Contrast enhancement in bladder tumors examined with CT urography using traditional scan phases

Abstract

Background

Bladder assessment in an early contrast-enhancing computed tomography urography (CTU) phase requires that bladder tumors be enhanced using contrast material.

Purpose

To investigate the enhancement pattern in bladder tumors using a CTU protocol where the scan is enhancement triggered.

Material and Methods

Fifty patients diagnosed with bladder cancer were examined during the unenhanced (UP), corticomedullary (CMP), and excretory phases (EP). Twenty-one patients, all aged 50 years or older, were also examined during the nephrographic phase (NP). A ROI placed in the aorta was used to start the scan during the CMP when the attenuation reached 200 Hounsfield units (HU). The NP and EP were started with a 40 s and 300 s delay, respectively, after the CMP was finished. Attenuation and size measurements were made in the axial plane.

Results

Mean contrast enhancement of bladder tumors was 37, 25, and 17 HU in the CMP, NP, and EP, respectively. The differences in contrast enhancement were significant across all three phases. Eighty-eight percent of patients showed the highest contrast enhancement in the CMP. In 96% of the cases, contrast enhancement >20 HU was seen. The mean value of the shortest dimension of the bladder tumors was 22 ± 12 mm.

Conclusion

The contrast enhancement is significantly higher in the CMP than in the NP and EP, suggesting that the CMP is preferable when assessing the bladder in the early contrast enhancing phase.

Keywords

CT neoplasms bladder tissue characterization

Introduction

Gross hematuria is a serious symptom, and the cause has been reported to be bladder tumor in up to approximately 20% (1 –3).

Routine work-up of patients presenting with gross hematuria usually involves computed tomography urography (CTU) and cystoscopy. Excretory urography used to be the primary imaging method in patients with gross hematuria, and because the sensitivity in detecting bladder cancer using excretory urography was low, all patients had to undergo a cystoscopy. Performing cystoscopy on all patients has remained routine. However, recent studies have suggested that CT can also be used to evaluate the bladder (4 –9).

The most common phase during which to evaluate the bladder is the excretory phase. In order to evaluate the bladder in the excretory phase, the bladder must be well distended with urine homogeneously mixed with contrast material of adequate concentration. In the majority of patients, achieving this is complicated but not impossible (4,8,10). However, the examination may be inconvenient and time-consuming for patients.

We and others (11) have found that bladder tumors are often enhancing in early contrast phases, which contribute to bladder cancer detection. The advantages of examining the bladder in early contrast-enhancing phases are shorter examination times and less complicated procedures for the patient since the bladder evaluation is not dependent on bladder distension with urine homogeneously mixed with contrast material of adequate concentration in the excretory phase.

The purpose of the present study was to investigate the enhancement pattern in bladder tumors using a CTU protocol where the scan is enhancement triggered.

Material and Methods

The regional ethical review board in Uppsala approved the study. Written informed consent was obtained from all patients.

From October 2005 to November 2008, 563 consecutive adult patients referred for CTU due to silent non-traumatic gross hematuria were included in a prospective study.

Routine work-up of patients presenting with gross hematuria includes cystoscopy and CTU in our hospital. The routine CTU protocol when examining patients presenting with gross hematuria includes unenhanced phase (UP), corticomedullary phase (CMP), and excretory phase (EP) in patients aged <50 years. In patients aged 50 years or older the protocol includes UP, CMP, nephrographic phase (NP), and EP. The entire urinary tract is examined in all scan phases.

The patient records and histopathological diagnosis were reviewed. Eighty-three of the 563 patients were diagnosed with bladder cancer. Of these 83 patients, 33 were excluded from further evaluation: patients with a previous history of treated bladder cancer (n = 6), patients who had undergone a transurethral resection or a biopsy of the tumor prior to the CT examination (n = 17), patients with bladders not distended enough to evaluate (e.g. catheter in the bladder) or beam hardening artifacts in the pelvis caused by hip prosthesis (n = 6), patients with a CT examination that did not include the bladder in the unenhanced phase (n = 1), and patients with tumors not visible at the CT examination (n = 3). Fifty patients were included in the study, 37 men and 13 women; the mean age was 70 ± 14 years (range, 22–93 years).

All patients were examined in UP, CMP, and EP. Twenty-one patients aged 50 years or older were examined with the four-phase CTU protocol including NP.

The CT examinations were performed on two different CT scanners (Siemens Medical Solutions, Forchheim, Germany): Somatom Sensation 16 or Somatom Definition. A dose of 60–80 mL of iohexol 350 mgI/mL (Omnipaque, GE Healthcare AS, Oslo, Norway) was administered at a rate of 4 mL/s followed by 50 mL saline bolus administrated at the same injection rate using a power injector (Stellant D, Medrad Inc, Indianola, PA, USA). The CMP started automatically with a 5-s delay when the attenuation value in a region of interest (ROI) placed in the aorta at the level of the diaphragm reached 200 Hounsfield units (HU). This represents a delay of 25–45 s after the start of contrast material injection depending on the patients' cardiovascular function. The NP was performed with a 40 s delay and the EP with a 300 s delay after the CMP had been completed. The scan time of the CMP is approximately 10 s and, consequently, the NP was performed with a delay of 75–95 s and the EP with a delay of 335–355 s after the start of contrast material injection.

The scanning parameters were as follows: tube voltage, 120 kV; quality reference, 60, 120, 80, and 80 mAs, respectively, for the UP, CMP, NP, and EP; rotation time, 0.5 s; collimation, 16 × 0.75 mm (Sensation 16) and 64 × 0.6 mm (Definition); pitch, 1.0 mm (Sensation 16) and 0.9 mm (Definition). Image reconstruction with slice thickness and increment, axial 3/2.5 mm and coronal 5/5 mm. Automatic tube current modulation (CARE Dose 4D, Siemens Medical Solutions, Forchheim, Germany) was used, and the effective tube current time setting was the input parameter for the Care Dose 4D software; the actual delivered dose actually deviated slightly from this number.

In order to obtain adequate bladder distension, patients drank 500–1000 mL of water and were told not to void either 1 or 2 h prior to the examination depending on the preparation protocol used. During the study period, different preparation protocols were used (10).

Histopathology data existed on 49 of the 50 patients included. All tumors were urothelial cell carcinoma. In one case where no histopathology data had been collected, the hemorrhage from the tumor was too profound to perform a cystoscopy with biopsy and the tumor was diagnosed based on the CTU result. No surgery was performed on this patient.

A radiologist with 5 years of training in radiology, including 1 year of uroradiology, performed the CT enhancement measurements. Attenuation was measured on the axial images using a circular ROI as large as possible in the center of the tumor to avoid falsely low attenuation values. The ROI was equally placed in all phases (Fig. 1). If the tumor was not visible in a phase, the ROI was placed using images from a phase where the tumor was visible. Tumor size was measured in the CMP (Fig. 2) on axial reconstructions. In case of multifocal bladder tumors, the attenuation and size measurements were made on the largest lesion.

Fig. 1.

Attenuation measurement in axial reconstructions in all phases: (a) unenhanced phase, (b) corticomedullary phase, (c) nephrographic phase, and (d) excretory phase.

Fig. 2.

Size measurement in the corticomedullary phase in axial reconstruction.

Statistical analysis

Comparisons of contrast enhancement across the various phases were performed using paired Student's t-tests. A P value of 0.05 was considered significant. All analyses were performed using R software version 2.15.2 (12).

Results

Tumor size

The mean value of the shortest dimension of the bladder tumors in the axial reconstruction was 22 ± 12 mm (range, 5–56 mm).

Tumor attenuation

Ninety-six percent of the tumors showed an enhancement of 20 HU or more. The enhancement pattern for all patients is presented in Fig. 3. The mean ± standard deviation (range) attenuation measurements are presented in Table 1.

Fig. 3.

Enhancement pattern in all patients. Mean values in bold. Enhancement in HU on the y-axis in CMP, NP, and EP, respectively, on the x-axis.

Table 1.

The attenuation in HU and the enhancement in HU.

Phase	Unenhanced Mean ± SD (range)	Corticomedullary Mean ± SD (range)	Nephrographic Mean ± SD (range)	Excretory Mean ± SD (range)
Attenuation	40 ± 8 (15–58)	77 ± 14 (45–110)	64 ± 8 (53–80)	57 ± 11 (25–86)
Enhancement	–	37 ± 13 (15–75)	25 ± 8 (10–40)	17 ± 9 (0–45)

The enhancement was calculated as the attenuation in HU in the corticomedullary phase, nephrographic phase, and the excretory phase, respectively, minus the attenuation in HU in the excretory phase.

The mean difference (95% confidence interval) in contrast enhancement between the CMP and the NP was 11.2 HU (6.25–16.2 HU); the mean difference between the CMP and the EP was 20.4 HU (16.0–24.8 HU); the mean difference between the NP and the EP was 8.4 HU (4.81–11.9 HU). The differences in the contrast enhancement were significant across all three phases with a P value <0.001.

In 44 of the 50 patients (88%) with detectable bladder tumors, the highest contrast enhancement was seen in the CMP. In three patients (6%), equal enhancement was seen in the CMP and EP, and in another three patients (6%), the highest contrast enhancement was seen in the EP.

Among the 21 patients undergoing the four-phase protocol, the highest contrast enhancement was seen in the CMP in 17 patients (81%). In three patients (14%), enhancement was equal in the CMP and NP, and in one of these patients, enhancement remained constant also in the EP. In one patient (5%), the highest contrast enhancement was seen in the EP, followed by the CMP and then the NP, where contrast enhancement was the lowest.

Enhancement distribution in the CMP, NP and EP, respectively, is presented in Fig. 4.

Fig. 4.

Enhancement distribution in the CMP, NP, and EP, respectively.

Discussion

Bladder tumor is the most commonly detected tumor in patients presenting with gross hematuria (1 –3). During the last decade efforts have been made to reduce CTU radiation dose and as a result, split-bolus protocols have been introduced or one of the traditional CTU phases has been excluded from the CTU protocol. The most common phase that has been excluded is the CMP. The decision to exclude the CMP is often based on studies from the 1990s (13 –16). For instance, Szolar et al. (16) reported that a larger number of small (<3 cm) renal masses was detected in the NP than in the CMP. However, their study only analyzed renal lesions, and the most common lesion missed in the CMP was medullary cysts, which have no clinical impact. Sheth et al. (17) stated that the NP is the most valuable for detecting renal masses and characterizing indeterminate lesions, referring to the studies made in the 1990s. But Sheth also concludes that the CMP is essential for accurate staging of renal cell carcinoma, evaluation of vessel anatomy and possible tumor extension in the renal vein, planning of surgery and metastasis evaluation. Renal tumors are often 4 cm or larger when they present with gross hematuria (18) and very rarely present with gross hematuria when 3 cm or smaller. Urothelial cell carcinomas can, however, present with gross hematuria while still small. Recent studies have shown that CTU plays a central role in bladder cancer detection since patients with bladder tumors detected with CTU can be directly referred for a rigid cystoscopy and simultaneous resection with reduction of delay to diagnosis and treatment as a result. In addition, the number of flexible cystoscopy examinations can also be reduced (8). Hence, it is of importance that the CTU protocol is designed for detecting urothelial tumors when examining patients presenting with gross hematuria. Small renal tumors are often detected incidentally (19,20) when the patient is undergoing a radiology examination of the abdomen for other reasons. Based on these findings, in our department the NP has been excluded in patients aged <50 years and the CMP has been used as the routine contrast-enhanced phase in CTU for >10 years (21).

In the studies from the 1990s, no consideration was given to bladder analysis. Since the mid-1990s, the CT technique has evolved rapidly, including fast multidetector scanners and multiplanar reconstructions that help to sharpen diagnostics.

The present study shows that the majority of bladder tumors contrast enhance and that contrast enhancement is preferably seen in the CMP.

Kim et al. (11) reported that 85% of bladder cancers enhanced maximally on the scans with a 60-s delay. Their enhancement study was based on 20 patients with bladder tumors measuring >1.5 cm in the short diameter, as diagnosed with cystoscopy prior to the CT examination. The CT scans were performed only covering the bladder tumors with fixed 40, 60, 80, and 100 s delay after contrast injection. In their study, the injection rate was 4 mL/s. The amount of contrast material varied, however, and there was no information about the concentration of the contrast material used. Hence, the contrast enhancement peak can be assumed to vary (22) considering variation in both patients' cardiovascular function and the amount of contrast material used. The scan delay of the CMP in our CTU protocol was individually adjusted to the patient's cardiovascular function. The CMP in our study started with a delay of 25–45 s and the bladder was examined almost 10 s later since the scan is performed in craniocaudal direction. This means that the bladder is examined with a delay of approximately 35–55 s. Because most patients are elderly (mean age, 70 years), they are probably examined with a delay close to 55 s since cardiovascular function usually decreases with age.

Attenuation measurements were made on the 3-mm axial reconstructions. Some tumors were small, the smallest only 5 mm in the shortest dimension. Despite the effort made to place the ROI in the center of the tumor to avoid false attenuation values, a partial volume effect in especially small tumors can result in falsely low attenuation values from the surrounding non-enhanced urine in the CMP and NP and falsely high attenuation values from the contrast material in the urine in the EP. The shortest dimension is used when reporting tumor size, as this dimension must be considered to affect the attenuation values the most. Thus, attenuation values in the CMP and NP may actually be somewhat higher and attenuation values in the EP may actually be somewhat lower. The possible falsely lower attenuation value in the CMP and NP must be assumed to be equal in both phases and the attenuation and enhancement difference between the phases unchanged.

The majority of bladder tumors had the highest contrast enhancement in the CMP. However, in some tumors enhancement was greater in the EP (n = 3) than in the CMP. These tumors were smaller than average (8–11 mm along the short axis). In one tumor, enhancement was highest in the EP, followed by the CMP, and the lowest contrast enhancement was seen in the NP. The size of this tumor was 8 mm along the short axis. The attenuation measurement in the EP, with high contrast concentration in the urine surrounding the tumor and some image noise caused by the relatively low radiation dose, may be uncertain in small lesions. Furthermore, if the tumor is lobulated, high contrast concentrated urine may intervene between the lobules and the attenuation measurement in the tumor may consequently be falsely high.

One drawback of the present study is the low number of patients examined in the NP, only 21/48 patients aged 50 years or older with bladder tumor underwent the four-phase protocol. The reason for this is uncertain. The protocol including the UP, CMP, and EP is preselected in the CT scanner to avoid patients aged <50 years being examined with the four-phase protocol. It is not mentioned in the referral which protocol the patient should undergo; the routines dictate that patients aged <50 years undergo the three-phase protocol and patients aged 50 years or more undergo the four-phase protocol. In patients aged 50 years or more, the CTU protocol must be actively changed. If a new nurse or a student as this is a teaching hospital, not familiar with the protocols, is performing the examination, this may be missed. Changing the protocol may also be missed for other reasons, lack of time being one of them.

Patients who had undergone a TUR-B or a biopsy prior the CT examination were excluded, as it is impossible to differentiate the contrast enhancement in bladder tumors from the contrast enhancement in the inflammatory tissue post treatment. Also patients with a previous history of treated bladder cancer were excluded, as the treatment consisting of BCG and chemotherapy installations, radiation treatment, partial resection of the bladder, and multiple TUR-B can be presumed to affect the bladder and alter the enhancement pattern. Furthermore, these patients are always subject to cystoscopy despite CT findings. Three tumors were not detectable on CT and excluded from the study. One was carcinoma in situ, and this patient also had a tumor in the distal ureter. It is questionable whether the carcinoma in situ in the bladder caused the gross hematuria. It is more likely that the gross hematuria was caused by the tumor in the distal ureter. One tumor was not detected with initial cystoscopy or CTU, cytology revealed malignant cells and the tumor was later detected at the second cystoscopy. The third patient had a small tumor that was reported to measure 3 mm at cystoscopy.

The mean size of bladder tumors in this study is relatively large (22 mm) and the smallest tumor detected was 5 mm in shortest dimension. It is possible that the excluded patients had smaller tumors than the patients included in this study, resulting in a falsely large mean bladder tumor size.

Attenuation values and enhancement varied relatively greatly (Table 1) both before and after contrast injection. Because the tumor type was the same (urothelial cell carcinoma) in all patients with histopathology data (49/50), the variation in attenuation and enhancement cannot be explained by differences in tumor type. The attenuation and enhancement variation can be assumed to come from variation in vascularization of the tumors, as bladder tumors are known to vary in vascularization (23).

Only one patient did not have histopathology data, as profound hemorrhage from the tumor made cystoscopy with biopsy impossible. The maximum size of the tumor was >6 cm measured in both axial and coronal planes on CT. Both urologists and oncologists accepted the diagnosis without histopathological data. The patient was included in the study because the diagnosis was considered clear.

In conclusion, this study shows that bladder tumors do enhance, and contrast enhancement is significantly higher in the CMP than in the NP and EP when the scan is enhancement triggered, suggesting that the CMP is preferable when assessing the bladder in the early contrast-enhancing phase.

Footnotes

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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