Correlation analysis of interstitial maturity and prognosis of colorectal cancer: Meta-analysis

Abstract

BACKGROUND

To investigate the relationship between interstitial maturity and prognosis of colorectal cancer.

AIM

To examine the correlation between interstitial maturity and the prognosis of colorectal cancer.

METHODS

The paper database PubMed, EMBASE, Cochranelibrary, Springerlink, CNKI, and Wanfang database were searched until December 2023. "tumor stroma maturity" "desmoplastic stroma reaction" "desmoplastic reaction" "stroma reaction" "degree of stroma reaction "" stroma classification" "stroma density" "colorectal cancer" "colon cancer" "rectal cancer" "prognosis" were searched for the search terms. Two system assessors independently screened the literature quality according to the inclusion exclusion criteria, Quality evaluation and data extraction were performed for the included literatures, and meta-analysis was performed for randomized control trials included at using Review Manager 5.2 software.

RESULTS

Finally, data of 9849 patients with colorectal cancer from 19 cosets in 15 literatures were included, including 4339 patients with mature type (control group), 3048 patients with intermediate type (intermediate group) and 2456 patients with immature type (immature group). The results of meta-analysis showed: Relapse-free survival [hazard ratio (HR) = 2.66, 95% confidence interval (CI): 2.30-3.08; P < 0.00001], disease-free survival (HR = 3.68, 95%CI: 2.33-5.81; P < 0.00001) and overall survival (HR = 1.70, 95%CI: 1.53-1.87; P < 0.00001) were significantly lower than those in mature group (control group); relapse-free survival (HR = 1.36, 95%CI: 1.17-1.59; P < 0.0001) and disease-free survival rate (HR = 1.85, 95%CI: 1.53-2.24; P < 0.0001) was significantly lower than the mature group (control group).

CONCLUSION

There is the correlation between tumor interstitial maturity and survival prognosis of colorectal cancer, and different degrees of tumor interstitial maturity have a certain impact on the quality of life of colorectal cancer patients.

Key Words: Colorectal tumor; Survival prognosis; Tumor interstitial maturity; Systematic review; Meta-analysis

Core Tip: Our study explored the correlation between interstitial maturity and the prognosis of patients with colorectal cancer through meta-analysis. We will collect and analyze data from the literature on interstitial maturity assessment and prognostic indicators in colorectal cancer patients to verify its relevance and evaluate its application prospects in clinical practice. This study will provide a new perspective for understanding the development mechanisms of colorectal cancer and provide a scientific basis for the formulation of clinical treatment strategies.

INTRODUCTION

The biological behavior of tumor cells is not only related to their own gene mutations but also plays an important role in the tumor microenvironment[1]. The tumor microenvironment includes the structural, functional, and metabolic environment of the mesenchyma, in which tumor-associated fibroblasts (CAFs) interact with tumor cells through the release of cytokines and promote the proliferation and invasion of tumor cells through the secretion of extracellular matrix. Studies have shown that the degree of fibrostromal reaction induced by the synthesis and remodeling of extracellular fibrostromal cells in the tumor microenvironment, that is, fibrostromal reaction-promoting (DR), can reflect the maturity of extracellular stromal cells. Based on HE staining, DR can be divided into mature, intermediate, and immature types according to the morphology of interstitial fibers. Studies have shown that DR is an independent factor affecting the prognosis of solid tumors such as colorectal cancer.

Numerous factors can affect the prognosis of colorectal cancer, which is a common malignant tumor. Over the past few decades, significant progress has been made in the treatment and management of colorectal cancer, but significant challenges remain. In recent years, more and more studies[2,3] have shown that there is a certain correlation between the interstitial maturity of tumors and the prognosis of patients with colorectal cancer. However, there are differences between the results of different studies, and there is no consistent conclusion. Therefore, a systematic review and meta-analysis of the correlation between interstitial maturity and the prognosis of colorectal cancer are of great significance[4]. With the deepening of cancer research, people gradually realize the importance of the microenvironment around tumors. As an important component of the tumor microenvironment, mesenchymal cells play a key role in tumor progression and therapeutic response. However, there is no comprehensive and consistent understanding of the specific impact of interstitial maturity on the prognosis of patients with colorectal cancer. Some studies have suggested that mature stroma may be associated with tumor development and a good prognosis, while others have argued otherwise. This phenomenon may be due to the heterogeneity of study samples, differences in research methods, and diversity of data analysis.

Given the inconsistent results of current studies on the relationship between interstitial maturity and the prognosis of colorectal cancer, it is important to conduct a systematic review and meta-analysis to integrate the existing research results and reveal the underlying regularities. Through systematic collection, screening, and analysis of existing literature, this study aims to explore the impact of interstitial maturity on the prognosis of patients with colorectal cancer in order to provide more valuable evidence support for clinical practice, provide a scientific basis for the formulation of an individualized treatment plan, and ultimately improve the prognosis and quality of life of patients with colorectal cancer.

In this study, published survival data on DR And colorectal cancer prognosis were meta-analyzed to determine the relationship between tumor interstitial maturity and colorectal cancer prognosis.

MATERIALS AND METHODS

Search strategy

"Tumor interstitial maturity", "pro-fibrostitial reaction", "pro-fibrostitial reaction", "interstitial reaction", "degree of interstitial reaction", "interstitial grade", "interstitial density", "colorectal cancer" and "prognosis" were used as search terms. Chinese databases such as web.com and VIP, as well as foreign language databases such as Cochrane Library, PubMed, SpringerLink, EBSCO, MEDLINE, etc. were included in prospective and retrospective cohort studies from inception to December 2023. In order to avoid bias caused by language limitations, this study searched both English literature. In order to avoid missing relevant studies, relevant references listed in the article and conference abstracts found in the search were traced (Figure 1).

Figure 1 Flow chart of the literature screening. ¹Consider, if feasible to do so, reporting the number of records identified from each database or register searched (rather than the total number across all databases/registers). ²If automation tools were used, indicate how many records were excluded by a human and how many were excluded by automation tools.

Document inclusion criteria

(1) All clinical studies on interstitial maturity and prognosis of colorectal cancer tumors, including clinicopathological characteristics and follow-up data; (2) The age and region of the research are clear; (3) The subjects were patients with colorectal cancer confirmed by pathological results; (4) Patients did not receive preoperative chemoradiotherapy; (5) Different subjects published by the same institution or author in the same year were included; (6) Tumor stromal maturity was divided into immature type, intermediate type and mature type according to DR degree; (7) The prognostic indicators included one of the 5-year recurrence-free survival, 5-year disease-free survival, and 5-year overall survival (OS); and (8) The design type was prospective or retrospective cohort study.

Document exclusion criteria

(1) Duplicate or published reviews or meta-analyses; (2) No literature on control group or non-exposed group; (3) The results of the study did not include literature on the degree of DR in the primary lesion of colorectal cancer; and (4) Unreasonable statistical methods; (5) Literature that did not contain or could not extract prognostic hazard ratio (HR) data from survival curves.

Bias analysis

The assessment of heterogeneity among studies was conducted using I² statistics, with 25%, 50%, and 75% respective reflecting low, medium, and high levels of heterogeneity. The sensitivity analysis involved the sequential removal of the included literature in order to assess the stability and reliability of the pooled effect estimates (Figure 2).

Figure 2  Risk of bias graph of literature quality evaluation chart.

Statistical analysis

The Cochrane Collaboration Center provided Rewiew Manger 5.2 software (Cochrane Information Management System) for statistical analysis, and the Risk ratio of dichotic variables was adopted. RR and 95% confidence interval (CI) were used as efficacy and side effects analysis statistics in meta analysis. χ² test (P < 0.05 as the test level), hypothesis test adopts the U test expressed by Z value and P value, and sets 0.05 as the significance level, that is, P < 0.05 is used when the difference is statistically significant. The results of hypothesis test are listed in the forest map. Heterogeneity was analyzed by χ² test. P < 0.10, r = 25%, 50% and 75% were considered as low, medium and high heterogeneity, respectively, and inverted funnel plot was used to analyze publication bias.

RESULTS

Literature retrieval results and included research characteristics

A total of 802 literatures were obtained through search, 107 literatures with obvious inconsistency were excluded by reading the title, and 110 literatures were preliminarily included; 25 literatures were included after irrelevant and non-clinical studies were excluded by reading the abstract; and 15 qualified literatures[5-19] were finally included by reading the full text according to the inclusion and exclusion criteria. Prospective and retrospective cohort studies evaluated by Newcastle-Ottawa Scale were all of high quality, with scores ranging from 6 to 8, as shown in Figure 1 and Table 1.

Table 1 Basic characteristics of included studies and Newcastle-Ottawa Scale scores (mean ± SD).

Ref.	Time	Research type	Cases	Gender (male/female)	Age (yr)	Stage	Follow-up time (months)	NOS score
Ueno et al[5]	2002	Cohort study	627	393/234	60.3 ± 12	Ⅰ-Ⅲ	153 (80-267)	6
Ueno et al[6]	2004	Cohort study	862	NA	NA	Ⅰ-Ⅲ	140	6
Wu et al[7]	2014	Cohort study	412	NA	61.4 ± 12	Ⅳ	61 (11-188)	7
Ueno et al[8]	2015	Cohort study	880	512/368	62.9 ± 13	Ⅱ-Ⅲ	68	8
Ueno et al[8]	2015	Cohort study	474	268/206	66.3 ± 13	Ⅱ-Ⅲ	68	6
Ueno et al[9]	2017	Cohort study	821	484/337	66.2 ± 12	Ⅱ-Ⅲ	59 (1-86)	7
Wu et al[10]	2018	Cohort study	466	264/202	59.9 ± 13	Ⅲ	59 (45-144)	7
Wu et al[10]	2018	Cohort study	432	247/185	65.1 ± 12	Ⅲ	58 (1-87)	8
Shin et al[11]	2019	Cohort study	151	88/63	63.2 ± 11	Ⅰ-Ⅳ	56	6
Konishi et al[12]	2018	Cohort study	851	407/444	66 ± 14	Ⅰ-Ⅲ	58	6
Nearchou et al[13]	2019	Cohort study	283	184/99	62.3 ± 11	Ⅱ	NA	6
Nearchou et al[13]	2019	Cohort study	163	87/76	63 ± 12	Ⅱ	NA	7
Ueno et al[14]	2019	Cohort study	679	400/279	64.0 ± 12	Ⅱ	91	8
Ueno et al[14]	2019	Cohort study	446	267/179	67.0 ± 12	Ⅱ	58	8
González et al[15]	2020	Cohort study	342	179/163	65.2 ± 12.6	Ⅰ-Ⅲ	NA	8
Hacking et al[16]	2020	Cohort study	234	111/118	64 ± 13	I-Ⅲ	NA	6
Ao et al[17]	2020	Cohort study	363	209/154	66.6 ± 12	Ⅲ	61 (1-136)	8
Gonzalez et al[18]	2021	Cohort study	372	189/183	65.7 ± 12.9	Ⅰ-Ⅲ	62 (1-170)	6
Ueno et al[19]	2021	Cohort study	991	601/390	65.5 ± 12.2	Ⅱ	69.7 (2.1-105.6)	7

NOS: Newcastle-Ottawa Scale.

Basic features of the included literature

The 15 literatures included were all foreign literatures, among which 4 literatures included two different cosets of subjects, and a total of 9849 patients with colorectal cancer were included in 19 cosets, including 4339 patients with mature tumor interstitium, 3048 patients with intermediate tumor, and 2456 patients with immature tumor. Two of the studies included patients in stage IV, while the rest were in stage I to III. The characteristic data of each study include publication time, region, study type, sample size, gender, age, stage, tumor site, follow-up time and observation indicators. The basic characteristics of each study are shown in Table 1.

Meta-analysis results of relapse free survival

A total of 8 literatures and 10 cohorts were used to study the relationship between tumor interstitial maturity and relapse-free survival. A meta-analysis was conducted using the fixed-effect model, and the results showed that: compared with the mature group, the immature group was better than the mature group. The relapse-free survival rate of patients was significantly lower than that of patients in the mature group (HR = 2.66, 95%CI: 2.30-3.08, P < 0.00001), as shown in Figure 3A. The relapse-free survival rate of patients in the intermediate group was also significantly lower than that of patients in the mature group (HR = 1.36, 95%CI: 1.17-1.59, P < 0.0001). There was no significant heterogeneity in all studies (I² = 0, P > 0.05), as shown in Figure 3B.

Figure 3 Results of meta-analysis between patients with immature interstitial tumor and those with maure tumor. A: Results of meta-analysis comparing relapse-free survival rate between patients with immature interstitial tumor and those with mature tumor; B: Results of meta-analysis comparing relapse-free survival rate between the intermediate tumor stromal group and the mature tumor group; C: Results of meta-analysis comparing disease-free survival rate between patients with immature tumor stroma and those with mature tumor; D: Results of meta-analysis comparing disease-free survival rate between patients with intermediate tumor stromal type and mature tumor group; E: Results of meta-analysis comparing the overall survival rate of patients with immature and mature tumors.

Meta-analysis results of disease free survival

A total of 3 literatures and 4 cohorts were used to study the relationship between tumor interstitial maturity and disease-free survival rate. The tumor stage ranged from stage I to stage IV. Meta-analysis showed that compared with the mature group, the disease-free survival rate of patients in the immature group was significantly lower than that in the mature group (HR = 3.68, 95%CI: 2.33-5.81), there was significant heterogeneity among studies (I² = 67%), and random effects model was adopted for analysis, as shown in Figure 3C. The disease-free survival rate of patients in the intermediate group was also significantly lower than those in the mature group (HR = 1.85, 95%CI: 1.53-2.24, P < 0.0001), no significant heterogeneity was found in all studies (I² = 43%, P > 0.05), and the fixed-effect model was used for analysis, as shown in Figure 3D.

Meta-analysis results of OS

A total of 5 literatures and 8 cosets were used to study the difference in OS rate between the immature group and the mature group, with tumor stages ranging from stage I to stage IV. Meta-analysis showed that compared with the mature group, the OS rate of the immature group was significantly lower than that of the mature group (HR = 1.70, 95%CI: 1.53-1.87, P < 0.00001), each study I² = 47% (P > 0.05), using the fixed effect model analysis, according to subgroup analysis with or without stage IV patients showed that the OS rate of the immature group was significantly lower than that of the mature group (HR = 1.61, 95%CI: 1.44-1.80, P < 0.00001).

Included in the study, I² = 47% (P > 0.05), including stage IV patients, the OS rate of the immature group was also significantly lower than that of the mature group (HR = 2.04, 95%CI: 1.65-2.54, P < 0.00001), and the study I² = 0 (P > 0.05). The unstudied total survival rate of patients with intermediate type is shown in Figure 3E.

Publication bias analysis

The funnel plot test was adopted, and the funnel plot was basically symmetric with good symmetry. Taking the funnel plot of the included literature on relapse-free survival as an example, the five cohort studies were basically distributed within 95% confidence interval, indicating no significant publication bias (Figure 4).

Figure 4 Funnel plot of literature publication bias. A: Funnel plot of publication bias in disease-free survival rate; B: Funnel plot of publication bias in overall survival rate.

Meta-regression analysis

Regression analysis of age, region, sex, stage, tumor site and degree of differentiation showed that age, region, sex, stage, tumor site and degree of differentiation did not affect relapse-free survival and OS (Table 2).

Table 2 Meta-regression analysis of recurrence survival and overall survival.

Interstitial maturity	Heterogeneous factor	Relapse free survival		Overall survival rate
		Coefficient	P value	Coefficient	P value
Immaturity	Age	0.098	0.8	0.06	0.93
	Region (Europe and America/Asia)	0.084	0.81	0.63	0.18
	Gender (male/female)	0.05	0.93	0.46	0.21
	Stage (Ⅰ-Ⅱ/Ⅲ-Ⅳ)	-0.73	0.16	-0.5	0.39
	Tumor site (node/rectum)	0.68	0.14	0.46	0.54
	Degree of differentiation (high/medium/low)	-0.02	0.95	-0.74	0.49

DISCUSSION

At present, there have been many studies on tumor microenvironment, and the changes in tumor microenvironment, especially the changes in tumor mesenchyma, are closely related to tumor progression[20]. Relevant studies[21-24] have found that tumor mesenchyma is more closely related to survival than tumor cells themselves in breast cancer. The tumor microenvironment, or tumor interstitium, is in a dynamic process of change with the progression of the tumor. There are studies that show the growth and changing of collagen fibers, mainly the growth of thick collagen bundles, at the point where the tumor and interstitium meet is a sign that the tumor interstitium has matured[25]. This dynamic fibrotic process is called DR. And is an important indicator of the tumor interstitium or tumor microenvironment. DR Maturity was divided into mature type, intermediate type, and immature type according to whether the tumor margin interstitial components contained hyaline scar collagen and mucoid interstitial[26-28]. In the early stage of tumor development, the fibrostroma immobilized tumor cells, representing a host response of tumor cells, but as the tumor progressed, tumor cells could break through the fibrostromal restraint and grow infiltratively around the tumor. Studies[29-32] have shown that the interstitial reaction at the tumor edge is closely related to the progression of colorectal cancer. Some in vitro experiments have shown that inhibition of the interstitial reaction in melanoma, for example, may promote the metastasis of tumors. However, Peng et al[33] believe that Colorectal cancer can up-regulate the synthesis of collagen fibers and limit the invasion of tumors. Fibrous interstitial reaction is a dynamic process in tumor progression and plays different roles in different stages of tumor progression.

At present, there have been many studies on the relationship between tumor interstitial maturity and the prognosis of colorectal cancer. This study confirmed, from the perspective of evidence-based medicine, that the lower the degree of tumor interstitial fiber differentiation, the worse the prognosis. TNM staging based on postoperative pathological HE sections is currently the gold standard for the prognostic staging of colorectal cancer. However, for some patients with stage II or III, although the stage is the same, the prognosis is significantly different. Therefore, it is of great significance to study and find more prognostic factors to stratify the risk factors of patients with the same period. The TNM staging is mainly concerned with the tumor cells themselves, but the microenvironment around the tumor is also significantly related to the tumor prognosis[34]. Therefore, DR focuses on the morphological observation of the tumor mesenchyma, which can be an important supplement to the TNM pathological staging of colorectal cancer.

This study systematically and quantitatively analyzed the relationship between tumor interstitial maturity and the prognosis of colorectal cancer[35]. The results of the meta-analysis showed that, compared with patients with mature interstitial, relapse-free survival, disease-free survival, and OS were significantly reduced in patients with immature and intermediate types. All patients included in the relapse-free survival study were in stages I to III, and the results of heterogeneity analysis showed no heterogeneity, indicating that the study results were stable. The heterogeneity of disease-free survival meta-analysis studies may be related to the small number of included studies and the inclusion of stage IV patients. Therefore, more studies on stage IV patients and disease-free survival are needed in the future. Two studies[36,37] involving stage IV patients were included in the meta-analysis of OS, and subgroup analysis showed that primary DR was also significantly associated with OS in patients with stage IV colorectal cancer with metastasis.

Studies[38-40] have shown that DR is closely related to CAFs. CAFs, as an important tumor stromal cell, have both pro- and anti-tumor properties in regulating the tumor microenvironment, and the phenotype of CAFs is closely related to DR. Through interaction with CAFs, tumor cells reconstitute immature fibrostroma, which is conducive to tumor cell invasion and metastasis. Meanwhile, CAFs promote epithelial-mesenchymal transformation of tumor cells by secreting chemical factors and cytokines, which is a recognized mode of tumor cell metastasis. At the same time, there were more tumor buds in the immature interstitial fibers, and tumor buds were a microenvironmental indicator closely related to the poor prognosis of tumors. Studies have shown that an "oligovascular" state in the immature stroma can make it hard for lymphocytes to get in, which lets tumor cells get away from the immune system. Therefore, the interaction between DR and tumor cells involves a variety of molecular mechanisms, and more in-depth studies are still needed.

This study also has some limitations: (1) Relatively few studies included patients in stage IV; (2) there is little literature on disease-free survival; (3) the included studies were mainly from Japan, Europe, and the United States, and there was a lack of large sample studies on Chinese patients; (4) there are differences in the level and mode of surgery in different countries and regions and among different operators, and the differences in postoperative adjuvant treatment plans may affect the results; and (5) DR classification is semi-quantitative, and subjective judgment may also affect the results.

CONCLUSION

In conclusion, this study shows that the level of tumor interstitial maturity is closely linked to the prognosis of colorectal cancer. This finding can be used in addition to the usual signs found in pathological sections. To be sure, a multicenter prospective cohort study for colorectal cancer patients in China is required.