Abstract
Background/Aim: The aim of this study was to evaluate hepatectomy cases that underwent preoperative chemotherapy to examine the relationship between the development of desmoplastic histopathological growth pattern (dHGP) and prognosis and recurrence and determine whether it is useful for evaluating preoperative chemotherapy. Patients and Methods: A total of 133 cases with hepatic metastasis for colorectal cancer that underwent surgical resection. Results: Of the 102 cases that underwent preoperative chemotherapy, 34 (33%) were determined to be dHGP positive, which was statistically significantly higher than the 2 of 31 cases (6.5%) that had not undergone preoperative chemotherapy. Regarding the 5-year recurrence-free survival, the dHGP group had a value of 50.3%, whereas the non-dHGP group had a value of 7.1%. For the 5-year overall survival, the dHGP group had a better prognosis than the non-dHGP group (57.6% vs. 37.1%, respectively), with a statistically significant difference. Univariate analysis of recurrence-free survival showed that the number of tumours, the Response Evaluation Criteria in Solid Tumors, and the presence or absence of dHGP were prognostic factors, whereas multivariate analysis showed that the presence or absence of dHGP was an independent prognostic factor. Univariate analysis of the overall survival showed that the number of tumours, the Response Evaluation Criteria in Solid Tumors, and presence or absence of dHGP were prognostic factors. Multivariate analysis showed that the presence or absence of dHGP was an independent prognostic factor. Conclusion: dHGP is useful as a new evaluation method for evaluating the efficacy of preoperative chemotherapy.
Colorectal cancer is one of the most frequently occurring malignancies worldwide (1). Approximately 60% of patients with colorectal cancer are reported to develop hepatic metastasis during the course of the disease (2). Surgical treatment for hepatic metastasis of colorectal cancer is a potentially curative therapy that strongly impacts prognosis. Preoperative hepatic function evaluations, perioperative chemotherapy, surgical techniques, and perioperative management improve the prognosis and increase the resection rate, but the main factor is chemotherapy (3-7). In addition, approximately 60% of hepatic metastasis cases of colorectal cancer that could be radically resected experience recurrence, 80% of which are unresectable (8), therefore, chemotherapy plays an increasingly important role. Preoperative chemotherapy for hepatic metastasis of colorectal cancer plays an important role in multidisciplinary treatment. In particular, chemotherapy has been shown to contribute to the shrinkage of tumours and increased curability of surgery (9), improved resection rate (10), and decisions on resection and subsequent chemotherapy regimens when no response is obtained (11).
There are various methods for determining the efficacy of chemotherapy for hepatic metastasis of colorectal cancer, which include comparing blood tumour markers and imaging tests before and after chemotherapy and histological evaluation of resected tumours. The Response Evaluation Criteria in Solid Tumors (RECIST) (12) is a widely used method for evaluating changes in tumour size. However, there have been reports in recent years indicating that good results in terms of prognosis and recurrence were obtained even if the shrinkage effect is not remarkable (13), and it is difficult to confirm that it is useful in all cases. Therefore, satisfactory results cannot be obtained only by evaluation based on the shrinkage effect, and a more accurate multifaceted evaluation may be necessary to determine the efficacy of chemotherapy. Several reports have shown the usefulness of histological evaluation in terms of prognosis, and one histological finding that has been reported involves fibrous pseudocapsule (14) or desmoplastic histopathological growth pattern (“dHGP”) (15). These characteristics are due to the presence of fibrous tissue between the tumor and the liver parenchyma, which is reported to have a better prognosis and recurrence than the others. It has been indicated that these characteristics are the result of immunological actions of the host against cancer and the antitumour effect of chemotherapy, and all these changes are histologically suggestive of antitumour effects (14-17). These are different evaluation methods from those used to assess the tumor shrinkage effect of preoperative chemotherapy, and may provide more accurate results in terms of prognosis and recurrence. This study aimed to use hepatectomy cases that underwent preoperative chemotherapy to examine the relationship between the occurrence of dHGP and prognosis and recurrence and to examine whether it is useful as an evaluation method for preoperative chemotherapy.
Patients and Methods
This study enrolled 133 patients with colorectal cancer hepatic metastases who underwent surgical resection at Kurume University Hospital and Kurume University Medical Centre from 2006 to 2019. This study included 102 cases of colorectal cancer liver metastasis resected after administration of preoperative chemotherapy at Kurume University Hospital and Kurume University Medical Center. Patients were classified into three groups, according to preoperative chemotherapy as follows: mFOLFOX6, after bolus injection of 400 mg/m2 5-FU, intravenous infusion of 85 mg/m2 oxaliplatin, and 200 mg/m2 dl leucovorin, followed by 2,400 mg/m2 5-FU, over 46 h administration; mFOLFOX6 combined with 5 mg/kg bevacizumab; mFOLFOX6 combined with cetuximab initially at 400 mg/m2 followed by 250 mg/m2, or combined with 6 mg/kg panitumumab. Patients with the combination including bevacizumab were treated with only mFOLFOX6 as their final chemotherapy regimen. Hepatectomy of patients with the combination treatment including bevacizumab was performed 6 to 9 weeks after the final treatment day, whereas hepatectomy of patients with the combination treatment including cetuximab or panitumumab was performed 4 to 7 weeks after the final treatment day.
The image-based judgment of the effectiveness of the preoperative chemotherapy was performed using contrast-enhanced computed tomography (CT) or contrast-enhanced MRI images obtained before and after chemotherapy, with evaluations conducted according to RECIST guidelines. Resected specimens fixed in 10% formalin (=10% buffered formalin) were used for histological evaluation. The cut surface was macroscopically observed and the tumour size and number of tumours were measured. Histologic sections were prepared at the maximum diameter of the tumour, and microscopically observed after haematoxylin and eosin (H&E) staining. The dHGP evaluation was positive when fibrous tissue intervened between the tumour and liver parenchyma and the tumour component was completely encapsulated by the fibrous tissue (Figure 1). When there were multiple hepatic metastases, all tumours were evaluated as dHGP-positive if the tumour components were completely encapsulated by fibrous tissue. Histological evaluation was conducted simultaneously by two pathologists, and in cases where it was difficult to make a judgment, another pathologist joined to make the final judgment. Cases were divided into a dHGP-positive group and a non-dHGP group.
Photomicrograph of desmoplastic histopathological growth pattern. The tumor is separated from the liver parenchyma by a desmoplastic capsule.
Statistical analysis. Continuous variables were compared using the Kruskal–Wallis test. Categorical variables were compared using the Chi-squared test or Fisher’s exact test. The overall survival (OS) was measured from the date of surgery to the date of death or the last follow-up date. Disease-free survival (DFS) was measured from the date of surgery to the date of recurrence based on radiological tests or the last follow-up date. Survival curves for OS and DFS were constructed using the Kaplan–Meier method, and differences between curves were evaluated using the log-rank test. Multivariate regression analysis was used to identify prognostic factors for survival or disease-free survival, which was conducted using the Cox proportional hazards model for factors with p<0.1 in univariate analysis. JMP® Pro 11.0.0 (SAS Institute, Cary, NC, USA) was used for all analyses.
The current study was approved by the Research Ethics Committee of Kurume University (approval no. 21293) and conducted in accordance with the Declaration of Helsinki. The requirement of informed consent was waived due to the retrospective nature of the study.
Results
Patient characteristics. Of the 133 patients, 90 were males and 43 were females, and the ages ranged from 36 to 82 years old, with an average age of 63 years. The site of the primary tumour was the colon in 74 cases and the rectum in 59 cases; meanwhile, lymph node metastasis from the site of the primary tumour was observed in 89 cases. Hepatic metastasis included 68 cases of synchronous hepatic metastasis and 65 cases of metachronous hepatic metastasis. There were 48 cases of solitary hepatic metastasis, 85 cases of multiple hepatic metastases, and 24 cases of tumour size >5 cm. Preoperative chemotherapy was conducted in 102 patients, all of whom were fluorouracil-based; 20 underwent concomitant administration of oxaliplatin, 54 underwent concomitant administration of oxaliplatin and bevacizumab, nine underwent concomitant administration of oxaliplatin and cetuximab or panitumumab, four underwent concomitant administration of irinotecan, eight underwent concomitant administration of irinotecan and bevacizumab, and seven underwent concomitant administration of irinotecan and cetuximab or panitumumab. The number of times chemotherapy was conducted was 3-23 times, with an average of 7.2 times. Surgical procedures included 77 cases of minor hepatectomy and 56 cases of major hepatectomy; of the major hepatectomy cases, nine underwent portal vein embolization. The surgical margin was histologically negative in 121 cases. No deaths were observed within 90 days after surgery. In the dHGP-positive group, 36 of 133 cases were judged as positive. When comparing the incidence rates with and without preoperative chemotherapy, 34 of 102 patients (33%) who underwent preoperative chemotherapy were judged to be dHGP-positive, which was statistically significantly higher than the two of 31 patients (6.5%) who had not undergone preoperative chemotherapy, and a significant relationship was observed between preoperative chemotherapy and dHGP incidence (p=0.0024). The tumour shrinkage effect of preoperative chemotherapy was judged according to the RECIST guidelines. There were 0 cases of complete response (CR), 48 cases of partial response (PR), 32 cases of stable disease (SD), and 22 cases of progressive disease (PD). The median follow-up period was 35 months (range=3-95 months) (Table I).
Baseline demographics and clinical characteristics (n=133).
Comparison of RFS and OS. Figure 2 shows the 5-year recurrence-free survival curve and 5-year overall survival curve for the PR group and SD group or PD group based on the RECIST classification. For the 5-year recurrence-free survival, the values were 26.0% for the PR group and 16.5% for the SD/PD group, and the recurrence rate of the PR group tended to be lower, but there were no statistically significant differences between the two groups (p=0.178). For the 5-year overall survival, the values were 55.5% for the PR group and 31.2% for the SD/PD group, and the PR group tended to have a better prognosis, although there were no statistically significant differences between the two groups (p=0.087). Figure 3 shows the 5-year recurrence-free survival curve and the 5-year overall survival curve for the dHGP and non-dHGP groups. For the 5-year recurrence-free survival, the values were 50.3% for the dHGP group and 7.1% for the non-dHGP group, with the former having a lower recurrence rate, with a statistically significant difference between the two groups (p<0.001). For the 5-year overall survival, the values were 57.6% for the dHGP group and 37.1% for the non-dHGP group, with the dHGP group having a better prognosis, with a statistically significant difference between the two groups (p=0.023).
Comparison of Kaplan–Meier curves for recurrence-free survival (RFS) and overall survival (OS) according to Response Evaluation Criteria in Solid Tumors (RECIST). PR: Partial response; SD: stable disease; PD: progressive disease.
Comparison of Kaplan–Meier curves for recurrence-free survival (RFS) and overall survival (OS) in the desmoplastic histopathological growth pattern (dHGP) and non-desmoplastic HGP (non-dHGP).
Univariate and multivariate analyses. The results of univariate and multivariate analyses on recurrence-free survival and overall survival are shown in Table II. Univariate analysis of the recurrence-free survival showed that the number of tumours [solitary vs. multiple (hazard ratio (HR)=1.63; 95% confidence interval (CI)=0.97-2.86), p=0.06] and the presence or absence of dHGP [dHGP vs. non-dHGP (HR=3.10; 95%CI=1.81-5.62), p<0.001] were prognostic factors. Multivariate analysis showed that the presence or absence of dHGP [dHGP vs. non-dHGP (HR=2.95; 95%CI=1.72-5.38), p<0.001] was an independent prognostic factor. Univariate analysis of the overall survival showed that the number of tumours [solitary vs. multiple (HR=2.13; 95%CI=0.94-5.69), p=0.07], RECIST [SD or PD vs. PR (HR=1.78; 95%CI=0.91-3.59), p=0.09], and presence or absence of dHGP [dHGP vs. non-dHGP (HR=2.51; 95%CI=1.16-6.27), p=0.018] were prognostic factors. Multivariate analysis showed that the presence or absence of dHGP [dHGP vs. non-dHGP (HR=2.38; 95%CI=1.09-5.94), p=0.028] was an independent prognostic factor.
Univariable and multivariable COX regression analyses for recurrence-free survival (RFS) and overall survival (OS) of all patients.
Discussion
The incidence of dHGP in patients who underwent preoperative chemotherapy was higher than the incidence of dHGP in patients who had not undergone preoperative chemotherapy. It has been recently reported that preoperative chemotherapy increases the incidence of dHGP (18). In addition, the incidence of dHGP may have increased due to the immunological effects of the host against cancer and the antitumour effects of preoperative chemotherapy. As shown in Figure 1, dHGP is observed as a smooth lesion with a clear border between the tumour and existing hepatic tissue because fibrous tissue intervenes between the tumour and the existing hepatic tissue. This may also appear as an image change. Shindoh et al. reported the usefulness of morphologic response (MR), where morphological changes in a tumour image due to chemotherapy are shown (19), and one of the evaluation criteria is that the boundary between the surrounding liver parenchyma and the tumour should be clear and smooth. Such an image morphology change may reflect the histological characteristics of dHGP.
As shown in Figure 2, dHGP evaluation is considered more useful for prognosis and recurrence prediction than RECIST evaluation. A problem with RECIST evaluation is that the shrinkage effect alone does not always reflect prognosis and recurrence. One of the reasons for this is the biological characteristics of gastrointestinal adenocarcinomas, including colon cancer. Adenocarcinomas may be accompanied by various degrees of fibrous stroma, but when this is prominent, the stromal component remains even if the tumour component is reduced by anticancer drugs. Therefore, as long as the stromal component remains, it will be visualized as a lesion in images, so this may deviate from the actual therapeutic effect. Moreover, the central part of the adenocarcinoma with fibrotic stroma may show degeneration or necrosis even without preoperative treatment. In this respect, the evaluation of the histopathological growth pattern is an evaluation of the tumour margin, so it has the advantage of not being a problem in this situation.
A study of prognosis and recurrence using the Cox proportional hazards model showed that the presence or absence of dHGP was an independent factor that determined recurrence and prognosis (20). This result is similar to that of recent reports, which have shown that dHGP is more powerful than other prognostic factors (20, 21). In this study, dHGP and non-dHGP were separately investigated, but HGP includes not only the desmoplastic type but also the replacement type and pushing type. These three types were also examined, but in terms of the prediction of recurrence and prognosis, grouping according to the presence or absence of dHGP was the most appropriate (data not shown). Other reports have conducted various investigations such as the thickness of dHGP and the degree of encapsulation, and discussion is needed on which type of dHGP is the most suitable.
In conclusion, dHGP is a strong predictor of recurrence and prognosis in patients who underwent preoperative chemotherapy. Therefore, it is extremely useful as an evaluation method for the efficacy of preoperative chemotherapy. Moreover, dHGP may play an important role in the selection of preoperative chemotherapy regimens in patients with hepatic metastasis of colorectal cancer who frequently undergo re-hepatectomies.
Acknowledgements
The Authors are deeply grateful to Ms Atsuko Matsuo for their assistance in the experiments.
Footnotes
Authors’ Contributions
Hiroaki Hirakawa designed the study, and wrote the initial draft of the manuscript. Hisamune Sakai and Toru Hisaka contributed to analysis and interpretation of data, and assisted in the preparation of the manuscript. All other authors have contributed to data collection and interpretation, and critically reviewed the manuscript. All Authors approved the final version of the manuscript, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Conflicts of Interest
The Authors declare no conflicts of interest associated with this study.
- Received May 13, 2023.
- Revision received June 1, 2023.
- Accepted June 2, 2023.
- Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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