Dr. M. SOFI MD; FRCP (London); FRCPEdin; FRCSEdin PHEOCHROMOCYTOMA Dr. M. SOFI MD; FRCP (London); FRCPEdin; FRCSEdin

PHEOCHROMOCYTOMA Catecholamine-secreting tumors that arise from chromaffin cells of the adrenal medulla are referred to as “pheochromocytomas” and from sympathetic ganglias “catecholamine-secreting paragangliomas” (“extra-adrenal pheochromocytomas”), respectively. Because the tumors have similar clinical presentations and are treated with similar approaches, many clinicians use the term “pheochromocytoma” to refer to both adrenal pheochromocytomas and catecholamine-secreting paragangliomas. However, the distinction between pheochromocytoma and paraganglioma is an important one because of implications for associated neoplasms, risk for malignancy, and genetic testing.

A pheochromocytoma is a rare, catecholamine-secreting tumor that may precipitate life-threatening hypertension. The tumor is malignant in 10% of cases but may be cured completely by surgical removal. Pheochromocytoma has classically been associated with 3 syndromes— Von Hippel-Lindau (VHL) syndrome Multiple endocrine neoplasia type 2 (MEN 2) Neurofibromatosis type 1 (NF1) (There are 10 genes that have been identified as sites of mutations leading to pheochromocytoma).

Signs and symptoms Pheochromocytoma manifests as spells with the following 4 characteristics: Headaches Palpitations Diaphoresis Severe hypertension Typical patterns of the spells are as follows: Frequency may vary from monthly to several times per day Duration may vary from seconds to hours Over time, spells tend to occur more frequently and become more severe as the tumor grows

The following may also occur during spells: Tremor Nausea Weakness Signs and symptoms The following may also occur during spells: Tremor Nausea Weakness Anxiety, sense of doom Epigastric pain Flank pain Constipation

Clinical signs associated with pheochromocytomas include the following: Hypertension: Paroxysmal in 50% Postural hypotension: From volume contraction Hypertensive retinopathy Weight loss Pallor Fever Tremor Neurofibromas Tachyarrhythmias Pulmonary edema Cardiomyopathy Ileus Café au lait spots

Indications for testing — suspected in patients who have one or more of the following The classic triad of headache, sweating, and tachycardia, whether or not they have hypertension. Hyperadrenergic spells (e.g., self-limited episodes of non-exertional palpitations, diaphoresis, headache, tremor, or pallor). However, most patients with spells do not have pheochromocytoma! Onset of hypertension at a young age (e.g., <20 years), resistant hypertension, or hypertension with new onset or atypical diabetes mellitus.

Indications for testing — suspected in patients who have one or more of the following A familial syndrome that predisposes to catecholamine-secreting tumors (e.g., multiple endocrine neoplasia type 2 [MEN2], neurofibromatosis type 1 [NF1], or von Hippel-Lindau [VHL]). A family history of pheochromocytoma. Adrenal incidentaloma with or without hypertension. Pressor response during anesthesia, surgery, or angiography. Idiopathic dilated cardiomyopathy. A history of gastric stromal tumor, pulmonary chondromas and extra- adrenal paraganglioma (Carney triad).

Low risk pheochromocytoma Resistant hypertension Hyperadrenergic spells (e.g., self-limited episodes of non-exertional palpitations, diaphoresis, headache, tremor, or pallor) An incidentally discovered adrenal mass that does not have imaging features consistent with pheochromocytoma 24-hour urine fractionated metanephrines and catecholamines High risk index of suspicion for a catecholamine-secreting tumor includes following scenarios: A family history of pheochromocytoma A genetic syndrome that predisposes to pheochromocytoma (MEN2) A past history of resected pheochromocytoma An incidentally discovered adrenal mass Measuring plasma fractionated metanephrines is a first-line test

Diagnostic tests for pheochromocytoma include the following: Diagnosis Diagnostic tests for pheochromocytoma include the following: Plasma metanephrine testing: 96% sensitivity, 85% specificity 24-hour urinary collection for catecholamines and metanephrines: 87.5% sensitivity, 99.7% specificity Test selection criteria include the following: Use plasma metanephrine testing in patients at high risk (i.e., those with predisposing genetic syndromes or a family or personal history of pheochromocytoma) Use 24-hour urinary collection for catecholamines and metanephrines in patients at lower risk

Diagnosis Imaging studies should be performed only after biochemical studies have confirmed the diagnosis of pheochromocytoma. Studies are as follows: Abdominal CT scanning: Has accuracy of 85-95% for detecting adrenal masses with a spatial resolution of 1 cm or greater MRI: Preferred over CT scanning in children and pregnant or lactating women; has reported sensitivity of up to 100% in detecting adrenal pheochromocytomas Scintigraphy: Reserved for biochemically confirmed cases in which CT scanning or MRI does not show a tumor PET scanning: A promising technique for detection and localization of pheochromocytomas

Imaging features of pheochromcytoma Contrast enhanced CT pheochromocytoma MRI pheochromocytoma

Diagnosis Additional studies to rule out a familial syndrome in patients with confirmed pheochromocytoma include the following: Parathyroid hormone level and a simultaneous serum calcium level to rule out primary hyperparathyroidism (which occurs in MEN 2A) Screening for mutations in the ret proto-oncogene (which give rise to MEN 2A and 2B) Genetic testing for mutations causing the MEN 2A and 2B syndromes Consultation with an ophthalmologist to rule out retinal angiomas (VHL disease)

Diagnostic Considerations Differentials to consider in the diagnosis include: Alcohol withdrawal Labile essential hypertension Hyperventilation Orthostatic hypotension Multiple pharmacologic agents:(MAOIs), decongestants, and sympathomimetics Illegal drug use: E.g., phencyclidine (PCP), lysergic acid diethylamide (LSD), and cocaine

Diagnostic Considerations Acute intermittent porphyria Cardiogenic pulmonary edema Renovascular hypertension Subarachnoid hemorrhage Lead toxicity Migraine headache Autonomic neuropathy (baroreflex failure) Stroke Toxemia of pregnancy (POEMS) syndrome

Factitious Disorder Imposed on Self Hyperthyroidism Hypoglycemia Differential Diagnoses Angina Pectoris Anxiety Disorders Factitious Disorder Imposed on Self Hyperthyroidism Hypoglycemia Insulinoma Intestinal Carcinoid Tumor Menopause Paroxysmal Supraventricular Tachycardia Systemic Mastocytosis

Management Surgical resection of the tumor is the treatment of choice and usually cures the hypertension. Careful preoperative treatment with alpha and beta blockers is required to control blood pressure and prevent intraoperative hypertensive crises. Preoperative medical stabilization includes: Alpha blockade with phenoxybenzamine 7-10 days pre-op Volume expansion with isotonic sodium chloride solution Encourage liberal salt intake Beta blocker only after adequate alpha blockade, to avoid precipitating a hypertensive crisis from unopposed alpha stimulation Administer the last doses of oral alpha and beta blockers on the morning of surgery

SUBSEQUENT MANAGEMENT — After thyroidectomy, it is important to evaluate patients to determine if surgery was curative. Measurement of serum calcitonin and carcinoembryonic antigen (CEA) are used to assess for cure. Subsequent management depends upon these values. Serum calcitonin and CEA measurement —  Serum calcitonin and CEA should be measured two to three months after surgery to detect the presence of residual disease. Patients who have normal serum CEA and undetectable serum calcitonin values are considered biochemically cured and have the best prognosis. PROGNOSIS — Age and stage of disease at the time of diagnosis has been shown to be an important factor that influences prognosis: 5 and 10-year disease-free survival rates are higher among patients 40 years old or less (95 versus 65 %). Patients over age 40 years and (75 versus 50 %). 10-year survival rates for patients with stages I, II, III, and IV (MTC) are 100, 93, 71, and 21 % respectively.

CEA: carcinoembryonic antigen; CT: computed tomography; Ctn: calcitonin; EBRT: external beam radiotherapy; MRI: magnetic resonance imaging; MTC: medullary thyroid cancer; TFT: thyroid function test; TKI: tyrosine kinase inhibitor; TSH: thyroid-stimulating hormone; TTX: total thyroidectomy; US: ultrasound. * Additional imaging includes CT or MRI of neck, chest, and abdomen; bone scan or bone MRI in patients suspected of having skeletal metastases.

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