Abstract
Background/Aim: Systemic inflammation has been implicated in the development and progression of cancer. Inflammatory markers have been identified as prognostic indicators in numerous malignancies. This study explored the prognostic relevance of the initial and postoperative neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) on relapse-free survival (RFS) and overall survival (OS) in patients with soft-tissue sarcoma (STS) who underwent curative resection. Patients and Methods: We included 89 patients with STS who underwent extensive and radical resection at the Kyungpook National University Chilgok Hospital between 2004 and 2018. Kaplan-Meier curves for RFS and OS were calculated using multivariate Cox proportional models. Results: A total of 67 (75.3%) patients demonstrated a high initial NLR (≥4.1) and 65 (75.3%) showed a high initial PLR (≥231). In the univariate and multivariate analyses, an elevated initial PLR ratio was significantly associated with a decreased RFS (p=0.017) and OS (p=0.003). Patients with a high PLR (PLR >231) had a median RFS of 24 months, whereas those with a low PLR (PLR ≤231) had a median RFS of 96 months. The median OS was 50 and 298 months for the high PLR and low PLR groups, respectively. Furthermore, a high postoperative PLR ratio was associated with a decreased RFS (p=0.001) and OS (p=0.038). Conclusion: Preoperative and postoperative PLR ratio can be used as a cost-effective prognostic marker for oncologic outcomes in patients with STS who undergo surgery.
Soft tissue sarcomas (STS) represent a complex group of tumors originating from mesenchymal tissues, accounting for approximately 0.7% of all cancers and 0.8% of cancer mortality (1). According to histopathological diversity, STS are classified into over 70 heterogeneous subtypes and exhibit varying levels of biological aggressiveness and clinical features (2). The standard treatment for localized STS includes surgical resection with or without adjuvant radiotherapy; however, the 5-year recurrence rate remains high and up to 50% of patients eventually experiences metastases and death despite undergoing definitive treatment (3-5). Thus, there is an unmet need to identify markers that determine the prognosis and biological behavior of STS, despite the presence of already established parameters, such as age at diagnosis, tumor site, tumor size, tumor depth, pathologic grade, histologic subtype, and margin status (6, 7).
Inflammation has been recognized as a hallmark of cancer that substantially contributes to the development and progression of malignancies (8, 9). Furthermore, there is increasing evidence for the roles of local inflammatory response and systemic inflammation in host immune surveillance, reduced therapeutic response, and induction of genetic instability (10). Furthermore, recent data indicated the prognostic implications of inflammatory markers, including C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and serum cytokines, including alterations in specific subsets of circulating peripheral blood cells in STS (11-13).
In recent years, systemic inflammatory indicators including pretreatment neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and lymphocyte/monocyte ratio (MNL) have been found to be associated with the prognosis of various cancers (14-18). In a meta-analysis by Liu et al., pretreatment NLR was associated with an unfavorable prognosis in conjunction with advanced clinicopathological features in patients with STS (19). They showed that an elevated NLR was significantly correlated with a worse overall survival (OS) [hazard ratio (HR)=1.59, 95% confidence interval (CI)=1.28-1.97, p<0.001] and progression-free survival (PFS) (HR=1.28; 95%CI=1.12-1.47; p<0.001). Additionally, elevated NLR was highly correlated with old age (≥65 years), increased tumor size (>5 cm), advanced tumor depth (deep), a high grade (G3), and tumor, node, metastasis stage (III-IV).
However, there are few reports on the prognostic role of PLR in patients with STS who underwent curative surgical resection. Moreover, the prognostic significance of serial preoperative and postoperative PLR in patients with STS has hardly been evaluated. This study aimed to clarify the relationship between preoperative and postoperative PLR and the oncologic outcome of patients with STS who underwent curative surgery.
Patients and Methods
Participants. In this retrospective study, a total of 89 patients with histologically confirmed STS, who underwent extensive and radical resection between 2004 and 2018 at the Kyungpook National University Chilgok Hospital (Daegu, Republic of Korea) were enrolled. Longitudinal measurements of neutrophil, lymphocyte, and platelet counts were all assessed before and after surgery. The laboratory test was conducted 1 to 4 weeks prior to the surgery and between 2 and 12 weeks after the surgery. None of the patients had received chemotherapy before collection of blood count data. Clinical information and histopathological parameters were retrospectively obtained through a database chart review. Disease staging was performed according to the American Joint Committee on Cancer (AJCC) 8th edition (20).
PLR was defined as the absolute platelet count measured in 109/l, divided by the absolute lymphocyte count measured in 109/l. The NLR was calculated as the absolute neutrophil count measured in 109/l, divided by the absolute lymphocyte count measured in 109/l.
Statistical analysis. Relapse-free survival (RFS) was estimated from the time of surgery until disease recurrence or death. OS was calculated from the date of diagnosis to death from any cause. Using the Kaplan-Meier method, the overall cumulative probability of survival was calculated, and differences in survival rates were determined using the log-rank test. The chi-square (χ2) test was used to analyze the relationship between PLR and NLR and clinicopathological factors. To derive a potentially suitable set of predictors, a multivariate analysis was conducted using variables with a value of p<0.1 in a univariate analysis using Cox’s proportional hazards model. Statistical significance was set at a two-sided p<0.05. Statistical analyses were performed using SPSS software version 20.0 (SPSS Inc., Chicago, IL, USA).
Results
Patient and tumor characteristics. The median age of the patients was 55 years (range=27-86 years), and the male-to-female ratio was approximately 1:1. The histopathological subtypes included liposarcoma in 30 (33.7%), leiomyosarcoma in 16 (18.0%), spindle cell sarcoma in six (6.7%), malignant fibrous histiocytoma (MFH) in eight (9.0%), synovial sarcoma in six (6.7%), rhabdomyosarcoma in six (6.7%), dermatofibrosarcoma protuberans (DFSP) in four (4.5%), and pulmonary artery sarcoma in two (2.5%) patients. The primary tumor sites were located in the abdomen/pelvis (n=37), thoracic/trunk (n=25), extremity (n=13), retroperitoneum (n=11), and head/neck (n=2) (Table I).
Association between clinicopathological features and the neutrophil-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR).
Tumor size and depth were stratified according to the pathological report, and a threshold of 5 cm used for size classification. Tumor size was defined as either the largest diameter described in the pathology report or the largest diameter measured in radiographic cross-sectional studies. The depth of the tumor was evaluated as deep or superficial in relation to the investing fascia of the extremity. Furthermore, staging was determined according to the 8th edition of the AJCC criteria. Because of a significant amount of data with unknown staging, these cases were classified as “unknown”.
The patients were categorized according to levels of preoperative and postoperative NLR and PLR using optimized cutoffs to predict survival as derived from the receiver operating characteristic curve (ROC) curve analysis (<4.1, <3.2, <231, and <228.8). A total of 23 patients (25.8%) were categorized as initially high NLR and 24 (38.2%) as high PLR. Regarding postoperative NLR and PLR, the elevated group included 34 patients (18%) for NLR, and 24 (27.0%) with PLR.
Regardless of the preoperative and postoperative NLR and PLR, the most common histologic type was liposarcoma, accounting for 32 cases (36%). Subsequently, leiomyosarcoma ranked second with 15 cases (16.9%), while the remaining subtypes exhibited a similar distribution.
No significant differences were observed in the distribution of tumor characteristics (depth, staging, size, and site), age, and sex between the groups with high or low preoperative NLR and PLR, and those with high or low postoperative NLR and PLR. In terms of recurrence and mortality rates, the initial PLR group demonstrated statistically different distributions compared with the other group. Furthermore, in terms of mortality rate, statistically significant differences in distributions were observed among the initial PLR, postoperative NLR, and postoperative PLR groups.
Survival analyses. At the time of data analysis, 16 patients (18%) had died. In the univariate analyses of RFS and OS, preoperative and postoperative PLR and tumor size were found to be prognostic factors (Table II). Multivariate analyses revealed that preoperative and postoperative PLR was also an independent prognostic factor for RFS and OS (Table III). In the univariate and multivariate analyses, an elevated initial PLR ratio was significantly associated with a decreased RFS (HR=2.778; 95%CI=1.154-6.741, p=0.033) and OS (HR=3.568; 95%CI=1.583-8.038, p=0.023). Patients with a high PLR (PLR >231) had a median RFS of 24 months, whereas those with a low PLR (PLR ≤231) had a median RFS of 96 months. The median OS was 52 months and 181 months for the high PLR and low PLR groups, respectively. Furthermore, a high postoperative PLR ratio was significantly associated with a decreased RFS (HR=3.921; 95%CI=1.738-8.845, p=0.001) and OS (HR=5.702; 95%CI=1.099-29.576, p=0.038). In the high postoperative PLR group, the median RFS was 17 months, whereas in the low postoperative PLR group, it was not reached, indicating a significant difference. Furthermore, the median OS in the high postoperative PLR group was 54 months, whereas that in the low postoperative PLR group was 116 months. A negative correlation was observed between postoperative PLR and RFS or OS.
Univariate and multivariate Cox proportional analysis regarding relapse-free survival (RFS).
Univariate and multivariate Cox proportional analysis regarding overall survival.
Tumors larger than 5 cm showed a gain in RFS (HR=1.132; 95%CI=1.021-1.256) compared with those smaller than 5 cm, although this difference was not statistically significant in the multivariate analysis. The tumor size did not impact OS.
Figure 1 depicts the Kaplan-Meier curves illustrating the preoperative and postoperative PLR in relation to RFS. According to the cutoff value determined using the ROC curve, the study was divided into two groups, illustrating the survival rates for each group. Both preoperatively and postoperatively, the group with a high PLR exhibited better RFS compared with the low PLR group (p=0.001, p=0.008). These results are consistent with OS outcomes, as lower PLR values were correlated with better OS in comparisons conducted both preoperatively and postoperatively (p=0.007, p=0.006) (Figure 2).
Comparison of recurrence-free survival (RFS) between two groups divided based on the cutoff value of platelet-to-lymphocyte ratio (PLR). In both preoperative and postoperative settings, lower PLR values were associated with better survival rates. mRFS: Median relapse-free survival; HR: hazard ratio.
Comparison of overall survival (OS) between two groups divided based on the cutoff value of platelet-to-lymphocyte ratio (PLR). In both preoperative and postoperative settings, lower PLR values were associated with better survival rates. mOS: Median overall survival; HR: hazard ratio.
Discussion
This study examined the role of PLR in the prognosis of patients with STS who underwent curative surgery. It revealed that preoperative and postoperative PLR plays a negative predictive role in the preoperative and postoperative survival of patients. PLR was associated with a shorter RFS in STS in the univariate analysis (HR=2.120; 95%CI=1.021-4.883, p=0.017; Table II) and remained significant in multivariate analysis (HR=2.778; 95%CI=1.154-6.741, p=0.033). This pattern showed consistent results both before and after surgery. PLR was also associated with a shorter OS in STS (HR=5.073; 95%CI=1.73-14.87, p=0.003) in the univariate analysis (HR=3.568; 95%CI=1.583-8.038, p=0.023) and multivariate analysis (Table III). This pattern is reminiscent of the findings of a recent study on NLR and PLR in undifferentiated pleomorphic sarcoma (21).
Inflammation plays a significant role in the progression of cancer, as demonstrated by numerous studies (4, 13-15). An increased platelet count has been demonstrated to have an unfavorable impact on survival rates in several types of cancer, such as renal, lung, and colon cancer (16, 20, 21). Although the exact relationship between an elevated platelet count and the characteristics of cancer remains unclear, it is known to be associated with inflammatory cytokines between cancer cells and hosts. Platelets contain substances that interact with cancer cells and are involved in the growth, invasion, and cancer cell angiogenesis (22). And platelets are capable of protecting tumor cells from cytolysis by NK cells, thereby promoting metastasis (23). Pretreatment PLR and neutrophil count have been shown to be predictive markers for metastasis in osteosarcoma (24).
The combined use of NLR and PLR is as a prognostic predictor in patients with operable STS (25). Moreover, preoperative PLR is superior to NLR as a prognostic factor for STS (26). Conversely, Que et al. highlighted preoperative PLR as a more valuable predictor of prognosis than NLR, whereas our study emphasizes the higher diagnostic value of both preoperative and postoperative PLR over postoperative NLR. To the best of our knowledge, our study is the first to compare preoperative and postoperative PLR as a prognostic marker in STS. A few studies have described the value of preoperative PLR as a prognostic marker, however, little is known regarding the timing of PLR. A retrospective study showed an association between postoperative elevated platelet count and poor prognosis in colorectal cancer (27). Additionally, it has been documented that elevated PLR persisting before and after chemotherapy, without surgery, is associated with poor metastatic-free survival (28). There is a meta-analysis demonstrating the prognostic value of PLR in various cancers but not in STS. This study showed a similar pattern with a cutoff of 160 and HR of 1.88 compared with our study (29).
Study limitations. There is a possibility that the inflammatory markers may have increased due to reasons other than STS. Because all data were retrospectively acquired and involved a single-center, clinical and survival comparisons may have been influenced by selection bias. There are limitations due to a significant amount of missing data and the heterogeneous timing of postoperative laboratory data. Furthermore, there may be doubts regarding whether a single complete blood count (CBC) profile at one time point can adequately represent the patient’s condition. Additionally, other systemic inflammatory immune indices known as prognostic factors, such as C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and albumin, were not included in our study (13, 30). Furthermore, various entities of diseases within STS were included; therefore, there may be limitations in interpretation.
Conclusion
A high PLR ratio before and after surgery is associated with poor RFS and OS. PLR is likely to be highly useful as an economical and practical prognostic marker. Patients with high PLR values both before and after surgery may require more frequent follow-up and intensive therapy. A meta-analysis on PLR seems warranted, and a subgroup analysis for the various sarcomas within STS is necessary.
Acknowledgements
This work was supported by Biomedical Research Institute grant, Kyungpook National University Hospital (2017).
Footnotes
Authors’ Contributions
IHL and JHN contributed equally to the writing of the manuscript, including the overall conceptualization, study design, statistical analysis. SJL conducted the overall review and provided critical revisions to the manuscript.
Conflicts of Interest
The Authors have no conflicts of interest to declare in relation to this study.
- Received March 13, 2024.
- Revision received April 12, 2024.
- Accepted April 18, 2024.
- Copyright © 2024, 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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