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Original Research |
1 Department of Radiology, Cleveland Clinic Foundation, 9500 Euclid Ave., A21,
Cleveland, OH 44195.
3 Glickman Urological Institute, Cleveland Clinic Foundation, Cleveland,
OH.
4 Department of Endocrinology, Diabetes and Metabolism, Cleveland Clinic
Foundation, Cleveland, OH.
Received August 24, 2004;
accepted after revision October 22, 2004.
Address correspondence to E. M. Remer
(remere1{at}ccf.org).
Abstract
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MATERIALS AND METHODS. The records from 335 adrenalectomies performed at our institution from 1995 to 2002 were reviewed, and 71 pheochromocytomas were identified. Thirty-three patients had CT examinations performed at our institution that were available for retrospective review. From electronic and hard-copy medical records, patient age and sex, the indications for imaging, and biochemistry activity were recorded. Pheochromocytomas were classified as symptomatic or incidental on the basis of clinical presentation. These groups were compared for differences in patient age, adrenal mass volume and maximal diameter based on CT dimensions, attenuation on unenhanced CT, attenuation on enhanced CT during the portal phase, the presence of calcifications, low attenuation or cystic changes, biochemical activity, and hypertension. Statistical significance was assessed with the Student's t test or chi-square test, as appropriate.
RESULTS. Nineteen incidental (57.6%) and 14 symptomatic (42.4%) adrenal pheochromocytomas were in the study. There was a significant difference between the two groups as to whether hypertension was present (incidental, 10/19 [52.6%]; symptomatic, 14/14 [100%]; p = 0.0025). We found a trend toward calcification present in more symptomatic patients (incidental, 0/19 [0%]; symptomatic, 4/14 [28.6%]; p = 0.0670). No statistically significant difference was noted in the mean patient age (incidental, 51.7 years; symptomatic, 45.9 years), mean volume of the mass (incidental, 74.0 cm3; symptomatic, 78.2 cm3), mean maximal diameter of the mass (incidental, 5.26 cm; symptomatic, 5.33 cm), mean attenuation on unenhanced CT (incidental, 36.6 H; symptomatic, 34.2 H), mean attenuation on enhanced CT (incidental, 93.7 H; symptomatic, 104.3 H), necrosis score or biochemical activity (incidental, 17/18 [94.4%]; symptomatic, 12/14 [85.7%]). No attenuation value of any pheochromocytoma was less than 10 H on unenhanced CT (median, 35 H; range, 17-59 H).
CONCLUSION. In our study population, 57.6% of the pheochromocytomas were incidental, more than in most reported series. A history of hypertension was more frequent in the symptomatic group (p = 0.0025), but no radiologic parameters that allow differentiation of incidental and symptomatic pheochromocytomas were found. None of the pheochromocytomas had attenuation values of less than 10 H on unenhanced CT scans.
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Virtually any adrenal neoplasm, whether later discovered to be hypersecreting or not, can be clinically silent and incidentally detected with thin-section CT [2]. Adrenal adenomas are the most common adrenal tumors [3] and the most common incidentally discovered masses. Although considered less often in the differential diagnosis of an incidentally discovered adrenal mass, pheochromocytomas have been reported to be asymptomatic in 10-17% of patients in prior clinical studies [4] and in up to 76% in an autopsy series [5]. One study suggested that clinical signs and findings in pheochromocytomas that are incidentally discovered are less robust than in those with symptoms but that most incidental tumors show biochemical activity [6].
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CT examinations were performed on a Somatom Plus 4, Plus 4 Volume Zoom, or Sensation 16 scanner (Siemens Medical Solutions) with a 2.5-, 3- or 5- mm collimation, 2.5- to 3-mm slice interval, and 2.5- or 5-mm slice thickness. In the incidental group, 17 masses were scanned without and with contrast material: 11 with a thin-section presurgical protocol and six with unenhanced CT (3- to 5-mm scans) followed by portal venous phase CT (5-mm scans). Only two were scanned without contrast material administration. In the symptomatic group, 13 masses were scanned without and with contrast material: seven with pre- and postcontrast 5-mm standard abdomen CT protocol and six with preoperative planning protocol, including unenhanced, vascular, and parenchymal postcontrast scans. One mass was scanned with a dedicated unenhanced adrenal CT protocol that included 2.5-mm slice thickness.
Patients received 150 mL of IV iodinated contrast material (300 mg I/mL Ultravist [iopromide], Berlex). Contrast material was administered at a rate of 2-4 mL/sec. No reactions to contrast material were recorded.
The two groups were compared for differences in patient age, biochemical activity, and hypertension; this information was obtained from the medical records. In the incidental group, a urinary catecholamine value was available in three patients, urinary and plasma catecholamine values were available in eight patients, and only a reference in the chart to positive catecholamines was available in the remaining eight patients. In the symptomatic group, a urinary catecholamine value was available in one patient, a plasma catecholamine value was available in one patient, and both values were available in five patients. For six of the seven remaining patients in the symptomatic group, only a reference in the chart to positive catecholamines was available. In one patient, no biochemical information was available.
One reviewer retrospectively evaluated CT examinations and recorded the volume of the mass, the attenuation of the mass on unenhanced CT, the attenuation of the mass on portal phase enhanced CT, the presence of calcifications, the presence of focal areas of low attenuation or cystic (water attenuation) changes, and homogeneity. The volume of each mass was determined by the following formula for volume of a prolate ellipsoid: [maximal axial CT diameter x perpendicular diameter x craniocaudal diameter from multiplanar reformation x 0.5236]. A circular region of interest (ROI) was used to measure CT attenuation values in Hounsfield units. The ROIs in the center of each adrenal mass were two thirds of the size of each lesion to ensure easy reproducibility [7]. Regions of calcification, cystic change, and necrosis were excluded from the ROIs.
Necrosis was defined as a focal round or confluent region of low attenuation compared with the remainder of the mass on unenhanced studies or an area of lower attenuation than the remainder of the mass on enhanced studies. A separate ROI of necrotic regions, when present, was obtained. The amount of necrosis was scored as 0 (none), 1 (1-25%), 2 (26-50%), 3 (51-75%), or 4 (76-100%) by two reviewers individually. Any differences were resolved by consensus. Cystic changes were identified as regions of water attenuation within the mass. Cystic or necrotic changes were excluded from ROI measurements.
A Student's t test was used to evaluate statistical significance when comparing means, and a chi-square test was used to evaluate percentages.
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There was a significant difference in the presence of a history of hypertension (incidental, 10/19 [52.6%]; symptomatic, 14/14 [100%]; p = 0.0025, chi-square test). A trend toward a higher prevalence of calcification in symptomatic patients was also noted (incidental, 0/19 [0%]; symptomatic, 4/14 [28.6%]; p = 0.0670, chi-square test) (Figs. 3A, and 3B).
No statistically significant difference between the incidental and symptomatic groups was detected in mean patient age, patient sex, side of tumor, mean attenuation on unenhanced CT, mean attenuation on enhanced CT, mean volume of the mass, mean maximal diameter of the mass, or the presence of biochemical activity (Table 1). In addition, there was no significant difference in the necrosis score (Table 2). Biochemical data were unavailable for one symptomatic patient.
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No attenuation value of any pheochromocytoma was less than 10 H on unenhanced CT (median, 35 H; range, 17-59 H). None of the necrotic regions in masses with more than 50% necrosis (necrosis scores 3 and 4) measured less than 0 H.
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Most studies have reported that the majority of patients with pheochromocytoma present with clinical symptoms of adrenal medullary hyperfunction and up to 11% are discovered incidentally [8-14]. However, nearly 58% of the adrenal pheochromocytomas in this series were incidental. This percentage is similar to those reported in several recent series, but it is higher than the most commonly quoted series that reported that approximately 11% of pheochromocytomas are incidental. Two series performed in Japan reported incidental masses in 23% and 59% of pheochromocytomas [6, 15], a recent series of patients who underwent laparoscopic adrenalectomy in the United States [16] reported 44% incidental pheochromocytomas, and one from Europe reported 48.4% incidental discovery [17]. One explanation for the discrepancy between the commonly quoted 11% incidental rate and these four recently reported series is that an increasing number of all types of adrenal masses are now being discovered incidentally because of the common use of CT to evaluate abdominal symptoms and diseases. Because pheochromocytomas are elusive clinically [18], the prevalence of an incidental tumor in any series would relate in part to how attuned the physician ordering the imaging study was to the symptoms of pheochromocytoma. One could argue that the ordering physicians were not attuned to the symptoms of the patients in this series. However, considering the indications for the CT examinations in our study group, which included pancreatitis, diverticulitis, pelvic pain, ulcerative colitis, or abdominal aortic aneurysm, it seems likely that incidental pheochromocytomas in this series were merely discovered during an evaluation of unrelated problems. It is possible that the ordering clinicians could have been more attentive to the possibility of pheochromocytoma. However, considering that these patients were scanned in a tertiary care medical center, it is more likely that the prevalence of incidental tumors represents "real-life" medicine in the era of common CT use.
We found no statistically significant size difference (maximal diameter or volume) between incidental and symptomatic masses. This result is similar to that of an autopsy series of 54 pheochromocytomas that found no size difference between pheochromocytomas diagnosed before death and those detected after death [4]. It is, however, in contradistinction to a study comparing 10 incidental and seven symptomatic tumors in which the mean diameter of the incidental pheochromocytomas was greater than that of the symptomatic ones [6]. The size difference was attributed to secreted catecholamines being metabolized within large tumors [19]. Smaller tumors, in contrast, have slower turnover rates and release free catecholamines into the circulation that lead to hyperadrenergic symptoms [20].
The median size of pheochromocytomas in this series was 4.25 cm. This value suggests that on the basis of size alone a pheochromocytoma would not be mistaken for an adenoma in many cases. However, the pheochromocytomas ranged from 2.6 to 11.2 cm and five of 14 in this series measured less than 3.5 cm in the longest diameter. Radiologists should be cognizant that it is the standard of practice to determine the functional status of an adrenal mass, including screening for pheochromocytoma and hypercortisolism [21].
In this series, there were no statistically significant differences between the groups in the age of the patients, attenuation of the mass on unenhanced CT, attenuation of the mass on enhanced portal phase CT, percentage of masses with calcification, percentage of masses with cystic or necrotic components, or the presence of biochemical activity. Pheochromocytomas associated with clinical symptoms cannot be differentiated on CT from those that do not produce symptoms.
No attenuation value of any pheochromocytoma in this series was less than 10 H on unenhanced CT (median, 35 H; range, 17-59 H). This information has important implications in day-to-day practice. These findings suggest that incidental pheochromocytomas will not be misdiagnosed as adenomas using unenhanced CT densitometry. These results confirm the findings in six pheochromocytomas reported by Szolar and Kammerhuber [22] in which unenhanced attenuation ranged from 35 to 43 H. They differ, however, from those of Blake et al. [23]. Those researchers found that two of nine lesions had an attenuation value of less than 10 H on unenhanced CT and thus mimicked adenomas. The two lesions consisted of one pheochromocytoma and one case of adrenal medullary hyperplasia that contained intracytoplasmic lipid on histopathology. Intracytoplasmic lipid previously has been shown to account for the low attenuation of adenomas on unenhanced CT [3]. The frequency with which pheochromocytoma can be expected to measure less than 10 H likely relates to the frequency of intracytoplasmic lipid and its amount.
The finding that the attenuation of pheochromocytoma may measure in the range that is typically diagnostic of adenoma should further reinforce the importance of obtaining biochemistry results on any adrenal mass. Because Blake et al. reported the first pheochromocytoma measuring less than 10 H on unenhanced scans and the technique has been in use for more than 13 years [7], the frequency is expected to be very low.
In the six masses reported by Szolar and Kammerhuber [22], the washout characteristics of pheochromocytomas also differed from those of adenomas. However, Blake et al. [23] showed that the two lesions that measured less than 10 H also had the washout characteristics of adenomas. We did not have washout values available for most of our patients because imaging either was performed before we routinely instituted adrenal washout studies at our hospital or was done for preoperative surgical planning. Further information on the washout characteristics of pheochromocytomas is needed.
The prevalence of necrotic changes in this series is high. It has been suggested that larger lesions may be heterogeneous because of tissue necrosis or internal hemorrhage [3]. However, most of the masses in this series had areas of decreased attenuation and heterogeneity regardless of size. These features should not be used to discriminate pheochromocytoma from other lesions because large degenerated adrenal adenomas, adrenal cortical carcinomas, and metastases also can have these features [24].
There was a statistically significant difference between these two groups in the percentage of patients with hypertension. Ten (52.6%) of the 19 patients with incidental masses and 14 (100%) of the 14 patients with symptomatic masses had a history of hypertension. This difference is more pronounced than that reported in a series performed in Japan in which six (60%) of 10 incidental and five (71%) of seven symptomatic masses were found in patients with hypertension [6], but it is similar to the results from an autopsy series in which 11 (85%) of 13 cases diagnosed before death and 22 (54%) of 41 cases diagnosed after death were in patients who had hypertension.
Our study has several limitations. First, it was performed retrospectively. Second, the study suffers from verification bias. Verification bias occurs when a study population includes only patients with a verified disease status. In this study, only patients with pathologically proven pheochromocytoma were included from the population of patients from 1995 to 2002. This bias could have affected our results in several ways. There were adrenal masses identified on CT during that timeframe of the study that had no additional workup and, therefore, no pathologic results available. Some percentage of those masses can be presumed to have been pheochromocytomas that were not clinically apparent. Hence, this study may underestimate the true prevalence of incidental pheochromocytoma. Another way that verification bias could have affected our findings relates to whether the imaging characteristics in the group of pheochromocytomas that never reached a pathologic diagnosis may differ from those with pathologic proof. For instance, the undiagnosed pheochromocytomas are likely to have been smaller than the ones included in this study, because the size of an adrenal mass is a factor in the decision to perform adrenalectomy. Third, if masses were incorrectly categorized as incidental or symptomatic, the prevalence information would be inaccurate. A detailed review of the electronic and hardcopy medical records was performed, but the information may have been incomplete. A fourth limitation is that CT examinations were available for retrospective review in only 33 of the 71 patients who had adrenalectomy for pheochromocytoma during the time period of the study. Fifth, adrenal contrast washout information was not available in enough cases to include it in the analysis. Sixth, biochemical data were inconsistently available. Specifically, serum metanephrine levels, now thought to be a key and the most sensitive biochemical indicator of pheochromocytoma, were available in only a few patients.
In conclusion, incidental pheochromocytomas may occur more frequently than previously thought, occurring in 57.6% of patients in this series. This may relate to the widespread use of cross-sectional imaging, analogous to the increasing detection rate of small renal cell carcinomas. The relative frequency of incidental pheochromocytoma underscores the importance of a biochemical workup in patients with incidentally discovered adrenal masses. None of the pheochromocytomas in this series had attenuation values of less than 10 H on unenhanced CT. More of the symptomatic patients had a history of hypertension (100%) than those with incidental masses (52.6%); however, no imaging feature was significantly different between the two groups.
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