Can neutrophil-lymphocyte ratio and mean platelet volume be used to predict metastasis in individuals with lung cancer?

Abstract

Chronic inflammation plays an important role in the etiopathogenesis of many life-threatening chronic diseases, including cancer. Currently, the relationship between inflammation, native immunity and cancer is widely accepted; however, many of the mechanisms mediating this relationship remain undetermined and the clinical significance of these markers is unclear. The purpose of this study was to investigate the potential of neutrophil-lymphocyte ratio (NLR) and mean platelet volume (MPV) to indicate the existence of metastasis in lung cancer. This retrospective cross-sectional study evaluated patients with lung cancer of any pathological type who was admitted to the Palliative Care Unit of the referral hospital in the region between January 2019 and February 2020. Patient characteristics, distant organ metastasis, treatments, NLR and MPV values were noted. Patients were grouped as with or without metastasis. Characters, NLR, MPV values were compared. One hundred twenty-six patients were included. The mean age of the patients was 61.17 ± 9.4 years and 7.9% (n = 10) were female. The patients with a history of chemotherapy were 47% (n = 60) and distant organ metastases were present in 38.9% (n = 49) of the patients. The mean MPV value of 49 patients with distant metastasis was 8.34 ± 0.8 fL. MPV values of those with metastasis were found to be significantly higher than those without (P = .010). There was no significant difference in NLR values between groups (P = .920). Lung cancer patients with metastasis were found with higher MPV values. MPV can be effective and most accessible test in prediction of metastasis in lung cancer patients regardless of the pathological type.

1. Introduction

Lung cancer is one of the most prevalent cancers worldwide. ^[1,2] In spite of the developments in treatment, the prognosis of patients with lung cancer remains poor with a 5-year survival rate of under 15%.^[3,4]

The chronic inflammation plays an important role in the etiopathogenesis of many life-threatening chronic diseases, including cancer.^[5] Tumors modulate the inflammatory response by the secretion of growth factors and chemo-attractant which suppress anti-cancer T cell responses.^[6] The inflammatory markers are being studied to predict the course and severity of chronic diseases. Neutrophils play a major role in tumor angiogenesis through the production of proangiogenic factors, which leads to the adhesion and seeding of metastasis.^[7,8] In current studies, it is defined that the total white blood cell count and its subtypes count and their ratio to lymphocytes neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio, eosinophil/lymphocyte ratio can be used as an indicative blood marker of systemic inflammatory responses.^[9–11] During the inflammatory reaction, the proportion of circulating leukocytes changes with lymphopenia observed relative to neutrophilia.

Platelets also play a significant role in cancer progression and metastasis.^[1] In cancer patients, the production, maturation and size of platelets may change with the effect of some pro-inflammatory cytokines such as interleukin-6, granulocytes colony stimulating factor and macrophage colony stimulating factor.^[1] Additionally platelets facilitate the hypercoagulability which leading cancer progression. Platelets take part in the different steps of angiogenesis including proliferation, migration, extracellular matrix degradation, and adhesion of endothelial cells.^[12] Mean platelet volume (MPV) is a platelet volume index which is associated with inflammation and considered to be a marker of platelet activation.^[13]

Some hematological and biochemical markers of inflammation were found to be associated with the presence or prognosis of several cancer types. ^[14,15] NLR and MPV are easily performed in daily routine at every clinics including primary health care clinics. Nevertheless, the clinical significance of these markers for metastasis in lung cancer patients is unclear. The aim of present study to investigate NLR and MPV measures and their predictive value in the lung cancer patients with metastasis.

2. Methods

In this retrospective cross-sectional study, records of all the patients with lung cancer with any pathological type admitted to the Palliative Care Unit of the referral hospital of the region, between January 2019 and February 2020 was evaluated. Individuals with a second history of malignancy, those with a history of post-obstructive pneumonia, rheumatological, hematological or other chronic diseases like diabetes, patients with acute or chronic infections; history of drug and steroid use that would disrupt coagulation cascade, patients with a history of surgery and blood transfusion in the last 3 months and patients with missing clinical and laboratory data, were excluded from the study. Characteristics of the patients, treatments, metastasis; NLR and MPV values were reported from the hospital database. Patients were categorized as with or without metastasis. Characteristics, NLR, MPV values were compared.

Data analysis was performed with SPSS (version 24i SPSS Inc, Chicago IL). All data were presented as the mean (± SD) or rate (%). A 1-sample Kolmogorov–Smirnov test was performed to analyze the distribution of clinical variables. The Student t test were used for the comparison of parametric variables. The Mann–Whitney U test and the χ2 test were used for the comparison of the nonparametric variables. Receiver-operating characteristics (ROC) curve analysis was further performed to identify optimum cutoff values of selected hematological parameter. Likelihood Ratio Positive test were performed to identify cutoff value. The results were evaluated at the 95% confidence interval. A P value of less than .05 was considered statistically significant. The study was approved by the local ethics committee (October 05, 2021).

3. Results

126 patients were included in the study admitted in the Palliative Care Center. The mean age of the all patients and the patients with metastasis was 61.17 ± 9.4 (32–86) and 59 ± 9.23 (41–86) years respectively. Seven-point nine percentage (n = 10) of the patients were female. The patients with a history of chemotherapy were 47.6% (n = 60). Distant organ metastases were present in 38.9% (n = 49) of the patients. In patients with distant organ metastases, brain was the first frequent region with 18.3% (n = 23), while bone was the second region with 8.7% (n = 11). Characteristics of the patient is presented in the Table 1. In the patients with present metastasis %42.9 (n = 21) had chemotherapy before and %98 (n = 48) of the patients were still on the ongoing radiotherapy.

Table 1 - Charactherics of the patients.

Characteristics	n (%)/x̄±SD (min-max)
Age (yr)	61,17 ± 9,4 (32–86)
Female	10 (7, 9)
Male	116 (92, 1)
Distant organ metastasis
Brain	23 (18, 3)
Bone	11 (8.7)
Widespread metastasis	4 (3.2)
Bone + brain	2 (1, 6)
Bone + surrenal gland	2 (1, 6)
Bone + liver	2 (1.6)
Kidney	1 (0, 8)
Skin	1 (0, 8)
bone + skin	1 (0, 8)
Brain + spinal cord	1 (0.8)
Spinal cord	1 (0.8)
History of chemotherapy	60 (47, 6)
Ongoing therapy	124 (98.4)

The mean MPV value of 49 patients with distant metastasis was 8.34 ± 0.8 fL, and the mean NLR value was 10.56 ± 9.1. Mean MPV value of patients without distant organ metastasis was found to be 8.0 ± 0.8fL, and mean NLR value was 10.9 ± 12.6. MPV values of those with metastasis were found to be significantly higher than those without metastasis (P = .010) (Table 2). There was no significant difference between the NLR values of the groups (P = .920). ROC curve analysis was used to determine the optimal cutoff value for MPV. Based on the ROC curve if the chosen cutoff point for MPV was 7.35 fL, the sensitivity and specificity were 0.878 and 0.234, respectively (area under curve = 0.637, 95% CI: 0.537–0.736, P = .010) (Fig. 1).

Table 2 - Comparison of age, MPV and NLR.

	No metastasis n = 77 x̄±SD (min-max)/Median (25.P-75.p)	Metastasis n = 49 x̄±SD(min-max)/Median(25.P-75.p)	P value
Age (yr)	62.1 ± 9.45 (32–82)	59 ± 9.23 (41–86)	.140*
MPV (fL)	7.8 (7.4–8.6)	8.3 (7.9–8.9)	.010†
NLR	7.8 (5.1–11.5)	7.3 (4.6–13.6)	.920†

MPV = mean platelet volume, NLR = neutrophil-lymphocyte ratio.

^*T test.

^† Mann–Whitney U test.

Figure 1.: ROC analyse of MPV.

4. Discussion

The significance of hematological parameters in the diagnosis of metastasis was evaluated in lung cancer in any pathological type. To the best of our knowledge, present study is first report that increased MPV in lung cancer patient is associated with the presence of metastasis.

An increased MPV is an early marker of platelet activation. Larger platelets may be more promptly stimulated to release mediators; therefore, larger platelets are recognized as being more reactive compared to smaller ones.^[16] Thrombocytes play major role in the development, progression, and metastasis of a tumor.^[17] Hypercoagulability is a sign of aggressive cancer, and thromboembolism is one of the primary causes of mortality.^[17] Thrombocytosis is common in lung cancer patients and is considered a reaction to the cancer. In line with the results of this study, recent studies revealed that thrombocytosis is linked to with progression in various tumor types, including lung cancer.^[1]In Omar et al^[18] study; higher MPV was suggested to have significant effect on the prognosis in patients with stage IIIB/IV non-small cell lung cancer as well as multiple metastatic cites at time of diagnosis. In another study evaluating the combined preoperative platelet counts and MPV values of 546 patients with non-small cell lung cancer who underwent curative resection, the combination of preoperative platelet count and MPV was found to be a significantly independent prognostic factor for overall survival.^[13] Although this results differ considerably from those of Kumagai et al^[16] study and several others.^[19,20]The reason for this rather contradictory results can be explained by different characteristics of the patients. Therefore, physicians shall take age, gender, ethnicity and body mass index into account when applying MPV values to diagnosis, because it is documented that there are different “normal” inflammation parameters.^[21]

In the study of Templeton et al^[22], it was found that high neutrophil count in peripheral blood was associated with tumor metastasis. As the neutrophil count increased, the tendency to decrease in lymphocyte count might occur as a result of a decrease in the peripheral circulation of the lymphocytes that infiltrate the tumor, in both an increased NLR value was seen. However, the consistency of the prognostic impact of NLR are unclear. Contrary to the results of this study, there are studies that showed tumors metastasis may occur more frequently in the patients with higher NLR.^[5] In a study evaluating 136 patients with small cell lung cancer, the median survival was found to be worse in the higher NLR group.^[23] Goksel et al^[24] showed that MPV, NLR values were significantly higher in patients who have not yet received any treatment and newly diagnosed lung cancer. In those patients as the stage and primary tumor size progressed, NLR value increased. Different stage and primary tumor size and treatments could point out the dissimilarity between other studies and these results. Accordingly, most of these studies were also held between healthy individuals and cancer patients which could impact the results. Also, there are studies showing that NLR may affect the response to chemotherapy and prognosis in many cancers type including lung cancer. ^[9,10,25] NLR level may be affected from patients infective disorders, additional diseases and some medicines like steroids. Comprehensive studies with larger series are needed on this subject.

Notably, it has long been recognized that multiple inflammatory mediators fundamentally contribute to metastasis, cell invasion, extravasation and metastatic outgrowth, but the underlying mechanisms have long remained obscure. Furthermore, inflammatory mediators promote the survival of circulating metastatic “seeds.” ^[6] An evidence from this work suggests; MPV, which is a pro-inflammatory and prothrombotic marker, can be used to predict metastasis in patients with lung cancer in centers with limited imaging and laboratory tests. In the long-term follow-up of lung cancers, which is one of the most common cancers in family medicine practices even in the rural areas, MPV value, which can be simply applied, can be early marker of the metastasis. If it is supported by a sufficient number of evidence-based studies, considering this single centered study with relatively small sample size and regardless of the lung cancer type, use of inflammation markers such as MPV and NLR can be included in the current practice, it can be used in the referral planning of the patient in terms of advanced examination, and treatment planning in the early period.

5. Conclusion

Lung cancer patients with metastasis were found with higher MPV values. MPV can be effective and most accessible test even in the rural areas, in in prediction of metastasis in lung cancer patients regardless of the pathological type.

Author contributions

Conceptualization: Yasemin Kiliç Öztürk.

Data curation: Burcu Şen Şahin, Merve Dağci.

Formal analysis: Yasemin Kiliç Öztürk.

Methodology: Yasemin Kiliç Öztürk.

Supervision: Yasemin Kiliç Öztürk.

Writing – original draft: Yasemin Kiliç Öztürk, Hande İleri, Burcu Şen Şahin, Merve Dağci.

Writing – review & editing: Yasemin Kiliç Öztürk, Hande İleri.