OL Oncology Letters 1792-1074 1792-1082 D.A. Spandidos 10.3892/ol.2016.4913 OL-0-0-4913 Articles Mean platelet volume provides beneficial diagnostic and prognostic information for patients with resectable gastric cancer ShenXiao-Ming 1 * XiaYou-You 2 3 * LianLian 1 4 * ZhouChong 5 LiXiang-Li 6 HanShu-Guang 6 ZhengYan 1 GongFei-Ran 7 TaoMin 4 8 9 10 MaoZhong-Qi 11 LiWei 4 8 10 Department of Oncology, Suzhou Xiangcheng People's Hospital, Suzhou, Jiangsu, P.R. China Department of Radiation Oncology, Lianyungang First People's Hospital, Lianyungang, Jiangsu, P.R. China The Fourth Clinical Medical College, Nanjing Medical University, Nanjing, Jiangsu, P.R. China Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, P.R. China Department of Radiation Oncology, Xuzhou Central Hospital, Xuzhou, Jiangsu, P.R. China Department of General Surgery, Suzhou Xiangcheng People's Hospital, Suzhou, Jiangsu, P.R. China Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, P.R. China Jiangsu Institute of Clinical Immunology, Soochow University, Suzhou, Jiangsu, P.R. China Institute of Medical Biotechnology, Soochow University, Suzhou, Jiangsu, P.R. China PREMED Key Laboratory for Precision Medicine, Soochow University, Suzhou, Jiangsu, P.R. China Department of Minimally Invasive Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, P.R. China Correspondence to: Dr Wei Li, Department of Oncology, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu 215006, P.R. China, E-mail: liwei10@suda.edu.cn Dr Zhong-Qi Mao, Department of Minimally Invasive Surgery, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu 215006, P.R. China, E-mail: maozq31@hotmail.com

Contributed equally

 10 2016 27 07 2016 12 4 2501 2506 05012016 26072016 Copyright: © Shen et al. 2016 This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Gastric cancer is the fourth most frequent cancer and the second cause of cancer-related mortalities worldwide. Platelets play an important and multifaceted role in cancer progression. Elevated mean platelet volume (MPV) detected in peripheral blood has been identified in various types of cancer. In the present study, we investigated the application value of MPV in early diagnostic and prognostic prediction in patients with resectable gastric cancer. In total, 168 patients with resectable gastric cancer were included and separated into the gastric cancer and healthy control groups according to median pre-operatic MPV value (MPV low, <10.51 or MPV high, ≥10.51). The results showed that the pre-operatic MPV level was significantly higher in gastric cancer patients compared with the healthy subjects. Low pre-operatic MPV level correlated with improved clinicopathological features, including decreased depth of invasion, less lymphonodus metastasis and early tumor stage. The Kaplan-Meier plots showed that the patients with higher pre-operatic MPV had decreased overall survival (OS) and disease-free survival (DFS). Surgical tumor resection resulted in a significant decrease in the MPV level. The patients whose MPV level decreased following surgery had an improved OS. Multivariate Cox regression analysis revealed that the depth of invasion, lymphonodus metastasis, American Joint Committee on Cancer (AJCC) stage, and changes in MPV following surgery were prognostic factors affecting OS, and the AJCC stage and pre-operatic MPV were prognostic factors affecting DFS. In conclusion, MPV measurement can provide important diagnostic and prognostic results in patients with resectable gastric cancer.

 mean platelet volume gastric cancer diagnosis prognosis Introduction

Gastric cancer is the fourth most common cancer and the second most common cause of cancer-related mortalities (1). Delayed diagnosis is the principal cause of increased mortality and morbidity associated with this type of cancer. At the time of diagnosis, only 25% of patients are able to undergo surgical resection. The 5-year survival rate is only 10–15% in individuals with advanced disease (1). Therefore, early diagnosis is crucial, especially given that early symptoms (dyspepsia, mild epigastric pain, nausea, and anorexia) are not very specific. Biomarkers including, CEA and CA 19-9, have been tested. However, these biomarkers have a low diagnostic ability to detect gastric cancer (2). Therefore, identification of novel biomarkers for the diagnosis and follow-up of gastric cancer is essential.

Platelets play an important and multifaceted role in cancer progression (3). Previous findings suggested that platelets accelerate the natural course of cancer by promoting neoangiogenesis, degradation of the extracellular matrix, release of adhesion molecules, and growth factors, thus providing essential components for tumor growth and metastatic spread (4). The presence of platelets is increased by proinflammatory cytokines released by cancer cells through the promotion of megakaryocyte proliferation (5). Given the relationship between platelet and cancer, platelet-based markers are potential candidates for the diagnosis and follow-up of gastric cancer. Elevated mean platelet volume (MPV) of peripheral blood has been identified in various types of cancer, including hepatocellular carcinoma (6), ovarian (7), colon (8) lung and breast (9) cancer. In the present study, we examined whether MPV is suitable as a diagnostic and prognostic marker for the detection of resectable gastric cancer.

 Materials and methods <sec> <title>Patients

The study was conducted as a retrospective study of patients with gastric cancer who had been referred to the First Affiliated Hospital of Soochow University between January, 2007 and January, 2010. Approval for the study was granted by the Medical Ethics Committees of the First Affiliated Hospital of Soochow University (Jiangsu, China). Patients with hypertension, hematological and renal disease, heart failure, chronic infection, hepatic disorder and other cancer types were excluded from the study. In total, 168 patients with resectable gastric cancer were recruited in this study. Patient characteristics are presented in Table I. The mean age (range) of study patients was 56.5 (31–82) years. The staging of cancer was determined according to the tumor-node-metastasis (TNM) classification, using the American Joint Committee on Cancer (AJCC) recommendations (10). The patients were followed regularly for 60 months. Thirty age- and gender-matched healthy individuals were also included in the present study.

 Blood analysis

Peripheral venous blood (5–7 ml) was collected into sterile EDTA tubes. Blood specimens were obtained in the morning between 06:30 and 07:30 a.m. to minimize the impact of circulating hormones (circadian rhythm) on the number and subtype distribution of white blood cells. Haematological parameters were analyzed within 30 min after blood collection using a haematology analyser Sysmex XE-2100 (Sysmex, Kobe, Japan). MPV was thus obtained and used in subsequent analyses.

 Statistical analysis

Statistical analyses were performed using SPSS 19.0 software (SPSS, Inc., Chicago, IL, USA). Measurement data were presented as mean ± standard variation. The association between MPV and clinicopathological features were tested using the Chi-square test. For the analysis of survival data, Kaplan-Meier curves were constructed, and statistical analysis was carried out using the log-rank test. The prognostic analyses were performed as disease-free survival (DFS) and overall survival (OS). OS was defined as the time from the diagnosed date to death from any cause. DFS was defined as the time from the primary operation to the relapse of tumor. The multivariate Cox regression was performed for each outcome parameter, using a backwards elimination technique to derive a potentially suitable set of predictors. P<0.05 was considered to indicate statistically significant results.

 Results <sec> <title>Pre-operative MPV is higher in patients with gastric cancer patients compared with healthy controls

The mean pre-operative MPV in the study patients was 10.82±1.06, which was significantly higher than that in the healthy individuals (8.37±0.78, p<0.001; Fig. 1). This result indicated that MPV is useful in the early diagnosis of gastric cancer.

 Low pre-operative MPV level predicts better outcomes

As shown in Table I, pre-operative MPV levels inversely correlated with clinicopathological parameters, including depth of invasion, lymphonodus metastasis and the AJCC stage.

Median OS for all the patients was 57 months, whereas the median was DFS 27 months (Fig. 2A).

The patients were separated into two groups according to median pre-operative MPV: low (<10.51) and high (≥10.51) MPV. The Kaplan-Meier plots showed the association between pre-operative MPV and OS and PFS (Fig. 2B and C). The OS and PFS rates of high pre-operative MPV were 29.8 and 11.9%, respectively, and were significantly different from corresponding rates in the low pre-operative MPV group (46.7 and 24.3%, respectively, both p<0.01). This result demonstrated that patients with higher pre-operative MPV had decreased survival rates.

 MPV changes before and after surgery predict improved outcomes

MPV increased significantly 3–4 days following surgery and returned to pre-operation levels one week after the surgery (Fig. 3A). Furthermore, surgical tumor resection led to a significant decrease in the average MPV one month after surgery (Fig. 3A).

When individual MPV changes were evaluated, it was observed that a decrease was present in 99 patients and absent in the remaining 69 patients. The Kaplan-Meier plots indicating an association between MPV values and OS are shown in Fig. 3B. It was evident that OS was improved in patients whose MPV decreased after surgery, compared with those without any change (40.5 vs. 28.9%, p<0.0037; Fig. 3B).

 Univariate and multivariate analysis of risk factors for OS and DFS

Univariate and multivariate analyses were performed to identify the risk factors associated with OS and DFS. As shown in Table II, univariate analysis revealed that 5 of 10 risk factors affected OS and DFS. These factors included depth of invasion, lymphonodus metastasis, AJCC stage, pre-operatic MPV, and changes in MPV after surgery. Multivariate analysis further confirmed that depth of invasion, lymphonodus metastasis, AJCC stage, and changes in MPV following surgery were the factors associated with OS. Furthermore, AJCC stage and pre-operative MPV were the prognostic factors for DFS.

 Discussion

The involvement of platelets and coagulation factors in hematogenous tumor metastasis are well known. Elevated thrombocytosis and platelet counts are associated with advanced, often metastatic, stages of cancer and to be negative prognostic markers for various types of cancer, including endometrial carcinoma, cervical, ovarian, gastric, and esophageal cancer (11).

Platelets participate in multiple steps of hematogenous metastasis. Covered with platelets, circulating cancer cells can transport more easily in the bloodstream and overcome countering effects of immune cells and physical factors such as shear force and mechanical trauma due to passage through microvasculature (12,13). Platelets can also promote tumor growth by increasing angiogenesis via the cytokine vascular endothelial growth factor (VEGF). The platelet content of VEGF is significantly elevated in cancer patients, and there is a direct correlation between the number of circulating platelets and the level of serum VEGF (3).

The cancer-promoting effects of platelets are amplified by stimulation of activation and aggregation of platelets caused by proinflammatory cytokines released by cancer cells (4). This involves proliferation and differentiation of early progenitor cells such as megakaryocyte progenitors. In addition, malignant cells possess the ability of aggregating platelets through a process known as tumor cell-induced platelet aggregation (TCIPA) (12). Therefore, the close involvement of the platelet with metastasizing cancer makes this cell type a promising candidate for early cancer diagnosis and treatment (11).

Large platelets are more reactive than their smaller counterparts, and are more likely to aggregate, leading to thrombosis. Large platelets are an independent risk factor for myocardial infarction, as platelet size is a predictor of recurrent myocardial infarction and death (14). The MPV tested in our study can be easily evaluated by hematological analyzers, which makes it a convenient marker of platelet functions and activation (3). Elevated MPV may indicate a tendency towards thrombosis, as it has been demonstrated for myocardial infarction and cerebrovascular embolus (15). Previous studies suggested that MPV is a potential biomarker for the diagnosis and follow-up of types of cancer (6–9).

Elevated MPV values may be a consequence of systemic inflammatory response (16), which is believed to play a critical role in the development and progression of different cancers by promoting cancer cell proliferation and survival, angiogenesis, cancer metastasis and modulating cancer cell response to therapies (3). Numerous types of cancer release proinflammatory cytokines, such as interleukin (IL)-1, IL-3, and IL-6, which promote the proliferation of megakaryocytes, resulting in platelet activation and aggregation (4). In ovarian cancer, elevated levels of IL-6 in ascites and cyst fluids have been associated with thrombocytosis. Furthermore, administration of recombinant IL-6 has been associated with increased platelet count (5). Elevated IL-6 is significantly higher in individuals with gastric cancer, as well as in patients with prostate cancer (17,18).

The close interplay between inflammation, coagulation, and cancer progression ignited intensive studies in this field (4). For example, long-term use of non-steroid anti-inflammatory drugs such as aspirin is associated with a reduced risk of esophageal cancer (1). Clinical and epidemiological studies demonstrated an association between chronic inflammation and gastric cancer (19–21). Based on these considerations, we postulated that elevated MPV values in patients with gastric cancer may be a consequence of systemic inflammatory response. Correspondingly, a decrease of MPV values after surgery may be due to a decreased systemic inflammatory response. Therefore, patients whose MPV values did not decrease after surgical resection of the cancer may continue to harbor untamed systemic inflammatory response, leading to an unfavourable prognosis.

In conclusion, the present study indicates an association of the pre-operative MPV level and changes between pre- and post-operative levels with the diagnosis and prognosis of gastric cancer. Although MPV is also a non-specific marker, this non-invasive, convenient and inexpensive biomarker may be a complement to the present biomarkers, and a benefit to the early detection and prognosis evaluation of gastric cancer.

 Acknowledgements

The present study was supported by the National Natural Science Foundation of China (grant nos. 81472296, 81101867, 81272542, 81200369 and 81372443), the China International Medical Foundation (grant no. CIMF-F-H001-057), the Special Foundation of Clinical Medicine of Jiangsu Provincial Bureau of Science and Technology (grant no. BL2014039), the Scientific Research Project of Jiangsu Provincial Bureau of Traditional Chinese Medicine (grant no. L213236), the Medical Scientific Research Project of Jiangsu Provincial Bureau of Health (grant no. Z201206), the Special Foundation of Wu Jieping Medical Foundation for Clinical Scientific Research (grant nos. 320.6753.1225 and 320.6750.12242), the Science and Education for Health Foundation of Suzhou for Youth (grant nos. SWKQ1003 and SWKQ1011), the Science and Technology Project Foundation of Suzhou (grant nos. SYS201112, SYSD2012137 and SYS201335), the Science and Technology Foundation of Suzhou Xiangcheng (grant nos. SZXC2012-70 and XJ201451), and a Project Founded by the Priority Academic Program Development of Jiangsu Higher Education Institutions.

 References WangWHHuangJQZhengGFLamSKKarlbergJWongBCNon-steroidal anti-inflammatory drug use and the risk of gastric cancer: a systematic review and meta-analysisJ Natl Cancer Inst9517841791200310.1093/jnci/djg10614652240 MroczkoBGroblewskaMŁukaszewicz-ZajacMBandurskiRKedraBSzmitkowskiMPre-treatment serum and plasma levels of matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of matrix metalloproteinases 1 (TIMP-1) in gastric cancer patientsClin Chem Lab Med4711331139200910.1515/CCLM.2009.25319728856 KemalYYucelIEkizKDemiragGYilmazBTekerFOzdemirMElevated serum neutrophil to lymphocyte and platelet to lymphocyte ratios could be useful in lung cancer diagnosisAsian Pac J Cancer Prev1526512654201410.7314/APJCP.2014.15.6.265124761879 SeretisCSeretisFLagoudianakisEPolitouMGemenetzisGSalemisNSEnhancing the accuracy of platelet to lymphocyte ratio after adjustment for large platelet count: a pilot study in breast cancer patientsInt J Surg Oncol20126536082012doi: 10.1155/2012/65360823304480 HerasPHatzopoulosAKritikosNKritikosKPlatelet count and tumor progression in gastric cancer patientsScand J Gastroenterol4510051006201010.3109/0036552100379722120377467 ChoSYYangJJYouEKimBHShimJLeeHJLeeWISuhJTParkTSMean platelet volume/platelet count ratio in hepatocellular carcinomaPlatelets24375377201310.3109/09537104.2012.70102822835043 KemalYDemirağGEkizKYücelIMean platelet volume could be a useful biomarker for monitoring epithelial ovarian cancerJ Obstet Gynaecol34515518201410.3109/01443615.2014.91262024832894 MutluHBerkVKaracaHErdenAAslanTAkcaZTreatment regimen with bevacizumab decreases mean platelet volume in patients with metastatic colon cancerClin Appl Thromb Hemost18546548201210.1177/107602961143095822203035 AksoySKilickapSHayranMHarputluogluHKocaEDedeDSErmanMTurkerAPlatelet size has diagnostic predictive value for bone marrow metastasis in patients with solid tumorsInt J Lab Hematol30214219200810.1111/j.1751-553X.2007.00947.x18479300 EdgeSBComptonCCThe American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNMAnn Surg Oncol1714711474201010.1245/s10434-010-0985-420180029 ErpenbeckLSchönMPDeadly allies: the fatal interplay between platelets and metastasizing cancer cellsBlood11534273436201010.1182/blood-2009-10-24729620194899 LianLLiWLiZYMaoYXZhangYTZhaoYMChenKDuanWMTaoMInhibition of MCF-7 breast cancer cell-induced platelet aggregation using a combination of antiplatelet drugsOncol Lett5675680201323420392 ShouLMZhangQYLiWXieXChenKLianLLiZYGongFRDaiKSMaoYXCantharidin and norcantharidin inhibit the ability of MCF-7 cells to adhere to platelets via protein kinase C pathway-dependent downregulation of α2 integrinOncol Rep3010591066201323835679 KaragözBBilgiOAlacacioğluAOzgünASayanOErikçiAAKandemirEGMean platelet volume increase after tamoxifen, but not after anastrazole in adjuvant therapy of breast cancerMed Oncol27199202201010.1007/s12032-009-9191-219263253 MutluHArtisTAErdenAAkcaZAlteration in mean platelet volume and platicrit values in patients with cancer that developed thrombosisClin Appl Thromb Hemost19331333201310.1177/107602961143364422345488 McMillanDCSystemic inflammation, nutritional status and survival in patients with cancerCurr Opin Clin Nutr Metab Care12223226200910.1097/MCO.0b013e32832a790219318937 Lukaszewicz-ZającMMroczkoBGrykoMKędraBSzmitkowskiMComparison between clinical significance of serum proinflammatory proteins (IL-6and CRP) and classic tumor markers (CEAand CA 19-9) in gastric cancerClin Exp Med118996201110.1007/s10238-010-0114-520938721 ShariatSFAndrewsBKattanMWKimJWheelerTMSlawinKMPlasma levels of interleukin-6 and its soluble receptor are associated with prostate cancer progression and metastasisUrology5810081015200110.1016/S0090-4295(01)01405-411744478 IlhanNIlhanNIlhanYAkbulutHKucuksuMC-reactive protein, procalcitonin, interleukin-6, vascular endothelial growth factor and oxidative metabolites in diagnosis of infection and staging in patients with gastric cancerWorld J Gastroenterol1011151120200415069709 LochheadPEl-OmarEMGastric cancerBr Med Bull8587100200810.1093/bmb/ldn00718267927 HussainSPHarrisCCInflammation and cancer: an ancient link with novel potentialsInt J Cancer12123732380200710.1002/ijc.2317317893866

Comparison of pre-operative MPV values between healthy controls and patients with gastric cancer. Measurement data are expressed by mean ± standard. *P<0.001 vs. healthy controls. MPV, mean platelet volume.

Association between pre-operative MPV, and OS and DFS. (A) Predicted probability of OS and DFS. (B) OS stratified based on low or high pre-operative MPV. (C) DFS stratified based on low or high pre-operative MPV. MPV, mean platelet volume; OS, overall survival; DFS, disease-free survival.

Association between changes in MPV values and overall survival. (A) Pre-operative vs. post-operative MPV values. Measurement data are presented as mean ± standard. *P<0.001 vs. pre-operation. (B) OS stratified based on post-operative decrease in MPV values. MPV, mean platelet volume; OS, overall survival; DFS, disease-free survival.

Relationship between pre-operative MPV and demographic and clinical parameters.

Parameters No. of patients Low MPV (<10.51), no. of patients High MPV (≥10.51), no. of patients χ2 P-value
Gender
  Male 116 62 54 1.7825 0.1818
  Female   52 22 30
Age (years)
  <65 96 45 51 0.8750 0.3496
  ≥65   72 39 33
Tumor size (cm)
  <5 108 51 57 0.9333 0.3340
  ≥5   60 33 27
Lauren type
  Intestinal   97 50 47 0.2195 0.6394
  Diffuse   71 34 37
Depth of invasion
  T1, T2   66 15 51 32.3422 <0.001a
  T3, T4 102 69 33
Lymph node metastases
  N0, N1   54 12 42 24.5614 <0.001a
  N2, N3 114 72 42
Degree of differentiation
  Highly differentiated   50 23 27 0.4556 0.4997
  Moderately or poorly differentiated 118 61 57
AJCC stage
  I, II   57 12 45 28.9161 <0.001a
  III, IV 111 72 39

P<0.05, statistically significant. MPV, mean platelet volume; AJCC, American Joint Committee on Cancer.

Univariate and multivariate analysis of risk factors for OS and DFS.

OS DFS
Univariate analysis Multivariate analysis Univariate analysis Multivariate analysis
Risk factors OR (95% CI) P-value OR (95% CI) P-value OR (95% CI) P-value OR (95% CI) P-value
Gender
  Male or female 0.75 (0.46–1.72) 0.806 – – 0.81 (0.44–1.60) 0.835 – –
Age (years)
  <65 or ≥65 1.16 (0.69–1.82) 0.629 – – 1.22 (0.68–2.03) 0.825 – –
Tumor size (cm)
  <5 or ≥5 1.37 (0.68–2.73) 0.227 – – 1.27 (0.65–2.42) 0.237 – –
Lauren type
  Intestinal or diffuse 1.29 (0.73–2.25) 0.605 – – 1.89 (1.33–2.40) 0.454 – –
Depth of invasion
  T1, T2 or T3, T4 2.61 (1.53–3.02) 0.036 2.53 (1.64–3.05) 0.028 2.60 (1.42–3.31) 0.040 – –
Degree of differentiation
  Highly or moderately/poorly differentiated 1.46 (0.72–1.85) 0.722 – – 1.38 (0.74–1.91) 0.757 – –
Lymph node metastases
  N0, N1 or N2, N3 3.54 (2.47–6.80) 0.022 3.64 (2.49–6.85) 0.021 2.92 (1.86–4.53) 0.037 – –
AJCC stage
  I, II or III, IV 4.82 (3.15–7.89) 0.002 4.32 (2.70–6.83) 0.003 4.39 (2.98–6.97) 0.002 4.25 (2.80–6.51) 0.003
MPV
  Low (<10.51) or High (≥10.51) 2.56 (1.42–3.37) 0.004 – – 2.78 (1.67–3.78) 0.003 2.41 (1.36–3.52) 0.001
Changes in MPV after operation
  Decreased or not decreased 3.52 (2.27–6.04) 0.001 3.57 (2.49–5.92) 0.001 3.55 (2.16–5.83) 0.001 – –

OS, overall survival; DFS, disease-free survival; OR, odds ratio; CI, confidence interval; AJCC, American Joint Committee on Cancer; MPV, mean platelet volume.