Background
Diffuse large B-cell lymphoma (DLBCL) is the most frequent type of non-Hodgkin lymphoma, accounting for approximately 30–40% of all malignant lymphomas worldwide [
1,
2]. DLBCL presents heterogeneous and aggressive status with different biological and clinical features [
3]. Since rituximab (R)-cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) regimen became the standard treatment over the past decade, over 60% of DLBCL patients are curable, whereas approximately 30% of patients experience primary refractory or relapsed disease [
4]. Prognostic biomarkers are important for survival prediction and therapeutic strategies selection. International prognostic index (IPI) is widely used for prognosis of DLBCL, however, the prognostic efficiency still needs to be improved [
5]. Therefore, search of cost-effective and easily available prognostic markers is of high importance for DLBCL treatment.
Inflammatory responses are involved in different steps of cancer development [
6]. Inflammation activity plays an important role in prognostication. The indexes derived from hematological parameters are investigated for prognosis of cancer patients in recent years. Platelet-to-lymphocyte ratio (PLR) is calculated as platelet counts divided by lymphocyte counts. PLR was shown to be a significant prognostic marker in various solid tumors including esophageal cancer [
7], head and neck squamous cell carcinoma [
8], ovarian cancer [
9], and breast cancer [
10]. Previous retrospective studies also explored the prognostic effect of PLR in DLBCL, whereas the results were inconsistent even contrary [
11‐
16]. Therefore, it is necessary to conduct a meta-analysis to comprehensively evaluate the prognostic and clinicopathological role of PLR in DLBCL patients.
Discussion
Inflammation plays a pivotal role in tumor progression [
24]. PLR was widely investigated for prognosis of DLBCL patients with distinct results. Previous studies reported the prognostic value of PLR in DLBCL patients [
11‐
16,
22,
23], whereas the results were inconsistent. For example, some studies [
22,
23] demonstrated that PLR was a significant prognostic factor for DLBCL patients, whereas other studies failed to find the prognostic value of PLR [
11,
13,
14]. As meta-analysis can aggregate data from a series of studies and make quantitative analysis, therefore, the results of meta-analysis are objective and credible.
In the present meta-analysis, we aggregated data from eight studies with 1931 patients to shed light on this issue. The results showed that a high PLR was a significant prognostic marker for poorer OS (HR = 1.73, 95% CI 1.29–2.31, p < 0.001). Furthermore, the prognostic efficiency enhanced for Asian patients (HR = 1.95, 95% CI 1.34–2.84, p < 0.001) and with a cut-off value > 150 (HR = 1.76, 95% CI 1.25–2.49, p = 0.001). However, PLR was not associated with PFS in DLBCL, regardless of ethnicity, sample size, or cut-off value of PLR. We also found that PLR was significantly correlated to presentation of B symptoms, elevated LDH, higher tumor stage, and ECOG PS ≥ 2. The results suggested that PLR was positively connected with clinical features reflecting high aggressiveness of the disease. Taken together, this study revealed that PLR was a significant prognostic factor for poor OS and invasiveness in DLBCL patients. To our knowledge, this is the first meta-analysis investigating the prognostic and clinicopathological value of PLR in DLBCL. Notably, the eight included studies are retrospective study design and recruited patients with one ethnicity. In the present meta-analysis, we collected the data and conducted subgroup analysis to investigate the prognostic value of PLR in different ethnicity, sample size, and cut-off values populations. We also investigated the correlation of PLR and clinical features with enlarged sample size compared with included studies. The current meta-analysis provides more comprehensive and systemic analysis than any single included study. Those factors were strengths of this meta-analysis.
Recent evidence suggests that inflammation response is involved in the processes of tumor angiogenesis, tumor growth, and metastasis [
25]. However, the mechanism underlying the correlation between high PLR and poor prognosis in DLBCL patients has not been determined. The increasing of platelet counts and/or decreasing of lymphocyte counts can result in a high PLR. On the one hand, activated platelets were involved in early and advanced stages of tumor angiogenesis [
26]. Platelets could secrete various biological molecules to facilitating angiogenesis in tumor microenvironment [
27]. In addition, platelets derive transforming growth factor-β1 (TGF-β1), work together with the direct interaction of platelets and tumor cells to activate epithelial–mesenchymal transition (EMT) related pathways and induce subsequent metastasis [
28]. On the other hand, lymphocytes exert critical roles in antitumor immune responses. Tumor-infiltrating lymphocytes (TILs) including CD3+ T cells, CD8+ T cells, Th1 CD4+ T cell could inhibit tumor cell proliferation and metastases [
29,
30]. Therefore, it is reasonable to apply PLR as an easily available immunological parameter to predict survival outcomes in cancer patients.
Previous studies also demonstrated the prognostic value of PLR in various tumors [
31]. A recent meta-analysis showed that a high NLR was significantly associated with decreased OS and PFS in ovarian cancer [
9]. Another work suggested that higher PLR was an indicator of poor progress in oral cancer [
32]. Those findings were in accordance with our results in DLBCL. In addition, in the present meta-analysis, we found that PLR was a significant prognostic factor for OS, especially in Asian patients and PLR > 150. Those results suggest that PLR may have enhanced prognostic role when the cut-off value > 150, which provides implications for clinical use. An elevated PLR was also correlated to aggressive tumor characteristics, which may imply that DLBCL patients with high PLR should be treated with strong therapeutic strategies. However, we did not observe significant prognostic impact of PLR on PFS, which may be explained by the relative short follow-up of PFS, compared to OS. In addition, the results suggested that cell of origin had non-significant association with PLR. However, because only two studies were included for analysis, which may lead to the negative results, therefore, more large-scale studies are still needed.
There are several limitations to this study. First, significant heterogeneity was observed in the analysis, although we applied random-effect model accordingly. Because the included studies recruited patients with different ethnicity, disease stage, cut-off values and treatment strategies, which could result in heterogeneity in the meta-analysis. The subgroup analysis showed that significant heterogeneity still exists in different sample size and cut-off values groups. These indicated that the heterogeneity could be inherent among included studies and various cut-off values may be a source of heterogeneity. According to the heterogeneity, we selected corresponding effects model (random effects model or fixed effects model) to pool the data. Second, the cut-off values of PLR were different in included studies, which may influence the distribution of low and high PLR groups and cause heterogeneity. Third, we only included studies published in English and Chinese, therefore, relevant studies published in other languages may be unavailable.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.