Association between tumor-stroma ratio and prognosis in solid tumor patients: a systematic review and meta-analysis

Abstract

Tumor-related stroma plays an active role in tumor invasion and metastasis. The tumor-stroma ratio (TSR) in the pathologic specimen has drawn increasing attention from the field of predicting tumor prognosis. However, the prognostic value of TSR in solid tumors necessitates further elucidation. We conducted a meta-analysis on 14 studies with 4238 patients through a comprehensive electronic search on databases updated on May 2016 to explore the relationship between TSR and prognosis of solid tumors. The overall hazard ratio showed that rich stroma in tumor tissue was associated with poor overall survival (OS) (14 studies, 4238 patients) and disease-free survival (DFS) (9 studies, 2235 patients) of patients with solid tumors. The effect of low TSR on poor OS was observed among various cancer types, but not in the early stage of cervical caner. A significant relationship between low TSR and poor OS was also observed in the subgroup analyses based on study region, blinding status, and Newcastle-Ottawa Scale (NOS) score. Subgroup analyses indicated that cancer type, clinical stage, study region, blinding status, and NOS score did not affect the prognostic value of TSR for DFS. Moreover, low TSR was significantly correlated with the serious clinical stage, advanced depth of invasion, and positive lymph node metastasis. These findings indicate that a high proportion of stroma in cancer tissue is associated with poor clinical outcomes in cancer patients, and TSR may serve as an independent prognostic factor for solid tumors.

Keywords: clinicopathological features; meta-analysis; prognosis; solid tumors; tumor-stroma ratio.

Figure 1. Flow diagram of the study selection process and specific reasons for exclusion in the meta-analysis

176 studies were preretrieved in accordance with the established search strategies. Of these articles, 104 were excluded because of clear lack of relevance. The remaining 72 studies were further screened out through browsing the titles and abstracts, and then 46 were removed based on the eligible criteria. After reading the full texts of 26 studies, 14 eligible studies were finally included in this meta-analysis.

Figure 2. Forest plots of the overall outcome for overall survival (OS)

Hazard ratios (HRs) for each trial are represented by the squares, and the horizontal lines crossing the square stand for the 95% confidence intervals (CIs). The diamonds represent the estimated pooled effect of the overall outcome for OS in all solid tumors. All P values are two-sided.

Figure 3. Forest plots of the overall outcome for disease-free survival (DFS)

Hazard ratios (HRs) for each trial are represented by the squares, and the horizontal lines crossing the square stand for the 95% confidence intervals (CIs). The diamonds represent the estimated pooled effect of the overall outcome for DFS in all solid tumors. All P values are two-sided.

Figure 4. Effect of individual studies on pooled hazard ratios (HR) for the relationship between tumor-stroma ratio (TSR) and prognosis of solid tumors

A. Sensitivity analysis for overall survival (OS). The vertical axis at 1.89 indicates the overall HR, and the two vertical axes at 1.56 and 2.29 indicate its 95% confidence interval (CI). Every hollow round indicates the pooled HR when the left study was omitted in a meta-analysis with a random model. The two ends of every broken line represent the respective 95% CI. B. Sensitivity analysis for disease-free survival (DFS). The vertical axis at 2.10 indicates the overall HR, and the two vertical axes at 1.67 and 2.63 indicate its 95% CI. Every hollow round indicates the pooled HR when the left study was omitted in a meta-analysis with a random model. The two ends of every broken line represent the respective 95% CI.

Figure 5. Begg's funnel plots for assessment of potential publication bias in studies of tumor-stroma ratio in patients with solid tumors

Each study represented by one circle. The horizontal line represented the pooled effect estimate. A. Begg's funnel plot of publication bias for studies reporting overall survival (OS). B. Begg's funnel plot of publication bias for studies reporting disease-free survival (DFS).