- Author: Anant Krishnan, MD; Chief Editor: Eugene C Lin, MD more...
In 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. Examples of pheochromocytomas are shown below.
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.
Usually, tumors are larger than 3 cm when seen. They are highly vascular (see the images below), and larger tumors are prone to hemorrhage and necrosis, even when they are benign.
Failure to make the correct diagnosis can create serious risks for the patient. Early surgical removal of the adrenal gland is important to prevent complications associated with pheochromocytomas. Delay can significantly increase the risk of an adverse event. Worse, if pheochromocytoma is not considered in the diagnosis, the injection of contrast material, especially ionic contrast material, can provoke a hypertensive crisis.
Therefore, exclusion of pheochromocytoma should be part of the diagnostic evaluation in every patient with a suprarenal mass. Some authors recommend iodine-131 metaiodobenzylguanidine (131I-MIBG) scintigraphy and/or the use of laboratory tests to confirm or rule out excessive production of catecholamines, prior to the use of invasive procedures.
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. Computed tomography (CT) scanning and magnetic resonance imaging (MRI) have higher sensitivity in detecting pheochromocytomas than do nuclear medicine scanning with 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.[3, 4, 5, 1, 6, 7, 8]
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%.
Luster et al investigated the specificity and sensitivity of (18)F-3,4-dihydroxyphenylalanine (DOPA) positron emission tomography (PET) scanning, CT scanning, and a combination of the 2 modalities in the identification and localization of adrenal and extra-adrenal pheochromocytomas. Nineteen lesions were detected by all 3 imaging methods, but only DOPA PET/CT scanning accurately characterized and localized them all, demonstrating, on a per-patient basis, a sensitivity of 100% and a specificity of 88%.
A further study by Gaertner et al concluded the (18)F-LMI1195 is a promising tracer for tumor imaging. Saad et al found in a study of 23 patients with a history of pheochromocytoma/paraganglioma that (18)F-FDG PET/CT was a superior tool for the localization of recurrent tumors.
Limitation of techniques
Unfortunately, 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. Although123 I-MIBG scanning requires a shorter imaging time than does131 I-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.
In comparison with other available modalities, radiography has limited value. Large adrenal masses may compress and deform the upper pole of the kidney (as shown in the image below); these may be discovered incidentally on intravenous urograms.
Pheochromocytomas are large tumors (often >3 cm), and they are usually round or oval masses with an attenuation similar to that of the liver. Larger lesions frequently demonstrate necrosis, hemorrhage, and fluid-fluid levels (see the images below). As a result, they often appear inhomogeneous. Calcification is rare, but it is reported.[7, 8]
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.
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 CT and axial MRI scans 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 MRI can be used to distinguish between the adrenal cortex and the medulla.
Degree of confidence
CT scanning has a sensitivity of greater than 93% in the detection of pheochromocytomas and a specificity of 95% in the diagnosis of these tumors.[10, 13]
Large, 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 multiple endocrine neoplasia (MEN) syndromes may have atypical findings, such as thickened and nodular adrenal glands without large, discrete masses.
Magnetic Resonance Imaging
The 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 MRI scans, 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. T1- and T2-weighted MRI scans appear below.
The use of flow-sensitive sequences is helpful in demonstrating the presence of intracaval extension of the tumor. On MRI scans 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).
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.
Degree of confidence
MRI is as sensitive as CT scanning, with sensitivities ranging from 86-100%.
Although 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 MRI scans.
Ultrasonography 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. Examples of an ultrasonographically identified adrenal mass are seen below.
A normal adrenal medulla is seen in approximately 30% of patients, with an uptake of less than that of the liver. In pheochromocytoma,131 I-MIBG scans show the tumor as a focal area in the adrenal gland that has prolonged increased uptake. (Such a focal area is seen in the image below.) Tumor metastases can be demonstrated in a similar fashion. Compared with131 I-MIBG imaging,123 I-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 of123 I-MIBG for adrenal imaging; thus, this technique is less commonly available for imaging.
In a prospective, observational study, Timmers et al concluded that combined (18)F-fluorodopamine (FDA) PET/CT scanning is the best means of localizing primary pheochromocytomas and ruling out metastases (78% sensitivity for nonmetastatic pheochromocytomas, 76% sensitivity for metastatic pheochromocytomas), with123 I-MIBG scintigraphy and DOPA PET scanning being the second-best alternatives. The study included 20 patients with nonmetastatic pheochromocytomas (11 with adrenal pheochromocytomas), 28 patients with metastatic pheochromocytomas (13 with adrenal pheochromocytomas), and 4 patients in whom the presence of pheochromocytomas had been ruled out.
131 I-MIBG and123 I-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 of131 I-MIBG or 9-10 mCi of123 I-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.
Other nuclear imaging modalities include imaging with the somatostatin analogue octreotide and imaging with positron emitters, such as carbon-11 (11 C) hydroxyephedrine, 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG), and11 C epinephrine.
The use of FDG, a glucose analogue used by metabolically active cells, with PET scanning is described. In a study of 29 patients with benign and malignant pheochromocytomas, Shulkin and colleagues reported tumoral uptake of FDG in 22 patients. 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.[15, 16, 17]
Degree of confidence
Reportedly, sensitivity is 86-90% for pheochromocytomas (especially in extra-abdominal tumors); specificity is as high as 99% with131 I-MIBG and is higher with123 I-MIBG (90% sensitivity, 100% specificity).
MIBG 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.
Angiography 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.
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