(Radiographics. 2002;22:935-940.)
© RSNA, 2002
Best Cases from the AFIP
Cystic Pheochromocytoma1
Terrence H. Lee, MD,
Chrystia M. Slywotzky, MD,
Michael T. Lavelle, MD and
Roberto A. Garcia, MD
1 From the Departments of Radiology (T.H.L., C.M.S., M.T.L.) and Pathology (R.A.G.), New York University Medical Center, New York, NY. Received December 19, 2001; revision requested January 15, 2002, and received February 21; accepted February 28. Address correspondence to T.H.L., 40 Hartwell St, New Brunswick, NJ 08901 (e-mail: leet72@hotmail.com).
Index Terms: Adrenal gland, neoplasms, 86.328 • Pheochromocytoma, 86.328
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History
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A 45-year-old woman with known hepatitis C and a history of substance abuse, but without any significant clinical complaint, was referred for abdominal ultrasonography (US). Upon review of systems, the patient stated that for 6 months she had occasionally had anxiety attacks with shortness of breath, diaphoresis, and palpitations. At presentation, results of physical examination were unremarkable, with vital signs well within normal limits.
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Imaging Findings
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Abdominal US revealed a 6.5-cm cystic mass with a thick wall and multiple septa in the right suprarenal fossa (Fig 1). Doppler interrogation demonstrated increased arterial flow in the rim and the septa of the mass.
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Figure 1. Transverse US image obtained at the level of the suprarenal fossa shows a thick-walled, complex mass with multiple thick septa and hypoechoic spaces. Retroperitoneal fat (arrow) separates the mass from the adjacent liver, thus confirming the retroperitoneal location.
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Abdominal computed tomography (CT) with and without intravenous contrast material demonstrated the mass. A normal right adrenal gland could not be identified. The left adrenal gland was normal in appearance. Unenhanced CT images showed no calcifications in the mass (Fig 2). After administration of intravenous contrast material, thick enhancing septa were evident in the mass with displacement of the inferior vena cava anteromedially (Fig 3). Vascular invasion could not be excluded.
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Figure 3. Contrast material-enhanced CT scan shows heterogeneous enhancement of the thick wall and the septa of the mass, which displaces the inferior vena cava anteromedially (arrow).
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Examination of the abdomen with magnetic resonance (MR) imaging confirmed the presence of a complex mass in the right suprarenal location. Again, a normal right adrenal gland was not identified. In-phase and opposed-phase T1-weighted images showed no change in the signal characteristics of the mass. On coronal T2-weighted turbo spin-echo images, there were multiple pockets of high signal intensity (Fig 4), which corresponded to areas absent of enhancement on the postcontrast T1-weighted images, thus confirming a significant cystic component. The thick wall and the septa briskly enhanced (Fig 5).
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Figure 5a. (a) Coronal nonenhanced T1-weighted MR image shows pockets of central low signal intensity in the mass (white arrow) with higher signal intensity along the periphery (black arrow). (b) Coronal contrast-enhanced T1-weighted MR image obtained during the nephrographic phase shows enhancement of the wall and septa of the mass.
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Figure 5b. (a) Coronal nonenhanced T1-weighted MR image shows pockets of central low signal intensity in the mass (white arrow) with higher signal intensity along the periphery (black arrow). (b) Coronal contrast-enhanced T1-weighted MR image obtained during the nephrographic phase shows enhancement of the wall and septa of the mass.
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Clinical Management
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Biochemical assays were performed to determine a functional component of the adrenal lesion. A 24-hour urine collection for levels of fractionated metanephrines and vanillylmandelic acid was remarkable for metanephrine values of 1.22 mg/24 h (normal, 0–0.4 mg/24 h); normetanephrine values of 3.42 mg/24 h (normal, 0–0.9 mg/24 h); total metanephrine values of 4.64 mg/24 h (normal, 0–1.30 mg/24 h); and vanillylmandelic acid values of 17.4 mg/24 h (normal, 1–6.5 mg/24 h).
The patient was admitted for an elective right adrenalectomy. Before surgery, the patient was given a regimen of esmolol and phentolamine. The right adrenal mass was resected without complications, and the postoperative course was uneventful.
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Pathologic Evaluation
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At gross analysis, the surgical specimen was a round, well-circumscribed, tan-pink to violaceous, encapsulated mass that measured 7.0 x 6.5 x 6.0 cm and weighed 115 g. At sectioning, the mass was completely cystic (Fig 6) and contained 50 mL of serosanguineous fluid with a component of yellow, translucent mucoid material. The cystic cavity was multiloculated with a smooth inner surface and showed focal areas of hemorrhage. No normal adrenal gland was identified.
Microscopic examination revealed that the mass was composed of large cells with abundant basophilic, granular cytoplasm with multiple large, pleomorphic, and bizarre nuclei. The nuclei had prominent nucleoli and coarse chromatin. Occasional intracytoplasmic hyaline globules positive for periodic acid–Schiff stain were present. There were extensive areas of hemorrhagic necrosis and fibrin deposition, mainly in the areas surrounding the cystic cavity (Fig 7). A thin rim of subcapsular lipid-rich adrenal tissue was identified. The interface between the tumor cells and normal adrenal tissue was irregular and ill defined. There was no evidence of vascular invasion or infiltration of the adrenal capsule by the tumor. The final pathologic diagnosis was cystic pheochromocytoma with hemorrhagic necrosis.
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Figure 7a. (a) Low-power photomicrograph (hematoxylin-eosin stain) shows that the mass is encapsulated (arrow) and is composed of large cells with abundant basophilic to amphophilic, granular cytoplasm with focal vacuolization. The cells are arranged in a vaguely organoid or trabecular pattern and have a richly vascularized background. (b) High-power photomicrograph (hematoxylin-eosin stain) shows tumor cells (straight solid arrow) with multiple large, pleomorphic, and bizarre nuclei with prominent nucleoli and frequent nuclear pseudoinclusions. The cells are adjacent to an area of extensive hemorrhagic necrosis (open arrow), which is close to the surface of the cystic cavity (curved arrow).
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Figure 7b. (a) Low-power photomicrograph (hematoxylin-eosin stain) shows that the mass is encapsulated (arrow) and is composed of large cells with abundant basophilic to amphophilic, granular cytoplasm with focal vacuolization. The cells are arranged in a vaguely organoid or trabecular pattern and have a richly vascularized background. (b) High-power photomicrograph (hematoxylin-eosin stain) shows tumor cells (straight solid arrow) with multiple large, pleomorphic, and bizarre nuclei with prominent nucleoli and frequent nuclear pseudoinclusions. The cells are adjacent to an area of extensive hemorrhagic necrosis (open arrow), which is close to the surface of the cystic cavity (curved arrow).
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Discussion
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The prevalence of pheochromocytomas confirmed at autopsy is 0.13%, and these uncommon neoplasms account for only 0.1%–0.3% of cases of hypertension (1). The tumor is composed of chromaffin cells, which are embryologically derived from the neuroectoderm. Following the "rule of 10’s," approximately 10% of pheochromocytomas are extraadrenal, bilateral, extraabdominal, malignant, familial, pediatric, and without blood pressure elevation (2). Close to 90% of pheochromocytomas originate in the medulla of the adrenal glands. The remaining 10% of pheochromocytomas are extraadrenal and are more commonly known as catecholamine-secreting paragangliomas. These are seen in close association with the sympathetic chain with the most common location in the organ of Zuckerkandl, located at the aortic bifurcation (3). Approximately 10% of pheochromocytomas are familial with an autosomal dominant transmission and are associated with von Hippel–Lindau syndrome, type 1 neurofibromatosis, and multiple endocrine neoplasia syndromes type IIA and type IIB. A family history of these disorders can guide clinicians toward screening for pheochromocytoma.
Approximately 90% of patients with pheochromocytomas present with hypertension secondary to the release of catecholamines (4). However, given the prevalence of hypertension in the general population, a history of hypertension that is refractory to standard treatment or labile with a dramatic response to an 
1-adrenergic antagonist is suggestive of a pheochromocytoma. The classic triad of symptoms associated with pheochromocytoma is palpitations, diaphoresis, and headache. More than 90% of patients with a pheochromocytoma will have one or more symptoms of the classic triad (5). Other symptoms include pallor, nausea, tremor or trembling, fatigue, anxiety, pain, and flushing (4). Characteristically, these symptoms are paroxysmal and may be precipitated by abdominal exertion, such as heavy lifting or performing the Valsalva maneuver. When a catecholamine-secreting tumor such as a pheochromocytoma or paraganglioma is clinically suspected, the appropriate screening study is a 24-hour urine collection to evaluate for levels of catecholamine and its metabolites, such as metanephrine and vanillylmandelic acid. In addition to urinary levels, serum catecholamine levels may also be used. After confirmation of elevated levels of catecholamine or its metabolites, diagnostic imaging is indicated for neoplasm localization.
CT is a commonly used modality to study the adrenal glands and retroperitoneum. The typical imaging characteristics of a pheochromocytoma are a round, well-circumscribed, homogeneous soft-tissue mass measuring over 3 cm (3). Because of the size of most pheochromocytomas, intravenous contrast material is not necessary for detection of the lesion. However, when intravenous contrast material is given, a pheochromocytoma will enhance heterogeneously, helping in the detection of extraadrenal lesions. There has been much debate over the use of adrenergic blockade prior to administration of intravenous contrast material in patients with pheochromocytomas. Raisanen et al (6) reported the effects of administration of intravenous ionic contrast material on catecholamine levels in patients with pheochromocytomas. They recommend -adrenergic blockade prior to intravenous administration of ionic contrast material. However, more recently, Mukherjee et al (7) studied the effects of nonionic contrast material on circulating levels of catecholamines in patients with pheochromocytomas. Although they recommend adrenergic blockade in patients to control their symptoms and prevent an adrenergic crisis, they concluded that it was not necessary to administer adrenergic blockers specifically for intravenous administration of nonionic contrast material. At our institution, all patients receive nonionic contrast material for CT. In the case described herein, the patient received 100 mL of iopamidol (Isovue; Bracco Diagnostics, Princeton, NJ), a nonionic contrast medium, during CT and tolerated the examination without complaint.
At MR imaging, smaller pheochromocytomas are isointense to muscle and hypointense to the liver on T1-weighted images. On T2-weighted images, they are typically very hyperintense to fat. This imaging characteristic helps distinguish pheochromocytomas from adrenal carcinomas, which are usually isointense or hyperintense to fat on T2-weighted images (3). Pheochromocytomas are lipid poor and will not decrease in signal intensity during out-of-phase sequences. The US characteristics of pheochromocytomas can be quite variable. Pheochromocytomas are usually round and well circumscribed, and they are easily distinguished from adjacent organs and structures. The majority of solid pheochromocytomas are isoechoic or hypoechoic to adjacent renal parenchyma (8).
Pheochromocytomas are quite vascular lesions. However, they frequently manifest with focal or partial cystic degeneration. Total or subtotal cystic degeneration of pheochromocytomas is not common. There have been several reports in the literature describing totally cystic tumors (9–12). It has been postulated that the process starts with intraparenchymal hemorrhage followed by necrosis; the areas of necrosis later undergo resorption. The triggering mechanism appears to be the tumor outgrowing its vascular supply (13). The cystic components of pheochromocytomas reflect this necrosis and liquefaction within the tumor. These areas are low in attenuation at CT (5,8). At MR imaging, areas of necrosis are hyperintense on T2-weighted images. According to one series, 32% of the pheochromocytomas studied with US were cystic or had cystic components (8).
The differential diagnosis of cystic adrenal lesions includes adrenal cyst, pseudocyst, adrenal carcinoma, and pheochromocytoma (11,12). Pheochromocytomas and adrenal carcinomas often have a functional component, and clinical symptoms and biochemical assays should help guide diagnosis of these lesions. Rozenblit et al (12) used CT to classify cystic adrenal lesions into three groups: uncomplicated, complicated, and indeterminate. They defined uncomplicated lesions as having a diameter less than 6 cm, homogeneous near-water attenuation, and thin walls measuring less than 3 mm. These cysts may also be uni- or multiloculated, and thin calcification may be seen. Cysts are placed into the indeterminate group if they are larger than 6 cm, have higher attenuation values up to 30 HU, or have a wall thickness between 3 and 5 mm. Cystic lesions are considered complicated if they have any of the following characteristics: high attenuation value (>30 HU), heterogeneous texture at CT, central stippled calcification, thick rim calcification, or a wall thickness of 5 mm or greater (12). The authors suggest that uncomplicated cysts may be followed conservatively. Complicated and indeterminate cystic lesions require histologic correlation and surgical intervention. In these cases, it is critical to determine which lesions are pheochromocytomas to avoid precipitation of a hypertensive crisis. Catecholamine-screening assays should be performed to rule out this diagnostic possibility. Our patient did not meet any of the criteria for an uncomplicated cyst and surgery was performed.
Although not performed in the case described herein, radioscintigraphy can also help in localization of the primary tumor or secondary lesions by using iodine-131 metaiodobenzylguanidine (MIBG) as the radiopharmaceutical. I-131 MIBG is an analogue of guanethidine that competes with norepinephrine at synaptic reuptake receptors. With catecholamine-producing masses, there is increased uptake of this radiopharmaceutical. The sensitivity of use of I-131 MIBG to visualize pheochromocytomas is 85% with a specificity of 96% (14,15). The advantage of radioscintigraphy is the ability to survey the entire body and localize extraadrenal lesions.
The definitive treatment of pheochromocytomas is surgical excision. For most intraadrenal pheochromocytomas, an adrenalectomy is performed. Preoperatively, these patients undergo adrenergic blockade to avoid any complications from release of catecholamines from the pheochromocytoma during surgery. After surgery, 24-hour urine levels of vanillylmandelic acid and other catecholamine metabolites are measured to determine if there is residual tumor, a second primary lesion, or metastases. In addition, postoperative surveillance of these patients includes annual quantification of 24-hour urinary catecholamine excretion for at least 5 years.
Benign and malignant pheochromocytomas are indistinguishable at histologic analysis. Benign lesions can be locally invasive, invading adjacent structures such as the inferior vena cava or renal capsule. Pheochromocytomas are considered malignant if metastases are present, and approximately 13% of pheochromocytomas are malignant (16). Common sites of metastases are the axial skeleton, liver, lungs, and retroperitoneal or mediastinal lymph nodes. Treatment of malignant pheochromocytomas usually involves decreasing catecholamine effects with - and ß-adrenergic blockade by using phenoxybenzamine and propranolol and decreasing catecholamine levels by inhibiting catecholamine production with drugs such as metyrosine and carbidopa. In addition, treatment for malignant pheochromocytoma may involve resection if the lesions are surgically accessible. Standard radiation therapy and chemotherapy have had only limited success in treating these malignant lesions. However, the combination of cyclophosphamide, vincristine, and dacarbazine shows promise as a chemotherapeutic regimen (16). The 5-year survival rate with malignant pheochromocytoma is less than 50% (5).
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Footnotes
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Editor’s Note.—Everyone who has taken the course in radiologic pathology at the Armed Forces Institute of Pathology (AFIP) remembers bringing two beautifully illustrated cases for accession to the Institute. In recent years, the staff of the Department of Radiologic Pathology has judged the "best cases" by organ system, and recognition is given to the winners on the last day of the class. With each issue of RadioGraphics, one of these cases is published, written by the winning resident. Radiologic-pathologic correlation is emphasized, and the causes of the imaging signs of various diseases are illustrated.
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References
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- Sutton MGSJ, Sheps SG, Lie JT. Prevalence of clinically unsuspected pheochromocytoma: review of a 50-year autopsy series. Mayo Clin Proc 1981; 56:354-360.[Medline]
- Young WF, Jr. Pheochromocytoma and primary aldosteronism: diagnostic approaches. Endocrinol Metab Clin North Am 1997; 26:801-827.[CrossRef][Medline]
- Kenney PJ, Lee JKT. The adrenals. In: Lee JKT, Heiken JP, Sagel SS, Stanley RJ, eds. Computed body tomography with MRI correlation. 3rd ed. Philadelphia, Pa: Saunders, 2000; 1185-1189.
- Young JB, Landsberg L. Catecholamines and the adrenal medulla. In: Wilson JD, Foster DW, Kronenberg HM, Larsen PR, eds. Williams textbook of endocrinology. 9th ed. Philadelphia, Pa: Saunders, 1998; 705-716.
- O’Connor DT. The adrenal medulla, catecholamines, and pheochromocytoma. In: Goldman L, Bennett JC, eds. Cecil textbook of medicine. 21st ed. Philadelphia, Pa: Saunders, 2000; 1259-1262.
- Raisanen J, Shapiro B, Glazer GM, Desai S, Sisson JC. Plasma catecholamines in pheochromocytoma: effect of urographic contrast media. AJR Am J Roentgenol 1984; 143:43-46.[Abstract/Free Full Text]
- Mukherjee JJ, Peppercorn PD, Reznek RH, et al. Pheochromocytoma: effect of nonionic contrast medium in CT on circulating catecholamine levels. Radiology 1997; 202:227-231.[Abstract/Free Full Text]
- Schwerk WB, Gorg C, Gorg K, Restrepo IK. Adrenal pheochromocytomas: a broad spectrum of sonographic presentation. J Ultrasound Med 1994; 13:517-521.[Abstract]
- Belden CJ, Powers C, Ros PR. MR demonstration of a cystic pheochromocytoma. J Magn Reson Imaging 1995; 5:778-780.[Medline]
- Bush WH, Elder JS, Crane RE, Wales LR. Cystic pheochromocytoma. Urology 1985; 25:332-334.[CrossRef][Medline]
- Klingler PJ, Fox TP, Menke DM, Knudsen JM, Fulmer JT. Pheochromocytoma in an incidentally discovered asymptomatic cystic adrenal mass. Mayo Clin Proc 2000; 75:517-520.[Medline]
- Rozenblit A, Morehouse HT, Amis ES. Cystic adrenal lesions: CT features. Radiology 1996; 201:541-548.[Abstract/Free Full Text]
- Munden R, Adams DB, Curry NS. Cystic pheochromocytoma: radiologic diagnosis. South Med J 1993; 86:1302-1305.[Medline]
- Manger WM, Gifford RW. Clinical and experimental pheochromocytoma 2nd ed. Cambridge, Mass: Blackwell Science, 1996; 309-314.
- Swensen SJ, Brown ML, Sheps SG, et al. Use of 131I-MIBG scintigraphy in the evaluation of suspected pheochromocytoma. Mayo Clin Proc 1985; 60:299-304.[Medline]
- Averbuch SD. Management of malignant pheochromocytoma. Manger WM, Gifford RW. Clinical and experimental pheochromocytoma. 2nd ed. Cambridge, Mass: Blackwell Science, 1996; 433-440.
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History
Imaging Findings
