Published online before print November 22, 2005, 10.1148/radiol.2381041765
(Radiology 2005;238:150-155.)
© RSNA, 2005
Delayed-Phase Dynamic CT Enhancement as a Prognostic Factor for Mass-forming Intrahepatic Cholangiocarcinoma1
Yoshiki Asayama, MD,
Kengo Yoshimitsu, MD,
Hiroyuki Irie, MD,
Tsuyoshi Tajima, MD,
Akihiro Nishie, MD,
Masakazu Hirakawa, MD,
Tomohiro Nakayama, MD,
Daisuke Kakihara, MD,
Akinobu Taketomi, MD,
Shin-ichi Aishima, MD and
Hiroshi Honda, MD
1 From the Departments of Clinical Radiology (Y.A., K.Y., H.I., T.T., A.N., M.H., T.N., D.K., H.H.), Surgery and Science (A.T.), and Anatomic Pathology (S.A.), Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. From the 2004 RSNA Annual Meeting. Received October 13, 2004; revision requested December 22; revision received January 27, 2005; accepted February 28; final version accepted March 18.
Address correspondence to Y.A. (e-mail: asayama{at}radiol.med.kyushu-u.ac.jp).
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ABSTRACT
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Purpose: To retrospectively determine whether the degree of contrast material enhancement at delayed-phase dynamic computed tomography (CT) for intrahepatic cholangiocarcinoma (ICC) is related to the patient's prognosis after surgery.
Materials and Methods: Neither institutional review board approval nor informed consent was required for this retrospective evaluation. Thirty-two patients (22 men, 10 women; mean age, 60.8 years; range, 33–80 years) with mass-forming ICC underwent dynamic CT. Delayed CT images obtained 4–6 minutes after the injection of contrast material were evaluated by two radiologists. Patients were classified in consensus into one of two groups: Group 1 included those in whom more than two-thirds of the tumor showed enhancement on delayed-phase scans. Group 2 included those in whom less than two-thirds of the tumor showed enhancement on delayed-phase scans. The imaging findings were correlated with pathologic findings. Survival curves were drawn by using the Kaplan-Meier method, and the differences between the groups were compared with the log-rank test. Multivariate analysis was performed to clarify prognostic factors.
Results: There were 13 patients in group 1 and 19 in group 2. The degree of enhancement on the delayed-phase images showed statistically significant correlation with the amount of fibrous stroma (P < .001) and the frequency of perineural invasion (P < .01). The survival rate in group 1 was significantly lower than that in group 2 (P = .016). Multivariate analysis revealed that enhancement of more than two-thirds of the ICC was a significant and independent prognostic factor.
Conclusion: The degree of enhancement on delayed-phase CT scans is a useful indicator for prediction of the prognosis of patients with mass-forming ICC.
© RSNA, 2005
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INTRODUCTION
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Intrahepatic cholangiocarcinoma (ICC) is a rare tumor usually associated with poor survival after resection. Although ICC accounts for only 7.7% of malignant tumors of the liver in the United States, it occurs more frequently in parts of southeast Asia (1). Several factors have been identified as prognostic factors in ICC, including status of microscopic margins, status of hilar lymph nodes, preoperative serum albumin levels, preoperative total bilirubin levels, Eastern Cooperative Oncology Group performance status and tumor grade (2), gross appearance, and protein p27 and keratin 903 expression levels determined at immunohistochemical analysis (2–7). To our knowledge, however, there have been no descriptions of prognostic factors related to preoperative imaging findings.
Patients with so-called scirrhous carcinomas in organs such as the stomach, colon, and breast that have extensive fibrosis with sparse tumor cell infiltration have been shown to have a very poor prognosis (8–10). Similarly, Kajiyama et al (11) showed that the survival rate in patients with the scirrhous type of ICC is significantly lower than that in patients with the nonscirrhous type of ICC. Conversely, it is well known that areas of delayed or prolonged enhancement in liver tumors at CT or magnetic resonance imaging correspond to fibrotic stroma at histopathologic examination (12,13). The aim of our study, therefore, was to retrospectively determine whether the degree of contrast enhancement at delayed-phase dynamic CT for ICC is related to the patient's prognosis after surgery.
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MATERIALS AND METHODS
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Forty-six consecutive patients underwent surgical resection of ICC at Kyushu University Hospital, Fukuoka, Japan, from November 1992 to December 2002. On the basis of the definition by the Japanese Liver Cancer Group (14), ICC is a malignant tumor that arises from the intrahepatic bile ducts and does not include tumors that arise from the bile duct confluence or the extrahepatic bile ducts. Among these 46 patients, tumors were classified according to their macroscopic features as follows: mass-forming type (n = 39), periductal infiltrative type (n = 4), and intraductal growth type (n = 3). In our study, we focused on the mass-forming type of ICC because most ICCs examined were of this type and because it is difficult to evaluate the delayed-enhancement volume of the periductal infiltrative and intraductal growth types. Patients with mass-forming ICC who underwent noncurative surgery (n = 7) were excluded from the study; the remaining 32 patients (22 men, 10 women, mean age, 60.8 years; range, 33–80 years) constituted the study population. Among the 32 patients, 16 were previously included in the study by Kajiyama et al (11). Our institutional review board did not require its approval or informed consent for the retrospective evaluation of patients' records and images.
CT Protocols
All patients underwent dynamic CT. Because the retrospective investigation dated back to 1992, a variety of CT scanners were used. Four patients underwent two-phase incremental dynamic CT (TCT-900S; Toshiba, Tokyo Japan). Contiguous, transverse 1-cm-thick sections were obtained after intravenous injection of 100 mL iopamidol (Iopamiron; Nippon Schering, Osaka, Japan) with 300 mg of iodine per milliliter at a rate of 2 mL/sec. After the early-phase image was obtained, delayed-phase scanning was begun 6 minutes after contrast material injection.
Twenty-two patients underwent single-helical multiphase CT (X vigor; Toshiba) and six underwent multiphase multi–detector row CT (Aquillion; Toshiba). The scanning parameters for single helical multiphase CT were as follows: section thickness of 7 mm, 1:1 pitch, and reconstruction thickness of 1 cm. The scanning parameters for multiphase multi–detector row CT were as follows: section thickness of 4 mm, pitch of 3, and reconstruction thickness of 5 mm. All patients underwent intravenous administration of 100 mL iopamidol solution at a rate of 2.5 mL/sec. Early-phase scanning was begun 45–60 seconds after the beginning of the injection. Delayed-phase scanning was begun 4–6 minutes after initiation of the injection.
Image Interpretation
Images of the largest transverse sections of the tumor were evaluated by two radiologists (Y.A. and K.Y., with 10 and 18 years of experience with CT of the liver, respectively) in consensus. All interpretations were performed with the film image, and the observers were blinded to the pathologic and clinical findings. Areas of contrast enhancement on delayed-phase images were qualitatively defined as those areas that showed higher attenuation than that of the surrounding hepatic parenchyma, regardless of the findings on the early or arterial phase images; namely, these areas showed prolonged or delayed enhancement (15). The patients were then classified into two groups: Group 1 included those in whom more than two-thirds of the tumor showed contrast enhancement compared with the surrounding nontumorous liver at semiquantitative (visual) interpretation. Group 2 included those in whom less than two-thirds of the tumor showed contrast enhancement compared with the noncancerous liver at semiquantitative (visual) interpretation. We used the parameter of two-thirds of the tumor as the cutoff for contrast enhancement because of previous pathologic criteria (11).
Pathologic Evaluation
For all 32 patients, an experienced pathologist (S.A., with 6 years of experience with liver disease) examined the resected specimens with no knowledge of preoperative CT findings. All specimens were cut, fixed in formalin, embedded in paraffin, and stained with hematoxylin-eosin. We categorized the mass-forming ICCs as scirrhous or nonscirrhous lesions on the basis of the ratio of the scirrhous areas according to the criteria used by Kajiyama et al (11), as follows: In scirrhous lesions, the scirrhous area was more than 70% in the largest cut surface; in nonscirrhous lesions, the scirrhous area was less than 70% in the largest cut surface. Other pathologic parameters—including tumor diameter, tumor differentiation (differentiated [including well to moderately differentiated adenocarcinoma] or undifferentiated [including poorly differentiated adenocarcinoma]), lymphatic permeation, venous invasion, perineural invasion, serosal invasion, lymph node metastasis, intrahepatic metastasis, scirrhous tumor stroma, and pTNM stage—were evaluated and recorded. The areas showing contrast enhancement and the regions of the histologic fibrous stroma were compared by the radiologists and the pathologist in cooperation.
Statistical Analysis
The degree of contrast enhancement, namely more than two-thirds enhancement versus less than two-thirds enhancement, was correlated to the various pathologic findings as mentioned earlier and to the patients' survival rates. Continuous variables, including age, are expressed as means ± standard deviations and were tested by using the Student t test. Categoric variables—including sex, tumor size, differentiation, the presence of lymphatic permeation, venous invasion, serosal invasion, perineural invasion, intrahepatic metastasis, lymph node metastasis, and the pattern of stromal desmoplasia—were tested by using the Fisher exact test. The Wilcoxon rank sum test was used to compare the two groups according to the pTNM stage on the basis of the criteria of the Japanese Liver Cancer Study Group (14). Survival curves were drawn by using the Kaplan-Meier method, and differences in the survival rates between the groups were compared with the log-rank test. The Cox proportional hazards model with a stepwise procedure was used in the multivariate survival analysis. A difference with a P value of less than .05 was considered statistically significant for all tests by using software (Stat View, version 5; Hulinks, Tokyo, Japan). All results were evaluated by one author (Y.A.).
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RESULTS
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The representative CT scans from groups 1 and 2 are shown in Figures 1 and 2, respectively. The clinicopathologic features of groups 1 and 2 are listed in Tables 1 and 2, respectively. No statistically significant differences were observed with regard to age, sex, or pTNM stage between the two groups. All 13 patients in group 1 and all 19 patients in group 2 had lesions that corresponded histopathologically to scirrhous ICC and nonscirrhous ICC, respectively. The regions that showed enhancement corresponded to the areas with scattered neoplastic cells in dense fibrous stroma. The number of patients with perineural invasion was significantly larger in group 1 than it was in group 2. Other pathologic features did not show a statistically significant correlation to the degree of contrast enhancement.
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Figure 1a: Transverse CT scans in a 67-year-old man with ICC. (a) Scan obtained 45 seconds after the administration of contrast material shows early peripheral enhancement of the tumor (arrows). (b) Scan obtained 300 seconds after the injection of contrast material shows progressive and concentric filling. Because more than two-thirds of the tumor showed delayed enhancement, the patient was placed in group 1. A pathology specimen (not shown) obtained from the area of delayed enhancement exhibited a cluster of carcinoma cells with abundant fibrous stroma accompanied by inflammatory cell infiltration.
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Figure 1b: Transverse CT scans in a 67-year-old man with ICC. (a) Scan obtained 45 seconds after the administration of contrast material shows early peripheral enhancement of the tumor (arrows). (b) Scan obtained 300 seconds after the injection of contrast material shows progressive and concentric filling. Because more than two-thirds of the tumor showed delayed enhancement, the patient was placed in group 1. A pathology specimen (not shown) obtained from the area of delayed enhancement exhibited a cluster of carcinoma cells with abundant fibrous stroma accompanied by inflammatory cell infiltration.
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Figure 2a: Transverse CT scans in a 57-year-old woman with ICC in the right lobe of the liver. (a) Scan obtained 60 seconds after the administration of contrast material shows early enhancement of most of the tumor (arrows). (b) Scan obtained 300 seconds after the injection of contrast material shows washout of contrast material. Because less than two-thirds of the tumor showed delayed enhancement, the patient was placed in group 2.
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Figure 2b: Transverse CT scans in a 57-year-old woman with ICC in the right lobe of the liver. (a) Scan obtained 60 seconds after the administration of contrast material shows early enhancement of most of the tumor (arrows). (b) Scan obtained 300 seconds after the injection of contrast material shows washout of contrast material. Because less than two-thirds of the tumor showed delayed enhancement, the patient was placed in group 2.
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The 1-, 3-, and 5-year survival rates for group 1 were 66.1%, 13.8%, and 0%, respectively. The 1-, 3-, and 5-year survival rates for group 2 were 83.3%, 57.6%, and 48.0%, respectively (Table 3). The survival rate for group 1 was significantly lower than that for group 2 (P = .016) (Fig 3). Table 3 also shows other statistically significant prognostic factors according to univariate analysis with the log-rank test. Seven variables were determined to be poor prognostic factors, and these included a tumor diameter of more than 5.1 cm, undifferentiated histologic differentiation, macroscopic presence of lymphatic permeation, vascular invasion, intrahepatic metastasis, lymph node metastasis, and a pTNM classification of T4N0M0, TXN1M0, and TXNXM1 (stage IV). Further evaluation with multivariate analysis by using the Cox proportional hazards model revealed that lymphatic permeation, venous invasion, lymph node metastasis, intrahepatic metastasis, and histologic differentiation were independent prognostic factors (Table 4).
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DISCUSSION
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Many studies have reported the radiologic findings of mass-forming ICC and the correlations between pathologic and radiologic findings (13,15–20). Researchers in these articles also described the correlation between areas with delayed contrast enhancement and pathologic findings in mass-forming ICC (13,15–18). The hyperattenuating areas in ICC on delayed-phase images seem to be related to the large amount of interstitial space in the fibrous stroma of the tumor (20). In a series by Valls et al (20), delayed-phase CT showed marked hyperenhancement in 81.8% of patients with severe stromal fibrosis, whereas none of the patients without stromal fibrosis showed hyperenhancement. To our knowledge, however, the relationship between the degree of delayed tumor enhancement and the patient's prognosis has not been discussed in previous studies.
In most cases of mass-forming ICC, although carcinoma cells proliferate in a compact pattern at the marginal areas, they proliferate sparsely with fibrous stroma in the central area (15). The gradation of fibrotic change from the edge to the center of the tumor is gradual and typically variable. In a pathologic study, Kajiyama et al (11) categorized ICC as scirrhous or nonscirrhous, as described earlier. In our study, groups 1 and 2 corresponded to scirrhous and nonscirrhous ICC, respectively, as defined by the criteria used by Kajiyama et al (11).
In our study, the mass-forming ICCs in group 1 showed statistically significant correlation with the presence of perineural invasion and were associated with a poor prognosis after surgical resection. Furthermore, results of multivariate analysis showed that a mass-forming ICC with more than two-thirds of contrast enhancement is a new independent prognostic factor. Our results suggest that the outcome of patients with mass-forming ICCs can be predicted before surgery by using delayed-phase contrast-enhanced CT, which is the most prevailing diagnostic modality in the world. In addition, delayed-phase imaging performed 4–6 minutes after the intravenous administration of iodinated contrast material is less dependent on the capacity of the equipment or the scanning protocol as compared with arterial or early-phase imaging, which necessitates faster scanning and injection of a bolus of contrast material. Our results, therefore, can be applied to various situations in the world in which CT equipment of various generations or capacities is involved. With use of this preoperative CT information, surgical strategies or adjuvant chemotherapy might be tailored on a patient-by-patient basis to improve the survival of patients with ICC in the future.
In contrast to our results, those of Kajiyama et al (11) failed to show that scirrhous ICC is an independent prognostic factor at multivariate analysis. A possible reason for this difference may be dependent on differences in the study groups. The patients in the study by Kajiyama et al had periductal infiltrative and intraductal growth type tumors. The clinical behaviors of these types of ICC are different from those of mass-forming ICCs (21,22). In the study by Kajiyama et al, all cases of periductal infiltrative and intraductal growth types were nonscirrhous. There is a possibility that the modes of desmoplastic change and tumor progression of these types are different from those of mass-forming ICCs.
There were some limitations in our study. Because patients with mass-forming ICC who have undergone curative surgery are rare, we used a retrospective design and a small study group. Patients were recruited during a 10-year period, and various types of CT scanners (ie, incremental and single– and multi–detector row technologies) and injection protocols were used. The attenuation of the tumor during the arterial-dominant phase or portal-dominant phase may not have been standardized; however, findings at delayed-phase imaging are considered to be less dependent on the modes of CT equipment or injection protocol, as mentioned earlier. Thus, we believe that we were able to evaluate the contrast enhancement of the tumors with acceptable consistency.
In conclusion, we categorized patients with mass-forming ICCs into two groups on the basis of the degree of contrast enhancement at CT. The survival rate of patients in group 1 (enhancement of more than two-thirds of the tumor) was significantly lower than that of those in group 2 (enhancement of less than two-thirds of the tumor). This preoperative routine CT finding, which we reported as an independent prognostic factor, can help predict the outcome of patients with mass-forming ICC before surgery.
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ACKNOWLEDGMENTS
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The authors thank Yoshihiko Maehara, MD, for providing clinical data and Masazumi Tsuneyoshi, MD, for providing pathologic data.
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FOOTNOTES
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Abbreviations: ICC = intrahepatic cholangiocarcinoma
Authors stated no financial relationship to disclose.
Author contributions: Guarantors of integrity of entire study, Y.A., H.H.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; approval of final version of submitted manuscript, all authors; literature research, Y.A., K.Y., S.A.; clinical studies, Y.A., A.T.; statistical analysis, Y.A.; and manuscript editing, Y.A., K.Y., H.H.
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ABSTRACT
INTRODUCTION
