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1
Department of Radiology-H66, The Cleveland Clinic Foundation, 9500 Euclid
Ave., Cleveland, OH 44195.
2
Present address: Department of Radiology, Weill Hospital, Cornell University
Medical Center, 525 E. 68th St., New York, NY 10021.
3
Urological Institute, The Cleveland Clinic Foundation, Cleveland, OH
44195.
4
Department of Biostatistics, The Cleveland Clinic Foundation, Cleveland, OH
44195.
Received June 29, 2001;
accepted after revision August 23, 2001.
Address correspondence to B. R. Herts.
Abstract
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MATERIALS AND METHODS. We reviewed the CT scans of 90 consecutive patients with renal masses who had undergone triphasic renal helical CT before a complete or partial nephrectomy (12 with papillary renal cell carcinomas, 66 with nonpapillary renal cell carcinomas, and 12 with benign lesions). Three radiologists who were unaware of the patients' diagnoses retrospectively and independently measured the attenuation of each patient's tumor, abdominal aorta, and normal renal parenchyma on the scans obtained during all three phases. Ratios of tumor-to-aorta enhancement and tumor-to-normal renal parenchyma enhancement were calculated for both of the phases performed after contrast material had been administered. Tumor heterogeneity was calculated as the difference between the highest and lowest attenuation values divided by the value of the enhancement of the aorta. Values were correlated with cell type and nuclear grade found at surgical pathology.
RESULTS. Low tumor-to-aorta enhancement and low tumor-to-normal renal parenchyma enhancement ratios on the vascular phase scans significantly correlated (p < 0.001) with papillary renal cell type carcinoma. Homogeneity and tumor-to-parenchyma enhancement ratios on the parenchymal phase scans also significantly correlated (p < 0.001) with papillary renal cell type carcinoma. Heterogeneity and tumor enhancement ratios did not correlate with the nuclear grade of the carcinoma.
CONCLUSION. Papillary renal cell carcinomas are typically
hypovascular and homogeneous. A high tumor-to-parenchyma enhancement ratio
(
25%) essentially excludes the possibility of a tumor being papillary
renal cell carcinoma. A low tumor-to-aorta enhancement ratio or
tumor-to-normal renal parenchyma enhancement ratio is more likely to indicate
papillary renal cell carcinoma.
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Ct remains the standard modality to use in diagnosing and staging renal neoplasms, and the widespread use of CT for abdominal imaging has led to earlier discovery of many small renal neoplasms [8,9,10,11,12]. In 1984, Press et al. [13] reported that papillary renal cell carcinoma should be suspected in patients with renal lesions that have soft-tissue attenuation, central calcifications, no or poor contrast enhancement, and low clinical stage at the time of disease presentation. Papillary renal cell carcinomas also tend to be hypovascular on CT and angiography [4, 14,15,16], but other studies have failed to establish a reliable association between morphology and appearance of renal neoplasms on CT and renal carcinoma cell subtype [9, 16,17,18]. Size is the most reliable factor that correlates with nuclear grade [19]. Because our institution and many others now routinely perform triphasic helical CT of the kidneys for diagnosis and staging, we sought to determine whether the degree of tumor enhancement or heterogeneity on triphasic helical CT scans of the kidneys could be used to predict papillary cell subtype or nuclear grade.
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The group studied was composed of 52 men and 37 women whose ages ranged from 29 to 80 years. The mean and median ages of the patients were 60.7 years and 62.3 years, respectively. At final pathology, findings for the group were oncocytoma (n = 9), benign complex renal cyst (n = 2), angiomyolipoma without fat attenuation on CT (n = 1), and renal cell carcinoma (n = 77). The subtypes of renal cell carcinoma subtypes were clear cell carcinoma (n = 52), papillary carcinoma (n = 12), and undifferentiated or unspecified cell type (n = 13).
CT Protocol
Triphasic renal helical CT was performed on a Somatom Plus 4 scanner
(Siemens Medical Systems, Forchheim, Germany) at 120 kVp and revolution time
of 0.75 sec. No oral contrast material was administered. First, unenhanced CT
of the kidneys was performed using a 5-mm collimation and a pitch of 1 (table
speed of 5 mm per revolution) at 200-240 mA, depending on body habitus of the
patient and the discretion of the technologist. The unenhanced CT scans
localized the kidneys, allowing us to obtain baseline tumor attenuation
measurements and to detect calcifications.
Next, a test bolus of 20 mL injected at 4 mL/sec was used to calculate the delay time for the vascular (corticomedullary) phase. Nonionic contrast media (iopromide, Ultravist 300; Berlex, Wayne, NJ)) was used for all scans. A single CT slice was performed in the patient's upper abdominal aorta, and images were obtained every second beginning at 10 sec for period of 40 sec. A region of interest was placed over the aorta, and the time to peak enhancement was calculated. The delay time for the vascular phase was the time to peak aortic enhancement plus an additional 5 sec to allow venous opacification.
We waited 2 min after the test injection before beginning the contrast medium injection for the vascular phase to permit filling of the collecting system. The vascular phase scan was then obtained using the delay time (calculated as previously described) after the initiation of the contrast medium injection. One hundred twenty mL of contrast medium was injected at 4 mL/sec. This scan was obtained using 3-mm collimation and a pitch of 1.0-1.7 (table speed of 3-5 mm per revolution) at 240 mA. Thinner collimation was used for the vascular phase than for the parenchymal and unenhanced phases to improve visualization of small renal vessels. Finally, a nephrographic (or parenchymal) phase scan was obtained using a 140-sec delay time from the initiation of the bolus contrast injection. The parenchymal phase scan was obtained at 5-mm collimation and a pitch of 1.0 (table speed of 5 mm per revolution) using the same techniques as used for the unenhanced scan to allow accurate characterization of all masses. All scans were reconstructed with a 50% image overlap and were reviewed on a picture archiving and communication system workstation (Magic View 1000; Siemens Medical Systems).
Determination of Tumor Enhancement and Heterogeneity
Three radiologists who were unaware of the patients' diagnoses
independently and retrospectively measured a region of interest of the highest
and lowest attenuation in each renal mass (as perceived by the individual
interpreter) on scans obtained during all three phases—unenhanced (NC),
vascular phase (VP), and parenchymal phase (PP). The interpreters also
measured the attenuation of the abdominal aorta and normal renal parenchyma on
scans obtained during all phases (Figs.
1A,1B,1C,2A,2B,2C,3A,3B,3C).
The observers were instructed to exclude calcifications, maximize the regions
of interest, and keep the sizes and locations of the regions of interest the
same for each patient's images from the three scanning phases. The reviewing
radiologists received no training session and no other instructions.
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Definition of Tumor Enhancement Ratios
Four different measures of tumor enhancement were calculated, two for each
post—contrast injection phase: the ratio of the tumor enhancement to the
aorta enhancement and the ratio of the tumor enhancement to normal renal
parenchyma enhancement. The highest observer-perceived attentuation value in a
region of interest was used for the tumor in all three scanning phases. The
equations used were as follows: the tumor-to-aorta enhancement ratio during
the vascular phase (equation 1) was calculated as [tumor (VP) — tumor
(NC)] / [aorta (VP) — aorta (NC)]; the tumor-toaorta enhancement ratio
during the parenchymal phase (equation 2) was calculated as [tumor (PP)
— tumor (NC)] / [aorta (PP) — aorta (NC)]; the tumor-to-kidney
enhancement ratio during the vascular phase (equation 3) was calculated as
[tumor (VP) — tumor (NC)] / [kidney (VP) — kidney (NC)]; and the
tumor-to-kidney enhancement ratio during parenchymal phase (equation 4) was
calculated as [tumor (PP) — tumor (NC)] / [kidney (PP) — kidney
(NC)].
Definition of Tumor Heterogeneity Ratios
Tumor homogeneity was calculated as the difference between the highest and
lowest attenuation values for the tumor divided by the enhancement of the
aorta for each post—contrast injection phase. The equations used were as
follows: The heterogeneity ratio during vascular phase (equation 5) was
calculated as [tumor's highest density (VP) — tumor's lowest density
(VP)] / [aorta (VP) — aorta (NC)] and the heterogeneity ratio during the
parenchymal phase (equation 6) was calculated as [tumor's highest density (PP)
— tumor's lowest density (PP)] / [aorta (PP) — aorta (NC)].
Statistical Methods
Logistic regression models using generalized estimating equations (SAS; SAS
Institute, Cary, NC) were fit so that the relationships between the
enhancement and heterogeneity variables and the probability of a papillary
lesion could be assessed. Methods for clustered binary data
[20] were used to estimate and
construct pointwise 95% confidence intervals for sensitivity, specificity,
positive predictive value, and negative predictive value for various values
for the variables.
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Correlation of Heterogeneity with Papillary Renal Cell Carcinoma
In general, low heterogeneity ratios correlated with papillary renal cell
carcinoma, indicating that these are homogeneous tumors
(Table 1). A low heterogeneity
score on the vascular phase scan also significantly correlated with papillary
cell type (p < 0.001). Sensitivity and specificity of triphasic
helical CT for papillary renal cell carcinoma were 72% and 87%, respectively
if the tumor heterogeneity ratio in the vascular phase was less than 0.25
(Table 4). The heterogeneity
score did not significantly correlate with papillary renal cell carcinoma on
the nephrographic phase (p = 0.185).
Nuclear Grade
The tumor-to-aorta enhancement ratio in the vascular phase significantly
correlated with nuclear grade (Pearson correlation coefficient = -0.195,
p = 0.003), but the range of values was small (from 0.53 for grade 1
to 0.42 for grade 4) and not thought to be clinically useful. Tumor
heterogeneity was not predictive of nuclear grade (p = 0.27).
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Papillary renal cell carcinomas are typically low stage and low grade at presentation, and may be multifocal or bilateral [3, 4, 6]. In most studies, papillary renal cell carcinoma has been reported to be associated with a better prognosis than nonpapillary renal cell carcinomas, especially when compared with the prognosis for other renal tumors at the same stage [3,4,5, 7, 22]. Although the stage at presentation and nuclear grade remain the most important factors for the prognosis of renal cell carcinoma [1], it nevertheless is important to be able to identify or effectively exclude a papillary cell subtype preoperatively. Papillary renal cell carcinomas are frequently found at a low stage, making nephron-sparing surgery an appropriate treatment. In addition, the possibility of bilateral tumors makes nephron-sparing surgery preferable to nephrectomy, despite the possibility of synchronous or metachronous tumors in the same kidney [13, 23, 24].
Many CT features of renal cell carcinomas have previously been evaluated in an attempt to predict stage, cell type, and nuclear grade. Enhancement, lack of tumor margins, and necrosis all have been found to correlate with increasing tumor size [18]. Increasing size and lack of sharp tumor margins have both been found to correlate with higher nuclear grade [19, 25]. High attenuation in tumors on CT has also been shown to correlate with clear cell carcinomas [26].
Papillary renal cell carcinomas are hypovascular on CT and angiography [4, 14,15,16]. Although calcifications and hypovascularity are frequently seen CT features of papillary renal tumors, most CT features have not been shown to be reliable predictors of the renal cell carcinoma subtypes [17, 18]. Furthermore, percutaneous needle aspiration is unreliable for determining nuclear grade and is generally inaccurate for distinguishing the papillary subtype of renal cell carcinoma [27, 28] from other subtypes.
In this study, we sought to determine whether we could reliably predict papillary renal cell carcinomas on the basis of enhancement characteristics. We sought to identify a numeric value that would be simple to use and have a high positive or negative predictive value. This value should be normalized relative to the contrast material bolus to ensure that it is independent of the variability frequently seen when evaluating the enhancement of small renal lesions [29]. Therefore, we used the enhancement values of the aorta and normal renal parenchyma as divisors to determine a relative enhancement ratio that might be more sensitive for and predictive of papillary renal cell carcinomas.
We found that three of the four enhancement ratios significantly correlated with papillary subtype and chose two ratios as the most clinically relevant—the enhancement ratio of the tumor to the aorta during the vascular phase and the enhancement ratio of the tumor to the normal renal parenchyma during the parenchymal phase. Tumor enhancement correlated most to the vascular concentration of contrast material on the bolus phase, and the enhancement of the tumor is compared with normal renal parenchyma on the scans obtained during the nephrographic phase when the normal kidney is concentrating the filtered contrast material. Triphasic renal helical CT studies have shown that the scans obtained during nephrographic phase remain the most sensitive for lesion identification and characterization [24, 30, 31]. Our results show that a low ratio of tumor-to-aorta enhancement during the vascular phase and enhancement of the tumor-to—normal renal parenchyma during the nephrographic phase have a high sensitivity, specificity, and negative predictive value for papillary renal cell carcinomas.
The best use for the results of our study is as a method of excluding the possibility that a lesion is a papillary renal cell carcinoma; the negative predictive value and specificity are high even in instances in which the positive predictive value is less than 50%. This result occurs because the prevalence of disease in this patient population (those with papillary renal cell carcinoma) is small (13%), and the findings of these hypovascular masses overlap with those of complex cysts or poorly enhancing nonpapillary tumors. We found that if the enhancement ratio of the tumor-to aorta or the tumor-to—renal parenchyma is more than 0.25, the likelihood that a lesion is a nonpapillary tumor is greater than 95% (negative predictive value).
If the enhancement ratio of the tumor-to aorta or the tumor-to—renal parenchyma is less than 0.25, the likelihood of the lesion being a papillary tumor is almost 50% (positive predictive value), a percentage more than three times higher than that would be expected from its incidence compared with other types of renal cell carcinomas in this study. We also found that papillary tumors are more often homogeneous than other renal cell carcinomas. This finding is compatible with the small size, low stage, and hypovascular nature of papillary renal cell carcinomas; it is consistent with previous reports [9, 13, 16, 18, 19] and is most likely a byproduct of the lack of vascularity.
Our study has several limitations. As Macari and Bosniak [32] correctly note, tumor enhancement is dependent upon the contrast bolus, among other factors, for delivery of the contrast medium to the tumor and to the normal kidney. Although we used ratios rather than absolute enhancement to attempt to correct for differences in each patient's body habitus and cardiac output in the contrast bolus, these results may not necessarily be applicable to lower flow rate injection techniques (i.e., 1-2 mL/sec). Possibly, our results are better than those reported in some previous studies because the combination of injecting the contrast medium at the high-flow rate of 4 mL/sec and more rapid scanning was not available until the introduction of helical CT. Higher levels of enhancement in the aorta and normal renal parenchyma might widen the gap between the papillary tumor and both the normal kidney and vascular tumors, increasing sensitivity, specificity, and negative predictive values as we found.
Another limitation of this study is that negative and positive predictive values are dependent on disease prevalence in the population. As a tertiary referral center for renal cell carcinoma and nephron-sparing surgery, we might see a larger share of patients with small, low-grade, or multiple tumors that could increase the prevalence of papillary tumors in our patient population. Other reports have estimated the prevalence of papillary renal cell carcinomas to be 5-15%. With a prevalence of 14% (excluding the renal cysts and angiomyolipoma), ours is at the high end of what is generally estimated [13].
A final limitation is that we only tested a limited number of enhancement ratios. We could potentially have had different results with different definitions of tumor enhancement that we did not test, such as more complex combinations of factors or different ratios. For example, in our study, the best way to discriminate papillary from nonpapillary lesions was to use a combination of all three variables reported in Tables 2,3,4. Using the same cutoff values of 0.25 for enhancement and 0.20 for heterogeneity, a papillary lesion was essentially excluded as a possible finding for patients who tested negative on all three ratios (a negative predictive value of 1). However, we sought to keep the calculations as simple as possible so that they could be used simply and easily.
We suggest using a tumor-to-aorta enhancement ratio in the vascular phase and a tumor-to-kidney enhancement ratio in the parenchymal phase of 0.25 as a good cutoff value for sensitivity, specificity, and negative predictive value. In general, a tumor-to-aorta ratio or a tumor-to-kidney ratio of less than 0.25 suggests a higher degree of likelihood of papillary renal cell carcinomas, and conversely, a ratio of more than 0.25 generally excludes the possibility of a papillary renal cell carcinoma. We also suggest using a heterogeneity ratio in the vascular phase of 0.20 as a cutoff value with similar implications.
In conclusion, papillary renal cell carcinoma is more often hypovascular and homogeneous on CT than other subtypes of renal tumors. The ratios we described can be used to predict an increased likelihood of the presence of papillary renal cell carcinoma or to exclude papillary renal cell carcinoma as a possible diagnosis. Such findings should be communicated to the referring urologist, especially if nephron-sparing surgery is an option.
Acknowledgments
We thank Jennifer Klauer for her assistance with manuscript
preparation.
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3 cm) renal masses: correlation of spiral CT features and
pathologic findings. AJR
1994;163:597
-605
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