Prognostic value of preoperative inflammatory response biomarkers in patients with esophageal cancer who undergo a curative thoracoscopic esophagectomy

Pathological features, including tumor stage, nodal status, and resection margin, are considered important in determining cancer patient survival [11]. However, it is now clear that cancer survival is not solely determined by tumor pathology; indeed, recent studies have shown that preoperative inflammation-based prognostic scores can predict the overall survival of patients with various types of cancers [2‐4]. In the present study, we retrospectively analyzed the clinical data of patients undergoing a potentially curative resection for esophageal cancer to determine whether the LMR, NLR, and PLR have prognostic values according to each TNM pStage. The results demonstrated that the LMR can be used as a novel predictor of postoperative CSS in patients with esophageal cancer after curative esophagectomy. Additionally, univariate analyses revealed that a low LMR was a significant risk factor for poor prognosis in stage III patients, whereas no prognostic factor was detected in patients with stage I or II cancer.

Interleukin-6 (IL-6) is a multifunctional inflammatory cytokine that triggers the proliferation and differentiation of a variety of cell types, including immune competent cells and hematopoietic cells. IL-6 induces not only neutrophil proliferation, but also the differentiation of megakaryocytes to platelets, and these events are similar to those underlying the systemic inflammatory response (SIR) [12, 13]. Theoretically, dynamic changes in the SIR resulting from tumor-host interactions are best estimated by directly measuring the serum IL-6 level. However, routine measurement of IL-6 in cancer patients in the clinical setting is expensive and inconvenient. On the other hand, the LMR, NLR, and PLR are based on blood cell components whose levels are regulated by cytokines, most notably, IL-6; these blood cell components proliferate and differentiate immediately after inflammatory cytokine release [14]. Moreover, measurement of the LMR, NLR, and PLR is easy, convenient, and cost-effective and therefore can be performed routinely.

In this study, we examined the prognostic significance of the LMR, NLR, and PLR in both elderly and non-elderly patients undergoing thoracoscopic esophagectomy for esophageal cancer. Esophageal cancer is the eighth most common cancer and the sixth most common cause of cancer deaths worldwide [15]. It occurs predominantly in elderly people, and the average age at the time of diagnosis continues to rise, with a peak incidence between 70 and 75 years of age [16]. Because age-specific prognostic factors in patients with esophageal cancer have not yet been described, we divided patients into two age groups in order to determine the age-specific prognostic values of the LMR, NLR, and PLR. The reason we chose a cut-off value of 70 years is because “elderly” is typically defined as a patient aged over 70 years in a plurality of studies on elderly patients with esophageal cancer [17‐19].

Platelets are a key element linking the processes of hemostasis, inflammation, and tissue repair. Previous studies have shown that proinflammatory mediators stimulate megakaryocyte proliferation and are responsible for platelet production [20, 21]. Consequently, platelet activation causes angiogenic growth factor release as well as platelet adherence to tumor microvessels and extravasation via increased vascular permeability; this process leads to platelet activation [22, 23]. Lymphocytes can cause systemic inflammation by releasing numerous inhibitory immunologic mediators, particularly interleukin-10 and transforming growth factor-ß, which may consequently cause suppression of antitumor immunity via decreased regulatory T cell levels [6]. Accordingly, there is increasing evidence that lymphocytes are essential for antitumor immune reactions owing to several mechanisms, including the ability to enhance tumor cell apoptosis, inhibition of tumor cell proliferation, and promotion of metastasis [24]. Neutrophils are known to not only produce angiogenic cytokines, but have also been shown to generate matrix metalloproteinase-9, which induces an angiogenic state in cancer cells [25].

Based on such inflammatory responses, systemic inflammatory markers such as the LMR, NLR, and PLR have been shown to predict mortality and recurrence in a variety of cancers, but their role in esophageal cancer remains controversial [7, 20, 26].

We revealed that a low LMR in patients with esophageal cancer was significantly correlated with more advanced TNM pStage (p = 0.0002), but a low LMR was found to be independently associated with poor prognosis via multivariate analysis (HR, 2.372; p = 0.0129), as determined by Kaplan-Meier analysis and a log-rank test (p = 0.0006). A definitive explanation for our findings remains speculative. Monocytes are known to promote tumorigenesis and angiogenesis through local immune suppression and stimulation of tumor neovasculogenesis [25]. Moreover, tumor-associated macrophages developing from mononuclear cell lineages have been demonstrated to be able to inhibit cancer progression and spread of metastatic tumors [27, 28]. This could explain why an elevated monocyte count confers poor clinical outcomes in various types of cancers [29]. A poor prognosis was observed in patients with a low LMR in this study, which is reasonable because both lymphopenia and monocytosis induce immune suppression, as mentioned above. Moreover, the results of subgroup analysis revealed that the preoperative LMR was the most significant prognostic factor in non-elderly patients (HR, 4.553; p = 0.0007), as determined by Kaplan-Meier analysis and a log-rank test (p < 0.0001), but not in elderly patients. The present study may have failed to demonstrate a prognostic significance of the LMR in elderly patients because these patients were more likely to have advanced age-related conditions that cause immune suppression. Further investigations are required to elucidate the precise mechanisms that affect the prognosis of esophageal cancer patients.

Changes in platelet count and platelet function have been identified as part of a paraneoplastic syndrome in many cancers [30], and a high platelet count was found to be closely associated with TNM pStage, metastasis, as well as a high risk of recurrence in many types of cancer [31, 32]. Consequently, the PLR may act as a marker of the balance between host inflammatory and immune responses. However, to the best of our knowledge, the relationship between the PLR and esophageal cancer has not yet been described. We therefore focused on the PLR and CSS in esophageal cancer patients. Although univariate analysis demonstrated that the PLR was a significant risk factor for poorer CSS, as determined by Kaplan-Meier analysis and a log-rank test (p = 0.0169), multivariate analysis failed to confirm that the PLR was a significant predictor of CSS. Similarly, in non-elderly patients, univariate analysis demonstrated that the PLR was a significant risk factor for poorer CSS (p = 0.0172), but this significance was lost when analysis was confined to elderly patients. Recent studies have demonstrated that termed combination of platelet count and mean platelet volume is a predictor for postoperative survival in esophageal cancer patients [33]. Further studies are necessary to examine the role of these inflammatory biomarkers in various types of cancers.

The NLR has been reported to be highly promising in stratifying the outcome in large cohorts of patients with cancer [34, 35]. The relationship between the NLR and prognosis is probably complex and remains unclear. Recently, many studies have shown that a high NLR may indicate an impaired host immune response to the tumor [36]. In this study, the NLR did not affect the prognosis of esophageal cancer patients following curative resection, which may be due to the small retrospective sample size and short follow-up duration of the study. However, other components of the systemic inflammatory response, including cytokines and chemokines, have proven prognostically important in some studies [37].

There were several potential limitations that warrant consideration in our study, which include single-institution retrospective analysis, short follow-up periods, and a small sample size, especially elderly patients. Furthermore, we excluded patients who had received adjuvant chemotherapy and/or radiotherapy, which may have influenced our analysis. Thus, large, prospective, randomized controlled trials are needed to confirm these preliminary results. In addition, the amount of weight loss are well-known prognostic factors for various types of cancers. Minimal weight loss and a good performance status are considered favorable prognostic factors. Needless to say significant weight loss may impact bone marrow function as well as the patient’s ability to mount a host-tumor response. But we could not reveal that weight loss were proven to be independent prognostic factors in esophageal cancer, because our study is retrospective analysis, and data about the weight loss are insufficient.