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CT of Pheochromocytoma and Paraganglioma: Risk of Adverse Events with IV Administration of Nonionic Contrast Material

¹ Division of Abdominal Imaging, Department of Medical Imaging, University Health Network and Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada.
² Department of Medical Imaging, Princess Margaret Hospital 3-956, 610 University Ave., Toronto, ON, Canada, M5G 2M9.

Received June 22, 2006; accepted after revision October 11, 2006.

 
Address correspondence to M. E. O'Malley.

Abstract

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OBJECTIVE. When pheochromocytoma or paraganglioma is suspected, many institutions perform only unenhanced CT because of a perceived risk of inducing a hypertensive crisis with IV administration of contrast material. The purpose of this study was to review our experience with the use of nonionic IV contrast material for CT of patients with pheochromocytoma or paraganglioma. The specific goal was to determine whether adverse events occurred.

MATERIALS AND METHODS. A retrospective review of radiology records identified 25 patients (17 women, eight men; mean age, 43 years; age range, 27-70 years) with 40 pathologically proven pheochromocytomas or paragangliomas who received nonionic IV contrast material for CT. There were 16 adrenal pheochromocytomas, 12 abdominal paragangliomas, five neck paragangliomas, and seven metastatic lesions. Medical records were reviewed to determine whether the tumors were sporadic or associated with a syndrome, incidentally detected, or biochemically active; and whether patients were taking -blocking medication at the time of CT. Adverse events were documented.

RESULTS. Nineteen patients had 23 sporadic tumors, and six patients had 17 tumors associated with a syndrome. In 12 (48%) of the 25 patients the diagnosis was clinically unsuspected at the time of CT. Elevated levels of urinary catecholamines or their metabolites were found in 19 (90%) of the 21 patients for whom this test was performed. No patients were taking -blocking medication at the time of CT. No adverse events occurred in association with IV administration of nonionic contrast material.

CONCLUSION. IV administration of nonionic contrast material for CT is a safe practice for patients with pheochromocytoma and related tumors even without -blocking medication.

Keywords: abdominal imaging • adrenal gland • contrast media • CT • paraganglioma • pheochromocytoma • safety

Introduction

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Pheochromocytoma is a neoplasm of the adrenal chromaffin cells, and paraganglioma is a neoplasm of the extraadrenal paraganglia. These tumors secrete catecholamines that can induce life-threatening hypertensive crises. Although there are reports that IV or intraarterial administration of ionic contrast material can induce hypertensive crisis in patients with pheochromocytoma or paraganglioma [1-3], in only one study [4] to our knowledge has the issue of IV administration of nonionic contrast material to patients with pheochromocytoma and related tumors been systematically addressed. In that study, there was no statistically significant increase in catecholamine levels after peripheral IV administration of nonionic contrast material versus injection of normal saline solution. Despite the findings of that study, there remains, both anecdotally and in the literature, a perceived risk of inducing hypertensive crisis with IV administration of nonionic contrast material to patients with pheochromocytoma or paraganglioma [5-8]. The purpose of our study was to review our experience with the administration of nonionic IV contrast material for CT of patients with pheochromocytoma or paraganglioma.

Materials and Methods

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This retrospective study was approved by our research ethics boards. Informed consent was not required. A computerized search of radiologic records at our institution from January 1999 to September 2005 was performed to identify patients with known or suspected pheochromocytoma or paraganglioma. In addition, our cancer registry records, which were available from January 1999 to December 2003, were searched electronically to identify additional patients with a diagnosis of pheochromocytoma or paraganglioma.

To be included in the study, each patient was required to have pathologically proven pheochromocytoma or paraganglioma and to have undergone CT with nonionic contrast material at our institution between January 1999 and September 2005. We identified 28 CT studies performed with nonionic IV contrast medium on 25 patients with one or more pathologically proven pheochromocytomas or paragangliomas, and these patients formed the study group. The patients were 17 women and eight men with a mean age of 43 years (range, 27-70 years).

The lesions were 16 adrenal pheochromocytomas, 12 abdominal paragangliomas (including one primary liver paraganglioma), five neck paragangliomas, and seven metastatic lesions. The medical records were reviewed to determine whether the tumors were sporadic or associated with a syndrome, clinically unsuspected or incidental as opposed to clinically suspected or known, and biochemically active and whether the patients were taking -blocking medication at the time of CT.

Patients were classified as having symptomatic tumors if there was a history of hyperadrenergic symptoms such as paroxysmal flushing, sweating, palpitations, and headaches. The presence of hypertension also was recorded. Patients with hypertension alone were considered to have asymptomatic lesions [9]. The type, volume, and rate of IV administration of contrast material were recorded.

At our institution, all CT scans are obtained and monitored by a CT technologist. Any adverse event is reported to the supervising radiologist at the time of scanning, and these patients are clinically examined by a radiologist. For each adverse event, an incident report is completed by the technologist and radiologist and recorded electronically. An electronic search was performed to match our study group with the incident reports at our institution during the study period to determine whether any of these patients experienced adverse events related to IV administration of nonionic contrast material.

The anatomic location, number, and type of tumor in each patient were recorded. One reviewer retrospectively recorded the maximal axial size and appearance of each tumor, including the presence of necrosis, cystic components, and calcification. The attenuation of each tumor was measured with the largest region of interest possible, excluding any necrotic, cystic, or calcified component. If a patient had multiple pheochromocytomas or paragangliomas, the attenuation value of the largest lesion of each type was recorded for each phase available to avoid the issue of correlated data. If the patient underwent CT more than once, only the attenuation values on the initial study were recorded.

Results

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Twenty-five patients with 40 tumors underwent 28 CT examinations with IV administration of nonionic contrast material. Twenty-two patients underwent one CT examination, and three patients underwent two examinations. The patient- and tumor-related data are summarized in Table 1. Nineteen patients had 23 sporadic lesions, that is, the lesions were not associated with a known syndrome. The other six patients had 17 lesions associated with a documented or suspected syndrome.

In 12 (48%) of the 25 patients, the diagnosis of pheochromocytoma or paraganglioma was clinically unsuspected at the time of CT. Five of these patients, however, had at least one paroxysmal hyperadrenergic symptom of palpitation, diaphoresis, or headache before CT that was revealed only at subsequent clinical assessment. Ten of these 12 patients had hypertension. Blood pressure measurements were available for only five patients, and they ranged from 150/80 to 170/105 mm Hg. For the other five patients, there was only a reference in the notes to the presence of hypertension.

Thirteen (52%) of the 25 patients had clinically suspected or known pheochromocytoma or paraganglioma. Four of these patients had at least one paroxysmal hyperadrenergic symptom, and one patient had stress cardiomyopathy from catecholamine excess. Four of these 13 patients had hypertension, with blood pressure levels ranging from 130/90 to 200/100 mm Hg.

Twenty-one of the 25 patients underwent biochemical testing. Levels of urine catecholamines or their metabolites were elevated in 19 (90%) of the 21 patients. One of the two patients with negative biochemical results had a small (20 mm) pelvic lymph node metastatic lesion from a previously resected functional paraganglioma of the bladder. The other patient had three small (20 mm, 7 mm, 7 mm) hepatic metastatic lesions from a previously resected functional pheochromocytoma.

Biochemical results were not available for four patients. Two of these patients were presumed to have functionally active tumors. One of these two patients had documented labile blood pressure at the time of unrelated surgery, and the other who had primary liver paraganglioma had severe hypertension that resolved after resection of the lesion. One of the other two patients had labile blood pressure when the paraganglioma was handled at surgery. The other patient, who had multiple endocrine neoplasia type 2a, had a 13-mm pheochromocytoma without symptoms of hypertension that was probably too small to be functionally significant.

View larger version (110K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 1 —38-year-old woman with left paraaortic paraganglioma. IV contrast-enhanced CT scan shows homogeneous enhancement of solid mass.

View larger version (120K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 2 —29-year-old man with large primary hepatic paraganglioma. IV contrast-enhanced CT scan shows evidence of central necrosis.

View larger version (137K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 3 —45-year-old woman with right adrenal pheochromocytoma. IV contrast-enhanced CT scan shows predominantly cystic lesion.

All CT scans were obtained with nonionic contrast material: iohexol 300 mg I/mL (Omnipaque 300, GE Healthcare) in 15 CT studies and iodixanol 270 mg I/mL (Visipaque 270, GE Healthcare) in 13 CT studies. In three patients, the volume of contrast material was not recorded. According to the CT protocol used for these patients, however, each would have received 100 mL. The mean volume of contrast material administered was 105 mL (range, 60-192 mL). Most CT scans (19/28) were obtained with 100 mL of contrast material. The mean rate of IV infusion was 3 mL/s (range, 2-5 mL/s).

None of the patients were taking -blocking medications at the time of CT. No adverse events related to IV administration of nonionic contrast material were recorded; specifically, no patient had hyperadrenergic symptoms. Blood pressure measurements were obtained immediately after completion of CT scanning for only two patients. For both patients, the CT report indicated that neither patient had hypertension; the blood pressure measurements were not recorded.

The mean diameter of the largest tumor in each patient was 54 mm (range, 13-135 mm). Including all 40 tumors, the mean diameter was 40.5 mm (range, 7-135 mm). The tumors were roughly grouped into three main morphologic types: 15 solid or predominantly solid tumors (Fig. 1), seven tumors with mixed solid and necrotic components (Fig. 2), and three predominantly cystic lesions (Fig. 3). Calcification was present in three tumors.

Unenhanced images from 16 CT examinations of 16 patients were available for review. No solid component of a tumor had an attenuation value less than 23 H, the mean attenuation of the solid components measured 41 H (range, 23-53 H). Arterial phase images obtained in 11 CT examinations of 11 patients showed a mean tumor attenuation of 172 H (range, 71-263 H). Portal venous phase images in 22 CT examinations of 22 patients showed a mean tumor attenuation of 114 H (range, 55-176 H).

Discussion

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None of the 25 patients with pheochromocytoma or paraganglioma in this study had adverse events related to IV administration of nonionic contrast material for CT. Most of the patients (21/25, 84%) were considered to have functionally active tumors, and no patients were taking -blocking medication at the time of IV administration of nonionic contrast material. Our results support the hypothesis that IV administration of nonionic contrast material for CT of patients with pheochromocytoma or paraganglioma is a safe practice.

In patients with pheochromocytoma, precipitation of hyperadrenergic symptoms and hypertensive crises have been known to occur with anesthesia, adrenal venography and arteriography with ionic contrast material, manipulation of the tumor during surgery, and biopsy of the tumor [1-3, 10-12]. Few studies have addressed the risk that IV administration of nonionic contrast material can induce a hypertensive crisis in association with pheochromocytoma. We found only one report [13] in the literature of induction of hypertensive crisis by IV administration of contrast material for CT. In that report, CT was performed with ionic contrast material, and the patient was given glucagon, which is a known potent inducer of catecholamine release. Using MEDLINE and EMBASE databases, we found no reports in the English-language literature of induction of hypertensive crisis by peripheral IV administration of nonionic contrast material.

The main systematic study of the possibility of induction of catecholamine release from these tumors with the use of IV administration of ionic, as opposed to nonionic, contrast material was conducted by Raisanen et al. [14]. Those investigators studied the effects of the ionic contrast agent iothalamate meglumine 60% (Conray 60, Mallinckrodt) on eight patients with pheochromocytoma and related tumors and on 12 control patients. In that study, there was an unpredictable rise in norepinephrine and epinephrine levels among the patients with pheochromocytoma and related tumors, but the increase was not statistically significant. The patients were taking -blockers, and no hypertension was induced. However, five patients had an increase in catecholamine level that the authors stated would have been high enough to have led to a pressor effect in a patient not taking an -blocker. The authors recommended that such patients be given an -blocker before IV administration of IV contrast medium. These investigators, however, took only one measurement of catecholamine release 10 minutes after infusion of contrast material. This factor makes it unclear whether a direct effect of the contrast material can be inferred, particularly because release of catecholamines by these tumors during direct venography and arteriography is known to occur almost immediately after injection [2, 3].

A study by Mukherjee et al. [4] is the only study of which we are aware that was a systematic examination of the catecholamine release induced by IV administration of nonionic contrast material in patients with pheochromocytoma and paraganglioma. That study included 10 patients with pheochromocytoma and related tumors who were taking -blocking medication and six healthy volunteers who were given the nonionic contrast agent iohexol (Omnipaque, Nycomed, now GE Healthcare). In the study, there was no statistically significant increase in epinephrine or norepinephrine levels in the 10 patients or six control subjects given injections of iohexol in comparison with 0.9% saline solution. The authors measured plasma catecholamine levels up to 60 minutes after injection in nine of the 10 patients. Catecholamine levels also were found to be highly fluctuant among these patients. In two patients, peak catecholamine changes occurred 25 and 60 minutes after injection. This finding led the authors to suggest that any apparent increase in catecholamine level after the injection of contrast material was probably spontaneous and unrelated to the injection of contrast material. The authors concluded that "pressor crises are unlikely to be evoked by the peripheral IV use of the nonionic contrast medium iohexol" and that "specific blockade may not be required before contrast medium-enhanced scanning with iohexol."

We reviewed five published articles [5-7, 9, 15] that included a total of 58 patients with pheochromocytoma who underwent CT studies with IV administration of nonionic contrast material in which the presence or absence of adverse effects was recorded. Although the focus of those studies was not the effect of nonionic IV contrast material on catecholamine release, no adverse events were reported. It was not stated in the articles whether the patients were taking an -blocker. It is likely, however, that most of the patients were not taking the medication because many of the tumors either were incidentally detected or were part of screening CT studies of patients with von Hippel-Lindau disease [5-7, 9, 15]. In another study [16], investigators directly compared the washout characteristics of 17 pheochromocytomas against adrenal adenomas. Adverse events were not mentioned in that article, and it was not stated whether the patients were taking -blocking medication.

In our study, 12 (48%) of the patients had incidental tumors. The high percentage of incidental tumors in our patient population is in accordance with the findings of four studies [9, 16-18] involving a total of 137 patients in whom 41-58% of pheochromocytomas were discovered incidentally on radiologic imaging. Adrenal incidentaloma is common, and washout CT is being used increasingly to characterize lipid-poor adrenal lesions, a small percentage of which are unsuspected pheochromocytoma. As a result, many pheochromocytomas are likely to be imaged with nonionic IV contrast-enhanced CT, so it is important that IV administration of nonionic contrast material is safe in this setting.

Our study had limitations. It was a retrospective review of a relatively small number of cases and relied on accurate record keeping. However, all CT scans are closely monitored at our institution, and all adverse events are reported to the supervising radiologist, who is responsible for documentation. A hypertensive crisis is a dramatic symptomatic event and is extremely unlikely to have occurred and gone unrecorded. Likewise, it is highly unlikely that any hyperadrenergic symptoms would not have been recorded.

In the past, because of the theoretic risk of induction of hyperadrenergic symptoms, it has been the general practice at our institution to avoid IV contrast material in patients with suspected or known pheochromocytoma. However, 13 patients underwent contrast-enhanced CT for which the indication on the requisition form was suspicion of pheochromocytoma or pheochromocytoma based on the patient's syndrome. The use of IV contrast material in imaging of these patients likely reflects a relative lack of clearly defined guidelines in the literature regarding this issue, and the situation is likely to be similar in other large medical imaging departments in which many staff radiologists and trainees are involved in protocols of CT studies.

Although approximately 90% of pheochromocytomas and paragangliomas are detected on unenhanced CT, the use of IV contrast medium can improve this sensitivity, particularly for extraabdominal lesions and for small retroperitoneal tumors and distant metastasis [19-21]. Routine use of IV contrast material also allows accurate assessment of blood vessels, and this capability may aid in surgical planning. This issue has become more relevant with the increasing use of laparoscopic surgery for adrenal lesions [22]. Some institutions may require -blocking medication for patients with pheochromocytoma before performing contrast-enhanced CT. However, these medications may have side effects such as orthostatic hypotension. In addition, IV administration of some -blockers may interfere with ¹²³I metaiodobenzylguanidine (MIBG) uptake [23]. At some institutions, MIBG is used to localize and identify pheochromocytoma and paraganglioma, especially when the presence of more than one tumor is suspected. Therefore, administration of -blockers for the specific purpose of performing IV contrast-enhanced CT may delay the evaluation and treatment of some patients.

In conclusion, none of the patients with pheochromocytoma or paraganglioma in this study experienced adverse events related to the peripheral IV administration of nonionic contrast material. Our results and the clinical practice described in the recent literature suggest that -blockade is not specifically required before IV administration of nonionic contrast material to patients with suspected or known pheochromocytoma or related tumors.

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