Sipple syndrome

Pheochromocytoma Pheochromocytomas are tumors that produce, store and release catecholamines.(1) They arise from chromaffin cells, which are embryologically derived from primitive neuroectoderm. These tumors may appear within the adrenal gland, the sympathetic ganglia and the paired organs of Zuckerkandl (at the aortic bifurcation) and in ectopic rests of neural crest cells in the bladder, gonads or gastrointestinal tract.(2)

Pheochromocytomas are rare tumors, occurring in approximately 0.1 percent of the hypertensive population. They are usually benign. The "rule of tens" roughly applies: 10 percent of the tumors are extra-adrenal, 10 percent are bilateral and 10 percent are malignant. The histologic features of benign and malignant lesions are quite similar; malignancy is therefore determined by local spread into adjacent organs or by distant metastasis to lymph nodes, liver, lung and bone.(3)

Clinical Features

Pheochromocytomas occur in all age groups but are most common in young adults. There is no sex predilection. The mean age at presentation is 37 years for sporadic tumors and 26 years for tumors associated with a familial syndrome. The most common complaints can be summarized by the "five Ps": elevated pressure, pain, palpitations, perspiration and pallor.

The hallmark of pheochromocytoma is hypertension. Fifteen percent of patients have sustained elevations in blood pressure, while 45 percent of patients have hypertension only during pheochromocytoma "crises" or "paroxysms" (paroxysmal hypertension). The remaining 40 percent of patients demonstrate both sustained and paroxysmal hypertension.(1)

Pheochromocytoma paroxysms usually have a sudden onset and may last from a few minutes to several hours. In addition to hypertension, the patient experiences headache, profuse sweating, palpitations and apprehension, often with a sense of impending doom. Pain may occur in the chest or the abdomen and is occasionally associated with nausea and vomiting. The paroxysms may be precipitated by any activity that displaces the abdominal organs or by numerous drugs.(1) Over the course of time, paroxysms commonly increase in frequency, duration and severity.

The diagnosis of pheochromocytoma can be established by the demonstration of increased amounts of catecholamines and/or catacholamine metabolites (metanephrines and vanillylmandelic acid) in a 24-hour urine collection or in the plasma. Radiology often plays a complementary or confirmatory role.

Associated Syndromes

In approximately 5 percent of cases, pheochromocytomas are inherited as an autosomal dominant trait, either alone or in association with various syndromes, including multiple endocrine neoplasia (MEN) types II and III, neurofibromatosis and von Hippel-Lindau disease.(1) Pheochromocytomas are more often bilateral than unilateral in the familial syndromes.

MEN II, also known as Sipple syndrome, consists of pheochromocytoma (often bilateral and occasionally extra-adrenal), medullary carcinoma of the thyroid, and parathyroid hyperplasia or adenoma with no pancreatic islet cell tumor or peptic ulceration.(1) MEN III, the mucosal neuroma syndrome, consists of pheochromocytoma and medullary thyroid carcinoma along with a constellation of mucocutaneous lesions, including neuromas of the face, tongue, larynx, bladder and intestines.

Neurofibromatosis, a phakomatosis, is an autosomal dominant disease consisting of cafe-au-lait spots, fibromatous skin tumors, meningiomas, gliomas, acoustic neuromas, optic neuromas and pheochromocytomas. Von Hippel-Lindau disease, another phakomatosis, is also called cerebelloretinal hemangioblastomatosis. In addition to the vascular malformations of the retina and cerebellum, the syndrome includes pheochromocytomas, an increased incidence of hypernephroma and hemangiomas of the adrenal gland, liver and lung.(1)

Radiologic Findings

Kidney-Ureter-Bladder (KUB) Film. The plain abdominal radiograph is often normal in patients with pheochromocytoma. The film may, however, show focal calcification in the region of the adrenal gland, which is highly suggestive of pheochromocytoma in the appropriate clinical setting.(2)

Intravenous Urogram. The intravenous urogram may reveal a suprarenal mass displacing the kidney from its normal position or axis. More than half of pheochromocytomas can be diagnosed by this modality if nephrotomography is employed and if the tumor is larger than 2.5 cm.(2)

Ultrasonography. This is a quick, noninvasive method of assessing the adrenal glands. Tumors must be 2 to 3 cm in diameter to be detected with confidence. An adrenal gland is abnormal if it is round (the usual configuration is an inverted "Y" shape), if any side is convex or if a focal loss of normal echotexture is noted. Areas of calcification show acoustic shadowing. The disadvantages of ultrasonography include inability to detect extra-adrenal tumors, operator dependency and artifacts created by overlying bowel gas.(4)

Computed Tomography (CT). This is currently the modality of choice for imaging the adrenal gland; it is 90 percent accurate. In patients with sufficient retroperitoneal fat, the adrenal glands are easily visualized. The right adrenal gland lies immediately posterior to the inferior vena cava and is slightly anterosuperior to the right kidney. The left adrenal gland lies anteromedial to the upper pole of the left kidney. Pheochromocytomas are often round or oval, with well-defined borders and an average diameter of 5 cm. Contrast injection results in inhomogeneous enhancement, which may have central low attenuation secondary to necrosis. Local invasion and metastases to liver, lung and spine are well demonstrated by CT,(5) as are areas of calcification.

Magnetic Resonance Imaging (MRI). Recent experience with MRI of the adrenal gland suggests that this method may become the imaging modality of choice for the diagnosis of pheochromocytoma.(6-8) Since MRI can display anatomy in axial, coronal and sagittal planes, the location and extent of adrenal masses can be exquisitely depicted. The normal adrenal gland is of intermediate signal intensity (slightly less than liver and renal cortex) on T1-weighted images and is much less bright than surrounding fat on T2-weighted images. Pheochromocytomas demonstrate a distinctive MRI appearance. On T1-weighted images, pheochromocytomas are hypo- to isointense, while on T2 sequences they become very bright compared with liver. An adrenal mass-to-liver T2-signal intensity ratio of 4:1 is diagnostic of pheochromocytoma in the appropriate clinical setting. Other adrenal tumors, such as adenoma, adrenal cortical carcinoma and metastasis, behave like pheochromocytomas in that they are dark on T1- and bright on T2-weighted images; however, the adrenal tumor-to-liver T2-signal intensity ratio is less than 4:1.(6)

Angiography. This method is most often used to delineate anatomy prior to resection. If CT or MRI has failed to demonstrate the site of the pheochromocytoma, angiography with venous sampling for catecholamines may help localize the tumor.(9) Angiographic contrast agents may induce an adrenal paroxysm; therefore, patients should be given an alpha-adrenergic blocking agent before the study.

Scintigraphy. Nuclear scintigraphy, using (131)I-labeled metaiodobenzylguanidine, is helpful in detecting recurrent or metastatic pheochromocytomas, since the whole body can be imaged relatively easily. This procedure is very sensitive but requires one to three days to complete.(10)

Treatment and Prognosis

Surgical removal of the tumor is the treatment of choice. The induction of alpha-adrenergic blockade, followed by Beta-adrenergic blockade to control tachycardia, is essential prior to surgical resection. When the tumor is unresectable, treatment with adrenergic blocking agents is used. If the manifestations of pheochromocytoma cannot be adequately controlled by adrenergic blockade, concomitant administration of alpha-methyltyrosine, which inhibits catecholamine production, may be helpful.(1)

In patients with benign pheochromocytomas, five-year survival after surgery approaches 95 percent, with a recurrence rate of less than 10 percent. The five-year survival rate for those with malignant tumors is less than 50 percent.(1)

PHOTO : Plain film of the abdomen, revealing focal right upper quadrant calcification (arrow)

PHOTO : superior to the right kidney. In the appropriate clinical setting, this finding is

PHOTO : suggestive of pheochromocytoma.

PHOTO : Right upper quadrant sonogram demonstrating a large, predominantly solid mass (open

PHOTO : arrows) superior to the right kidney (not visible). Hyperechoic focus with acoustic

PHOTO : shadowing is seen within the mass (solid arrow), a finding consistent with calcification.

PHOTO : Noncontrast CT scan showing a large, complex right adrenal mass (arrows) with a central

PHOTO : low attenuation area suggestive of necrosis.

PHOTO : Contrast-enhanced CT scan at a similar level, demonstrating an inhomogeneously enhancing

PHOTO : mass (open arrows) with a nonenhancing central low attenuation region consistent with

PHOTO : necrosis (solid arrow). Note focal calcification in the center of the mass.

PHOTO : T2-weighted axial MR image. The large right adrenal mass shows very high signal intensity

PHOTO : compared with both liver and fat, a finding diagnostic of pheochromocytoma (large arrows).

PHOTO : The central round, dark area (small arrow) represents the previously noted focal area of

PHOTO : calcification. REFERENCES (1)Landsberg L, Young JB. Pheochromocytoma. In: Petersdorf RG, ed. Harrison's Principles of internal medicine. 11th ed. New York: McGraw-Hill 1987:1775-8. (2)Dunnick NR. The adrenal gland. In: Taveras JM, Ferrucci JT, eds. Radiology: diagnosis, imaging, intervention. Vol. 4. Philadelphia: Lippincott, 1986. (3)Robbins SL, Cotran RS, Kumar V. Pathologic basis of disease. 3d ed. Philadelphia: Saunders, 1984:1244-7. (4)Sample WF, Sarti DA. Computed tomography and gray scale ultrasonography of the adrenal gland: a comparative study. Radiology 1978;128:377-83. (5)Laursen K, Damgaard-Pedersen K. CT for pheochromocytoma diagnosis. AJR 1980;134:277-80. (6)Egglin TK, Hahn PF, Stark DD. MRI of the adrenal glands. Semin Roentgenol 1988;23:280-7. (7)Chang A, Glazer HS, Lee JK, Ling D, Heiken JP. Adrenal gland: MR imaging. Radiology 1987;163:123-8. (8)Chezmar JL, Robbins SM, Nelson RC, Steinberg HV, Torres WE, Bernardino ME.Adrenal masses: characterization with T1-weighted MR imaging. Radiology 1988;166:357-9. (9)Kadir S. Diagnostic angiography. Philadelphia: Saunders; 1986:525-30. (10)Quint LE, Glazer GM, Francis IR, Shapiro B, Chenevert TL. Pheochromocytoma and paraganglioma: comparison of MR imaging with CT and I-131 MIBG scintigraphy. Radiology 1987;165:89-93.

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