adenoma (25%):

– MEN IIB (MEN III): Pheochromocytoma (50%), medullary carcinoma of the thyroid (100%), ganglioneuromatosis, multiple mucosal neuromas of eyelids, lips, tongue

• Neurofibromatosis Type I (von Recklinghausen syndrome): 1% has pheochromocytoma; 5% of patients with pheochromocytoma have neurofibromatosis.

• Von Hippel–Lindau disease (retinal cerebellar hemangioblastomatosis): 10% with pheochromocytoma

Genetics

• Germ-line mutations specific to each syndrome

• Syndromes are all autosomal dominant

– Men IIA: Codon 634 of RET protein

– Men IIB: Mutation in intracellular domain of RET protein

– Von Hippel–Lindau: VHL tumor suppressor gene on chromosome 3p35

– Von Recklinghausen syndrome: Neurofibromatosis type 1 gene

– Familial nonsyndromic paraganglioma: Succinate dehydrogenase gene (1)

PATHOPHYSIOLOGY

• Tumors arise from chromaffin cells of neural crest origin in the sympathetic nervous system

• Rule of 10 (10% bilateral, 10% extra-adrenal, 10% familial, 10% malignant) no longer accurate:

– 10% of sporadic tumors bilateral, 50% of familial tumors bilateral

– Extra-adrenal up to 20%

– Hereditary 20–30%

– Malignant up to 5% in adrenal pheochromocytoma, 33% for extra-adrenal pheo

• Histologic determination of malignancy is not possible; diagnosed based on metastases

• Tumors contain enzymes necessary to convert tyrosine to catecholamines

• Clinical manifestations secondary to the release of these catecholamines, NE, and EPI

• Bladder pheochromocytomas account for <1% of bladder tumors and <1% of pheochromocytomas:

– Can present with micturition syncope

– Partial cystectomy is the treatment of choice. Transurethral excision is contraindicated because it may precipitate a hypertensive crisis

ASSOCIATED CONDITIONS

• MEN IIA

• MEN IIB

• Von Recklinghausen syndrome

• Von Hippel–Lindau disease

GENERAL PREVENTION

• No specific preventive measures exist.

• Screening of patients with familial pheochromocytomas allows earlier diagnosis and treatment.

DIAGNOSIS

HISTORY

• Most patients symptomatic

– Paroxysmal HTN with severe headache, drenching, perspiration, and palpitations

– Additional symptoms include nervousness, tremor, pallor, panic, pain in the chest and abdomen, nausea, fever, and flushing

PHYSICAL EXAM

• Hypertension: Most common sign

– Sustained HTN: Children and MEN II

– Paroxysmal HTNL dramatic attacks, 3–4 times a week

– Sustained hypertension with superimposed paroxysms: 50% incidence

• Fine tremors, pallor, perspiration

• Palpable tumor (rare)

• Accelerated hypertensive retinopathy: Papilledema, exudate, A-V knicking

• Raynaud phenomenon

• Hyperhidrosis

DIAGNOSTIC TESTS & INTERPRETATION

Lab

• Plasma or urinary-fractionated metanephrines are the best screening tests:

– Chromaffin cells metabolize NE to NMN and EPI to MN

– Fractionated metanephrines refers to MN and NMN

– Both plasma metanephrines and urine metanephrines are acceptable options; current recommendations do not recommend either test over the other

– Plasma metanephrines have a high sensitivity (96–100%) but poor specificity, particularly in older patients (77–89%) (2)

• Urine test: 24-hr urine for NE, EPI, MN, NMN, and VMA:

– VMA highly specific (95%) but not sensitive (64%)

– If urinary values are >3 times normal, then proceed to localize the tumor

– If urinary values are <3 times normal and suspicious, then repeat the test and proceed to pharmacologic testing

• Plasma metanephrine testing

– No caffeine prior

– No acetaminophen for 5 days prior

– Rest supine for 20 min prior to draw

– MN >96 pg/mL, NMN >130 pg/mL, or total metanephrines >200 abnormal (2)

• Pharmacologic testing:

– Stimulation and suppression tests are generally not utilized

– Provocative tests dangerous, with several reported deaths

• Clonidine suppression test:

– Centrally acting α₂-agonist that suppresses sympathetic outflow

– Normally results in decreased BP and lower levels of plasma catecholamines

– Draw blood for NE/EPI before and 3 hr after administering clonidine (0.3 mg/70 kg)

– Plasma catecholamines remain the same or elevated in patients with pheochromocytoma

Imaging

• Localization studies should be started only if clinical evidence for the tumor’s existence is strong (hereditary predisposition or signs and symptoms with very high MN/NMN)

• CT or MRI for initial localization:

– Neither CT nor MRI is recommended above the other

– Pheochromocytoma characteristically hyperintense of T2-weighted images

– Scan abdomen and pelvis 1st

– If no tumor found, scan chest and neck

– Metastases in long bones may be missed

– Cannot reliably differentiate between types of adrenal tumors

• Iodine¹²³-labeled MIBG scintigraphy is more specific for localization of pheo:

– Provides both anatomic and functional characterization of the tumor

– Concentrated in sympathomedullary tissue through the catecholamine pump

– Useful to evaluate for residual or multiple tumors, and MEN syndromes

Diagnostic Procedures/Surgery

ALERT

Biopsy of adrenal mass should not be performed until pheochromocytoma has been ruled out.

Pathologic Findings

• Sporadic tumors are solitary, well-circumscribed, and encapsulated.

• Malignant pheo cannot be differentiated from benign pheo by exam of primary tumor. Malignant pheo is defined by metastases.

DIFFERENTIAL DIAGNOSIS

• Essential HTN

• Renovascular disease

• Anxiety, tension states, psychoneurosis

• Hyperthyroidism

• Paroxysmal tachycardia

• Menopause

• Vasodilating headaches (migraine and cluster)

• Acute hypertensive encephalopathy

• Nephrologic diseases

• Cocaine, amphetamines

TREATMENT

GENERAL MEASURES

Surgical removal of the tumor is the only definitive method of treatment.

MEDICATION

First Line

• Appropriate antihypertensive drugs to manage HTN, control symptoms, and prepare for surgery

• α-Adrenergic blocking agents essential before surgery:

– Phenoxybenzamine 0–40 mg BID or TID

– Prazosin 1–10 mg BID

• β-Blocking agents contraindicated in the absence of established α-blockade:

– Use only for concomitant cardiac arrhythmias or persistent tachycardia

– Blockade of peripheral vasodilatory β-adrenergic receptors results in unopposed α-adrenergic stimulation with resultant hypertension

– Can precipitate cardiomyopathy and pulmonary edema due to chronic catecholamine excess

Second Line

See “Additional Therapies”

SURGERY/OTHER PROCEDURES

• Preoperative adrenergic blockade is mandatory

• Volume expansion with high sodium diet (>5,000 mg/daily) recommended on day 2 or 3 of α-blockade due to catecholamine-induced volume contraction

• Laparoscopic surgical removal of the tumor is the preferred treatment for tumors <10 cm (3):

– Initial dissection aimed at early ligation and division of the adrenal vein before manipulation of the tumor

– Malignant pheochromocytoma is slow growing

Resection should be attempted

Large masses can be debulked for palliation

ADDITIONAL TREATMENT

Radiation Therapy

An option for malignant pheochromocytoma

Additional Therapies

• Malignant pheochromocytoma

– Iodine¹³¹-MIBG radiation is the most effective treatment after surgery

– Combination chemotherapy with cyclophosphamide, vincristine, and dacarbazine: 50–60% partial response

– Local radiation or chronic blockade with metyrosine for symptomatic disease

Complementary & Alternative Therapies

No recommended complementary or alternative therapies exist.

ONGOING CARE

PROGNOSIS

• 10-yr survival for nonmalignant tumors: >80%

• 5-yr survival for malignant pheo: 34–60%:

– Currently no cure for malignant pheo

COMPLICATIONS

• Retinopathy and nephropathy from persistent HTN

• Catecholamine-nduced cardiomyopathy

– Cardiomyopathy reversible with α-blockade and β-methylparatyrosine

– All patients should have preop cardiac evaluation including echocardiogram

• Cerebral vascular accident

• Hypertensive encephalopathy

• Renal insufficiency

• Hemorrhagic necrosis

• Dissecting aneurysm

• Ischemic enterocolitis

• Neurogenic pulmonary edema

FOLLOW-UP

Patient Monitoring

• Because of uncertainties about which tumors are malignant, measure urinary or plasma catecholamines 1–2 wk postoperatively and annually for 5 yr.

• BP should be monitored every month for the 1st 6 mo, then every 6 mo thereafter.

• 25% of patients have persistent HTN after surgery.

Patient Resources

www.pheochromocytoma.org

REFERENCES

1. Mittendorf E, Evans DB, Lee JE, et al. Pheochromocytoma: Advances in genetics, diagnosis, localization, and treatment. Hematol Oncol Clin North Am. 2007;21(3):509–525.

2. Lender JW, Pacak K, Walther MM, et al. Biochemical diagnosis of pheochromocytoma: Which test is best? JAMA. 2002;287:1427–1434.

3. Vargas HI, Kavoussi LR, Bartlett DL, et al. Laparoscopic adrenalectomy: A new standard of care. Urology. 1997;49:673–678.

ADDITIONAL READING

• Karagiannis A, Mikhailidis DP, Athyros VG, et al. Pheochromocytoma: An update on genetics and management. Endocrine-Related Cancer. 2007;14:935–956.

• Lenders JW, Eisenhofer G, Mannelli M, et al. Phaeochromocytoma. Lancet. 2005;366:665–675.

• Pacak K, Eisenhofer G, Ahlman H, et al. Pheochromocytoma: Recommendations for clinical practice from the 1st International Symposium. Nat Clin Pract. 2007;3:92–102.

See Also (Topic, Algorithm, Media)

• Adrenal Mass

• Adrenal Mass, Algorithm