You are in: eMedicine Specialties > Radiology > GENITOURINARY PheochromocytomaArticle Last Updated: Aug 15, 2007AUTHOR AND EDITOR INFORMATIONSection 1 of 12
  Author: Anant Krishnan, MD, Consulting Staff, Department of Radiology, William Beaumont Hospital Coauthor(s): Ali Shirkhoda, MD, Director, Division of Diagnostic Imaging, William Beaumont Hospital; Clinical Professor of Radiology, University of California in Irvine and Wayne State University Editors: Bernard D Coombs, MB, ChB, PhD, Consulting Staff, Department of Specialist Rehabilitation Services, Hutt Valley District Health Board, New Zealand; Arnold C Friedman, MD, FACR, Associate Chairman, Department of Radiology, University of Florida Health Science Center; Chief, Department of Radiology, Shands-Jacksonville Hospital; Robert M Krasny, MD, Consulting Staff, Department of Radiology, The Angeles Clinic and Research Institute; Eugene C Lin, MD, Consulting Staff, Department of Radiology, Virginia Mason Medical Center Author and Editor Disclosure Synonyms and related keywords: adrenal medullary tumor, paragangliomas, chemodectomas INTRODUCTIONSection 2 of 12
  BackgroundIn 1912, a pathologist named Pick coined the term pheochromocytoma—after the Greek words phaios, meaning dark or dusky, and chroma, meaning color—to describe the chromaffin reaction seen in adrenomedullary tumors. The tumors arise from the chromaffin cells of the adrenal medulla and are associated with increased catecholamine production. Although chromaffin tissue is also present elsewhere in the body, such as in the mediastinum, along the aorta, and in the pelvis, the term pheochromocytoma is reserved for tumors that arise from the adrenal medulla. Chromaffin cell tumors at other locations are more appropriately called paragangliomas or chemodectomas, although the term extra-adrenal pheochromocytoma is still applied. Detecting the tumors is important for a number of reasons. First, hypertension is usually cured with the removal of the tumor, whereas untreated patients are at risk for a lethal hypertensive paroxysm and long-term sequelae of the disease. Second, the discovery of a pheochromocytoma may indicate the presence of a familial disorder. Third, approximately 10% of pheochromocytomas are malignant. Incidentally, pheochromocytomas are called the 10% tumor because they are associated with a 10% risk of malignancy, because 10% of the tumors are bilateral, and because 10% of the tumors are extra-adrenal. Early detection may reduce the risk of metastasis. PathophysiologyPheochromocytomas most commonly arise sporadically, but they can also appear as part of a syndrome, such as multiple endocrine neoplasia (MEN) syndrome type 2A or 2B, von Hippel-Lindau syndrome, tuberous sclerosis, neurofibromatosis, Carney complex, and Sturge-Weber syndrome, among others. In 10% of patients, pheochromocytomas are inherited. These familial cases tend to occur in younger patients. The location and tendency to involve multiple sites vary depending on whether the tumor is part of a syndrome. Thus, bilateral adrenal pheochromocytomas are seen more commonly in the MEN syndromes, although they may be seen in approximately 10% of sporadic cases. Furthermore, the presence of adrenomedullary hyperplasia preceding the occurrence of pheochromocytomas is highly suggestive of an underlying MEN syndrome. Establishing the diagnosis is important for the patient and family because the risk of other tumors involves the entire family, and early detection of the other components of the syndrome is important for successful management. Usually, tumors are larger than 3 cm when seen. They are highly vascular, and larger tumors are prone to hemorrhage and necrosis, even when they are benign. Approximately 10% of pheochromocytomas are malignant. Some authors believe that the size of the tumor is poorly correlated with malignancy. The diagnosis of a benign or a malignant pheochromocytoma cannot be accurately determined by the histologic appearance; it depends on the presence or absence of metastasis. Metastases have been reported in lymphatic tissue, as well as in the lungs, liver, bones, and brain. Vascular invasion, local or distant metastasis, and a deoxyribonucleic acid (DNA) ploidy pattern (DNA diploidy is more benign than other patterns) affect the prognosis. The risk of malignancy is lower in patients with familial tumors than in patients with sporadic tumors. FrequencyUnited StatesThe true incidence is unknown. InternationalThe true incidence is unknown. Tumors are believed to increase blood pressure in approximately 0.1-0.5% of patients with newly diagnosed hypertension. Some authors report a higher incidence of right-sided adrenal pheochromocytomas, whereas others report the same incidence of pheochromocytomas in both glands. Mortality/MorbidityAlthough rare, pheochromocytomas can, if unrecognized, result in serious morbidity or in mortality.
RaceNo racial predilection is reported in patients with tumors that arise sporadically. SexThe male-to-female ratio is almost 1:1. AgePheochromocytomas most commonly occur in adults aged 20-40 years. In children, the disease is almost always inherited. AnatomyThe adrenal glands are paired, solid organs that lie within the perirenal fascia near the kidneys. Each adrenal gland is anatomically, functionally, and embryologically divided into the peripheral cortex, which forms most of the bulk of the gland, and the medulla. The medulla is composed of chromaffin cells derived from the neural crest; thus, it is related to the sympathetic nervous system. The adrenal gland on the right side is located directly posterior to the inferior vena cava (IVC), between the right crus of the diaphragm and the liver. The left adrenal gland is located more caudally and may be seen on the same imaging section that shows the kidney. On computed tomography (CT) scans and axial magnetic resonance images, each gland is seen as a linear or inverted Y- or V-shaped organ located superior, medial, and anterior to each kidney. Note that neither CT scanning nor magnetic resonance imaging (MRI) can be used to distinguish between the adrenal cortex and the medulla. Many extra-adrenal pheochromocytomas are at the pelvic brim in the organ of Zuckerkandl. Clinical DetailsIncreased catecholamine production by a pheochromocytoma results in hypertension, which may be episodic, as classically described, or sustained. Not uncommonly, patients are entirely normotensive between episodes. A triad of headaches, palpitations, and diaphoresis is described in pheochromocytoma and is seen in most patients. Patients with familial syndromes may be asymptomatic. Patients with pheochromocytomas in the bladder wall may present with postvoiding loss of consciousness as a result of catecholamine release. Patients who may be referred for imaging of the adrenal glands include those with new or worsening diabetes mellitus (owing to impaired glucose regulation) and those with hypertensive crisis after anesthesia, surgery, or treatment with medications. Imaging may also be performed in patients with a known history of multiple endocrine problems. Laboratory tests include the estimation of serum or urinary catecholamine levels, of urinary vanillylmandelic acid and metanephrine levels, and of other metabolite levels. Pheochromocytoma is diagnosed when a combination of clinical signs and symptoms and elevated catecholamine levels are present. Preferred ExaminationCT scanning and MRI have higher sensitivity in detecting pheochromocytomas than do nuclear medicine scanning with iodine-131 metaiodobenzylguanidine (131I-MIBG), although 131I-MIBG uptake is more specific. Some authors prefer to use metaiodobenzylguanidine (MIBG) uptake scanning as the initial screening modality because it enables whole-body imaging, making it useful for the detection of extra-adrenal tumors and metastatic deposits. Once an adrenal or extra-adrenal tumor is detected, CT scanning or MRI of the region may be performed for anatomic localization prior to surgical removal. If 131I-MIBG uptake is negative but the clinical findings suggest pheochromocytoma, CT scanning or MRI of the chest or abdomen may be performed, because the false-negative rate of MIBG scintigraphy is 10%. Limitations of TechniquesUnfortunately, the cost and lack of availability of MIBG studies restrict its use. In addition, imaging with 131I-MIBG can be time-consuming, and the technique has limited ability to provide sufficiently accurate information for surgery. Therefore, some authors recommend the use of at least 2 of the following modalities: CT scanning, MRI, and MIBG uptake studies. Although 123I-MIBG scanning requires a shorter imaging time than does 131I-MIBG scanning, it is less available, and the Food and Drug Administration has not yet approved it for use in adrenal imaging. CT scanning is quick and relatively inexpensive, and it offers good spatial localization. CT scan findings are not specific enough to distinguish masses caused by pheochromocytoma from other adrenal masses. Additionally, some authors report a risk of hypertensive crisis after the injection of contrast material. MRI is more specific for pheochromocytomas than is CT scanning, but some patients cannot tolerate MRI. DIFFERENTIALSSection 3 of 12
Adrenal Adenoma Adrenal Carcinoma Adrenal Metastases RADIOGRAPHSection 4 of 12
FindingsIn comparison with other available modalities, radiography has limited value. Large adrenal masses may compress and deform the upper pole of the kidney; these may be discovered incidentally on intravenous urograms. CT SCANSection 5 of 12
FindingsPheochromocytomas are large tumors (often >3 cm), and they are usually round or oval masses with an attenuation similar to that of the liver (see Image 1). Larger lesions frequently demonstrate necrosis, hemorrhage, and fluid-fluid levels. As a result, they often appear inhomogeneous. Calcification is rare, but it is reported. As a result of the large size of the tumors, contrast material is not essential for their detection. In addition, some authors believe that the administration of the contrast agent may precipitate a hypertensive crisis in an unmedicated patient, although newer reports counter this view. Some authors recommend alpha-adrenergic and beta-adrenergic blockade prior to administration of contrast material. When administered, the tumor demonstrates varying degrees of enhancement. Degree of ConfidenceCT scanning has a sensitivity of greater than 93% in the detection of pheochromocytomas and a specificity of 95% in the diagnosis of these tumors. False Positives/NegativesLarge, necrotic masses can be seen in other conditions, such as adrenal cortical carcinomas and metastasis. Thus, the diagnosis must be made in the setting of an appropriate clinical history. Patients with MEN syndromes may have atypical findings, such as thickened and nodular adrenal glands without large, discrete masses. MRISection 6 of 12
FindingsThe superior tissue characterization capability of MRI imaging combined with its multiplanar abilities affords it an advantage over CT scanning in the imaging of pheochromocytomas. On magnetic resonance images, pheochromocytomas are usually hypointense or isointense relative to the liver on T1-weighted spin-echo (SE) images, and they are highly intense on T2-weighted SE images. The reason for this difference is unknown, but it likely results from the high water content in cellular homogeneous tumors or from the high water content in necrotic regions. Tumors that have bled show the features typical of hemorrhage, depending on the age of the hemorrhage. The use of flow-sensitive sequences is helpful in demonstrating the presence of intracaval extension of the tumor. On magnetic resonance images obtained with gadolinium diethylenetriamine pentaacetic acid (DTPA), tumors demonstrate brisk and prolonged enhancement; however, contrast enhancement rarely provides additional information. Gadolinium-based contrast agents (gadopentetate dimeglumine [Magnevist], gadobenate dimeglumine [MultiHance], gadodiamide [Omniscan], gadoversetamide [OptiMARK], gadoteridol [ProHance]) have recently been linked to the development of nephrogenic systemic fibrosis (NSF) or nephrogenic fibrosing dermopathy (NFD). For more information, see the eMedicine topic Nephrogenic Fibrosing Dermopathy. The disease has occurred in patients with moderate to end-stage renal disease after being given a gadolinium-based contrast agent to enhance MRI or magnetic resonance angiography (MRA) scans. As of late December 2006, the FDA had received reports of 90 such cases. Worldwide, over 200 cases have been reported, according to the FDA. NSF/NFD is a debilitating and sometimes fatal disease. Characteristics include red or dark patches on the skin; burning, itching, swelling, hardening, and tightening of the skin; yellow spots on the whites of the eyes;joint stiffness with trouble moving or straightening the arms, hands, legs, or feet; pain deep in the hip bones or ribs; and muscle weakness. For more information, see the FDA Public Health Advisory or Medscape. Degree of ConfidenceMRI is as sensitive as CT scanning, with sensitivities ranging from 86-100%. False Positives/NegativesAlthough pheochromocytomas typically have high signal intensity on T2-weighted images, this finding is not universal. In 20-33% of patients, T2-weighted images show atypical findings. As a result, an alternate diagnosis of necrotic metastasis or adrenal cortical carcinomas may be made if this variance is not kept in mind. On the other hand, comparable high signal intensity may be seen in some necrotic adrenal metastases and adrenal cysts; as a result, these lesions cannot always be distinguished from pheochromocytomas on magnetic resonance images. ULTRASOUNDSection 7 of 12
FindingsUltrasonography has largely been replaced by CT scanning and MRI, and it is limited as a result of the effects of overlying bowel gas, especially in the assessment of the left adrenal gland. Therefore, the use of ultrasonography is limited to differentiating cystic lesions from solid lesions in the adrenal gland. Even in the pediatric population, MRI is the preferred imaging modality. NUCLEAR MEDICINESection 8 of 12
Findings131I-MIBG and 123I-MIBG are concentrated in the sympathomedullary system and then sequestered in neurosecretory granules. After pretreatment with Lugol iodine to saturate thyroid uptake, 0.5-1.0 mCi of 131I-MIBG or 9-10 mCi of 123I-MIBG is intravenously injected, and posterior adrenal images are obtained after 24, 48, and 72 hours. Technetium-99m DTPA also is used to improve localization of the kidneys. A normal adrenal medulla is seen in approximately 30% of patients, with an uptake of less than that of the liver. In pheochromocytoma, 131I-MIBG scans show the tumor as a focal area in the adrenal gland that has prolonged increased uptake. Tumor metastases can be demonstrated in a similar fashion. Compared with 131I-MIBG imaging, 123I-MIBG imaging offers better image quality, single-photon emission CT (SPECT) capability, lower radiation exposure, and shorter imaging time. However, the FDA has not approved the use of 123I-MIBG for adrenal imaging; thus, this technique is less commonly available for imaging. Other nuclear imaging modalities include imaging with the somatostatin analogue octreotide and imaging with positron emitters, such as carbon-11 (11C) hydroxyephedrine, 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG), and 11C epinephrine. The use of FDG, a glucose analogue used by metabolically active cells, with positron emission tomography (PET) is described. In a study of 29 patients with benign and malignant pheochromocytomas, Shulkin and colleagues reported tumoral uptake of FDG in 22 patients.1 They noted that as many as 17 of the 29 patients had malignant pheochromocytoma, which may have resulted in this high degree of positivity. Although the sensitivity and specificity of FDG PET were lower than those of MIBG scanning, FDG uptake occurred in all cases in which MIBG accumulation did not. Thus, when findings with other modalities fail to reveal or confirm the presence of the tumor, FDG PET may be useful. Other reports have since described the uptake of FDG in calvarial metastases from pheochromocytoma.2 Degree of ConfidenceReportedly, sensitivity is 86-90% for pheochromocytomas (especially in extra-abdominal tumors); specificity is as high as 99% with 131I-MIBG and is higher with 123I-MIBG (90% sensitivity, 100% specificity). False Positives/NegativesMIBG uptake may be poorly visualized in tumors, even large tumors, with extensive necrosis. Occasionally, activity in the bowel can create false-positive findings, especially when extra-adrenal tumors are considered. The study can be repeated 24 hours later, when activity in the gut is displaced. As a result of the 10% false-negative rate with MIBG scanning, some authors recommend abdominal CT scanning or MRI if a high clinical suspicion of pheochromocytoma exists but a causative tumor is not identified by assessing MIBG uptake. ANGIOGRAPHYSection 9 of 12
FindingsAngiography and venous sampling are no longer used because of the higher sensitivity and specificity of other available, and noninvasive, tests. In addition, angiography is hazardous without premedication, and a hypertensive crisis can result. If performed, angiograms show increased vascularity in the tumors. INTERVENTIONSection 10 of 12
Optimal treatment for pheochromocytoma includes prompt surgical referral for excision, because patients are at significant risk for lethal complications, such as hypertensive crisis and adrenal hemorrhage. Biopsy does not need to be performed and in fact can be dangerous, because hypertension is triggered by direct manipulation of the adrenal gland. Medical/Legal Pitfalls
Special Concerns
MULTIMEDIASection 11 of 12
REFERENCESSection 12 of 12
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