The clinical implications of mean platelet volume and mean platelet volume/platelet count ratio in locally advanced esophageal squamous cell carcinoma

The clinical implications of mean platelet volume and mean platelet volume/platelet count ratio... SUMMARY As a hallmark of platelet activation, mean platelet volume (MPV) has been identified to be associated with various malignancies. However, the correlation between MPV, mean platelet volume/platelet count ratio (MPR), and esophageal squamous cell carcinoma (ESCC) remains unclear. The aim of this study is to clarify the relevance of MPV and MPR in patients with locally advanced ESCC. Four hundred and fifty-seven cases with newly diagnosed locally advanced ESCC followed by radical surgery and 240 healthy subjects matched for age and gender were included in this study. We retrospectively compared various hematological variables between groups and analyzed the correlation between MPV, MPR, and patients’ clinicopathologic characteristics. Preoperative MPV and MPR were found to be significantly decreased in locally advanced ESCC when compared to healthy controls, they were (8.14 ± 1.09 fL vs. 10.23 ± 0.78 fL, P < 0.0001) and (0.03875 ± 0.02645 vs. 0.04463 ± 0.00972, P = 0.001), respectively. In addition, patients with advanced tumor length (≥4 cm) tended to have lower MPV levels (8.03 ± 1.11 fL versus 8.33 ± 1.21 fL, P = 0.005), while there was no difference between other subgroups. Moreover, decreased MPR was significantly correlated with advanced tumor length (P < 0.001) when divided at a median of 0.03420. Decreased MPV and MPR were significantly associated with locally advanced ESCC. Thus, they might be helpful in screening and risk stratification for locally advanced ESCC in combination with other approaches. INTRODUCTION Esophageal cancer is the eighth most common cancer and fourth cause of cancer-related death worldwide, with more than 480 000 new cases and 400 000 deaths each year, half of which occur in China.1,2 The main pathological subtypes include esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). EAC remains the major subtype in some Western countries, whereas ESCC is the predominant histological type in certain regions of Asian countries.3,4 Although great progress has been made in the early diagnosis of ESCC in last decades, only 25% of ESCC patients can undergo a potentially radical resection and the prognosis still remains poor.5 Thus, identification of promising markers contributing to the screening and risk stratification of locally advanced ESCC might improve their long-term survival.6,7 Systemic inflammation response and the proinflammatory cytokines have been confirmed to be involved in the process of tumor invasion, progression, distant metastasis, and suppression of adaptive immunity.8,9 With their secretions of proinflammatory factors, chemokines and growth factors, activated platelets play an important role in the pathophysiology of various disorders, including malignant tumors.10–22 As indicators of platelet activation, mean platelet volume (MPV) and mean platelet volume/platelet count ratio (MPR) have attracted serious attention in the past few decades with numerous studies assessing the correlation between them and diverse malignancies. Several studies have demonstrated that MPV levels were significantly higher in colon cancer, gastric cancer, hepatocellular carcinoma and papillary thyroid carcinomas than healthy subjects. In addition, MPV could serve as an easily available biomarker for screening and monitoring the healthy populations for such malignancies and might prompt physicians to make early diagnosis.19–22 Whereas one research showed that MPV and MPR were significantly decreased in the nonsmall cell lung cancer (NSCLC) group and MPR was closely associated with patients’ survival.23 However, the roles of MPV and MPR in patients with ESCC have not yet been comprehensively investigated. Therefore, the aim of this study is to clarify the relevance of them in patients with locally advanced ESCC. PATIENTS AND METHODS Patients and healthy populations We selected a consecutive cohort of 510 patients who underwent radical esophagectomy and histopathologically diagnosed with locally advanced ESCC at the Department of Thoracic Surgery, Anhui Cancer Hospital and Anhui Provincial Hospital between January 2006 and December 2012. Exclusion criteria were as follows: patients with synchronous or metachronous cancer other than ESCC, patients who had received preoperative chemotherapy and/or radiotherapy, patients who had concurrent disease that would affect the hemostatic system (e.g., liver disease and blood coagulation disorders), those who received anticoagulants, corticosteroids, estrogen, or aspirin treatment within 1 month before the surgery. Additionally, to eliminate the influences of noncancer diseases on hematological indices, patients with a history of hypertension, renal disease, heart attack or stroke, chronic inflammatory diseases including autoimmune disorder and infection were also excluded. Therefore, a group of 457 cases met the inclusion and exclusion criteria and were included in our finial analysis. The 240 age- and sex-matched healthy controls were randomly selected from those who had undergone regular medical examination in our physical examination center. Clinical and laboratory parameters Patients’ baseline characteristics including demographic parameters, tumor histology and stage, and laboratory variables including the complete blood count (CBC) were retrospectively reviewed and collected from the electronic medical records. The AJCC/UICC TNM staging system (the 7th ed.) was applied to classify the tumor stage. The tumor length was defined as the long diameter measured with the general postoperative pathological specimens. The tumor locations were classified into upper esophagus, middle esophagus, and lower esophagus. And the degree of differentiation was categorized into poorly/not differentiated, moderately differentiated and well differentiated. CBC and various parameters were measured using ethylenediaminetetraacetic acid (EDTA)-treated blood in Advia 2120 (Siemens Healthcare Diagnostics Inc., Tarrytown, NY, USA) within 2 hours. Ethics statement All included patients and healthy controls were asked to provide written informed consent for their information to be recorded and used in our cancer registry. The study was approved by independent ethics committees at Sun Yat-sen University Cancer Center and was performed in accordance with the ethical standards of the World Medical Association Declaration of Helsinki. Statistical analysis Continuous and categorical variables were presented as the mean ± standard deviation, the frequency and proportion (%), respectively. Independent t-test was performed to compare the parameters of preoperative locally advanced ESCC patients and healthy controls, as well as MPV levels between subgroups. Chi-square or Fisher's exact test was utilized to access the correlation between MPV and clinicopathologic parameters. All statistical analyses were conducted with SPSS 17.0 (SPSS Inc., Chicago, IL, USA). And a two-sided P value of less than 0.05 was considered to be statistically significant. RESULTS Baseline characteristics The baseline clinicopathologic characteristics, laboratory tests of patients, and control groups were demonstrated in Table 1. No statistically significant difference was found between the groups regarding age and gender. Preoperative MPV and MPR levels were significantly decreased in locally advanced ESCC patients when compared to the comparator group, they were (8.14 ± 1.09 fL vs. 10.23 ± 0.78 fL, P < 0.0001) and (0.03875 ± 0.02645 vs. 0.04463 ± 0.00972, P = 0.001), respectively (Fig. 1), as well as the hemoglobin (HB) and mean corpuscular hemoglobin concentration (MCHC). On contrary, the white blood cell (WBC), neutrophil cell (NEC), monocyte (MNC), mean corpuscular volume (MCV), and mean corpuscular hemoglobin (MCH) were significantly elevated in locally advanced ESCC than in the control group. However, the platelet count (PLT) and lymphocyte (LYM) did not differ significantly between groups. Fig. 1 View largeDownload slide Dot plot analyses of the mean platelet volume (MPV), mean platelet volume/platelet count ratio (MPR) between locally advanced ESCC and healthy controls. Fig. 1 View largeDownload slide Dot plot analyses of the mean platelet volume (MPV), mean platelet volume/platelet count ratio (MPR) between locally advanced ESCC and healthy controls. Table 1 Baseline characteristics of localized ESCC patients and healthy controls Variables  ESCC patients  Healthy controls  P value    N = 457  N = 240    Age, years      0.911   Median (range)  59 (22–88)  59 (23–87)    Gender         Male  344  169     Female  113  71    PC (109/L)  238.0 ± 68.8  237.0 ± 39.8  0.838  MPV (fL)  8.14 ± 1.09  10.23 ± 0.78  <0.0001  MPR  0.03875 ± 0.02645  0.04463 ± 0.00972  0.001  WBC (109/L)  7.43 ± 2.36  6.15 ± 1.18  <0.001  NEC (109/L)  4.54 ± 2.03  3.49 ± 0.95  <0.001  LYM (109/L)  2.08 ± 0.65  2.13 ± 0.53  0.333  MNC (109/L)  0.56 ± 0.22  0.37 ± 0.12  <0.001  HB (g/L)  135.8 ± 15.5  142.1 ± 11.1  <0.001  MCV (fL)  90.84 ± 8.12  89.28 ± 3.00  0.004  MCH (pg)  30.84 ± 3.18  30.40 ± 1.40  0.043  MCHC (g/L)  337.8 ± 19.1  341.1 ± 8.0  0.011  Variables  ESCC patients  Healthy controls  P value    N = 457  N = 240    Age, years      0.911   Median (range)  59 (22–88)  59 (23–87)    Gender         Male  344  169     Female  113  71    PC (109/L)  238.0 ± 68.8  237.0 ± 39.8  0.838  MPV (fL)  8.14 ± 1.09  10.23 ± 0.78  <0.0001  MPR  0.03875 ± 0.02645  0.04463 ± 0.00972  0.001  WBC (109/L)  7.43 ± 2.36  6.15 ± 1.18  <0.001  NEC (109/L)  4.54 ± 2.03  3.49 ± 0.95  <0.001  LYM (109/L)  2.08 ± 0.65  2.13 ± 0.53  0.333  MNC (109/L)  0.56 ± 0.22  0.37 ± 0.12  <0.001  HB (g/L)  135.8 ± 15.5  142.1 ± 11.1  <0.001  MCV (fL)  90.84 ± 8.12  89.28 ± 3.00  0.004  MCH (pg)  30.84 ± 3.18  30.40 ± 1.40  0.043  MCHC (g/L)  337.8 ± 19.1  341.1 ± 8.0  0.011  Data are presented as mean ± standard deviation. ESCC, esophageal squamous cell carcinoma; HB, hemoglobin; LYM, lymphocyte; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration; MCV, mean corpuscular volume; MNC, monocyte; MPR, mean platelet volume-platelet count ratio; MPV, mean platelet volume; NEC, neutrophil cell; PC, platelet count; WBC, white blood cell. View Large MPV and MPR levels between subgroups Furthermore, we conducted additional analyses to investigate if the preoperative MPV and MPR levels varied between subgroups. The results indicated that patients with advanced tumor length (≥4 cm) tended to have lower MPV levels (8.03 ± 1.11 fL vs. 8.33 ± 1.21 fL, P = 0.005). Whereas MPV and MPR levels did not differ significantly between subgroups regarding age, gender, degree of tumor differentiation, depth of invasion or other variables (Table 2). Table 2 MPV and MPR levels between subgroups of ESCC patients Parameters  Patients  MPV (fL)  P value  MPR  P value    N (%)          Age (years)      0.115    0.558   <60  242 (53.0)  8.21 ± 1.11    0.03938 ± 0.03318     ≥60  215 (47.0)  8.05 ± 1.06    0.03804 ± 0.01581    Gender      0.301    0.656   Male  344 (75.3)  8.11 ± 1.07    0.03907 ± 0.02901     Female  113 (24.7)  8.23 ± 1.15    0.03779 ± 0.01643    Tumor length (cm)      0.005*    0.180   <4  155 (33.9)  8.33 ± 1.21    0.04107 ± 0.01686     ≥4  302 (66.1)  8.03 ± 1.11    0.03756 ± 0.03017    Differentiation      0.625    0.501   Poor/undifferentiated  104 (22.8)  8.09 ± 0.94    0.03920 ± 0.02933     Moradate/Well  353 (77.2)  8.15 ± 1.13    0.03721 ± 0.01241    Depth of invasion      0.527    0.748   T1–T2  116 (25.4)  8.19 ± 1.08    0.03807 ± 0.01458     T3–T4  341 (74.6)  8.12 ± 1.09    0.03898 ± 0.02943    Lymph node involvement      0.929    0.799   Negative  242 (53.0)  8.14 ± 1.10    0.03846 ± 0.01629     Positive  215 (47.0)  8.13 ± 1.08    0.03909 ± 0.03459    TNM stage      0.729    0.500   I–II  259 (56.7)  8.15 ± 1.05    0.03802 ± 0.01486     III  198 (43.3)  8.12 ± 1.13    0.03971 ± 0.03645    Alcohol consumption      0.850    0.374   No  300 (65.6)  8.14 ± 1.06    0.03955 ± 0.03061     Yes  157 (34.4)  8.12 ± 1.14    0.03723 ± 0.01566    Smoking      0.224    0.920   No  168 (36.8)  8.22 ± 1.06    0.03859 ± 0.01544     Yes  289 (63.2)  8.09 ± 1.10    0.03885 ± 0.03114    Parameters  Patients  MPV (fL)  P value  MPR  P value    N (%)          Age (years)      0.115    0.558   <60  242 (53.0)  8.21 ± 1.11    0.03938 ± 0.03318     ≥60  215 (47.0)  8.05 ± 1.06    0.03804 ± 0.01581    Gender      0.301    0.656   Male  344 (75.3)  8.11 ± 1.07    0.03907 ± 0.02901     Female  113 (24.7)  8.23 ± 1.15    0.03779 ± 0.01643    Tumor length (cm)      0.005*    0.180   <4  155 (33.9)  8.33 ± 1.21    0.04107 ± 0.01686     ≥4  302 (66.1)  8.03 ± 1.11    0.03756 ± 0.03017    Differentiation      0.625    0.501   Poor/undifferentiated  104 (22.8)  8.09 ± 0.94    0.03920 ± 0.02933     Moradate/Well  353 (77.2)  8.15 ± 1.13    0.03721 ± 0.01241    Depth of invasion      0.527    0.748   T1–T2  116 (25.4)  8.19 ± 1.08    0.03807 ± 0.01458     T3–T4  341 (74.6)  8.12 ± 1.09    0.03898 ± 0.02943    Lymph node involvement      0.929    0.799   Negative  242 (53.0)  8.14 ± 1.10    0.03846 ± 0.01629     Positive  215 (47.0)  8.13 ± 1.08    0.03909 ± 0.03459    TNM stage      0.729    0.500   I–II  259 (56.7)  8.15 ± 1.05    0.03802 ± 0.01486     III  198 (43.3)  8.12 ± 1.13    0.03971 ± 0.03645    Alcohol consumption      0.850    0.374   No  300 (65.6)  8.14 ± 1.06    0.03955 ± 0.03061     Yes  157 (34.4)  8.12 ± 1.14    0.03723 ± 0.01566    Smoking      0.224    0.920   No  168 (36.8)  8.22 ± 1.06    0.03859 ± 0.01544     Yes  289 (63.2)  8.09 ± 1.10    0.03885 ± 0.03114    *P < 0.05. TNM, tumor-node-metastasis. View Large Correlation between MPV, MPR levels, and clinicopathologic parameters We then analyzed the correlation between MPV (<8.00 fL/≥8.00 fL), MPR (<0.03420/≥0.03420) and the clinicopathological characteristics (Table 3). MPR levels were found to be significantly correlated with advanced tumor length (P < 0.001), but not other parameters. Table 3 Correlation between MPV, MPR, and clinicopathologic parameters in 457 ESCC patients Clinicopathologic  MPV (N, %)  P value  MPR (N, %)  P value  characteristics  <8.00 fL  ≥8.00 fL    <0.03420  ≥0.03420    Age (years)      0.057      0.96   <60  109 (48.4)  133 (57.3)    121 (52.8)  121 (53.1)     ≥60  116 (51.6)  99 (42.7)    108 (47.2)  107 (46.9)    Gender      0.098      0.343   Male  177 (78.7)  167 (72.0)    168 (73.4)  176 (77.2)     Female  48 (21.3)  65 (28.0)    61 (26.6)  52 (22.8)    Tumor lacation      0.187      0.609   Upper  23 (10.2)  16 (6.9)    17 (7.4)  22 (9.6)     Middle  144 (64.0)  141 (60.8)    147 (64.2)  138 (60.6)     Lower  58 (25.8)  75 (32.3)    65 (28.4)  68 (29.8)    Tumor length (cm)      0.394      <0.001*   <4  72 (32.0)  83 (35.8)    60 (26.2)  95 (41.7)     ≥4  153 (68.0)  149 (64.2)    169 (73.8)  133 (58.3)    Differentiation      0.766      0.387   Well  55 (24.4)  62 (26.7)    53 (23.1)  64 (28.1)     Moradate  116 (51.6)  120 (51.7)    125 (54.6)  111 (48.7)     Poor/undifferentiated  54 (24.0)  50 (21.6)    51 (22.3)  53 (23.2)    T stage      0.613      0.193   T1  19 (8.4)  23 (9.9)    15 (6.6)  27 (11.8)     T2  41 (18.2)  33 (14.2)    39 (17.0)  35 (15.4)     T3  147 (65.4)  160 (69.0)    155 (67.7)  152 (66.7)     T4  18 (8.0)  16 (6.9)    20 (8.7)  14 (6.1)    Lymph node involvement      0.458      0.954   N0  121 (53.8)  121 (52.2)    118 (51.5)  124 (54.4)     N1  60 (26.7)  59 (25.4)    61 (26.7)  58 (25.4)     N2  32 (14.2)  44 (19.0)    36 (15.7)  40 (17.5)     N3  12 (5.3)  8 (3.4)    14 (6.1)  6 (2.6)    TNM stage      0.948      0.066   I  19 (8.4)  21 (9.1)    13 (5.7)  27 (11.8)     II  107 (47.6)  112 (48.3)    114 (49.8)  105 (46.1)     III  99 (44.0)  99 (42.6)    102 (44.5)  96 (42.1)    Alcohol consumption      0.890      0.742   No  147 (65.3)  153 (65.9)    152 (66.4)  148 (64.9)     Yes  78 (34.7)  79 (34.1)    77 (33.6)  80 (35.1)    Smoking      0.068      0.314   No  72 (32.0)  96 (41.4)    79 (34.5)  89 (39.0)     Yes  153 (68.0)  136 (58.6)    150 (65.5)  139 (61.0)    Clinicopathologic  MPV (N, %)  P value  MPR (N, %)  P value  characteristics  <8.00 fL  ≥8.00 fL    <0.03420  ≥0.03420    Age (years)      0.057      0.96   <60  109 (48.4)  133 (57.3)    121 (52.8)  121 (53.1)     ≥60  116 (51.6)  99 (42.7)    108 (47.2)  107 (46.9)    Gender      0.098      0.343   Male  177 (78.7)  167 (72.0)    168 (73.4)  176 (77.2)     Female  48 (21.3)  65 (28.0)    61 (26.6)  52 (22.8)    Tumor lacation      0.187      0.609   Upper  23 (10.2)  16 (6.9)    17 (7.4)  22 (9.6)     Middle  144 (64.0)  141 (60.8)    147 (64.2)  138 (60.6)     Lower  58 (25.8)  75 (32.3)    65 (28.4)  68 (29.8)    Tumor length (cm)      0.394      <0.001*   <4  72 (32.0)  83 (35.8)    60 (26.2)  95 (41.7)     ≥4  153 (68.0)  149 (64.2)    169 (73.8)  133 (58.3)    Differentiation      0.766      0.387   Well  55 (24.4)  62 (26.7)    53 (23.1)  64 (28.1)     Moradate  116 (51.6)  120 (51.7)    125 (54.6)  111 (48.7)     Poor/undifferentiated  54 (24.0)  50 (21.6)    51 (22.3)  53 (23.2)    T stage      0.613      0.193   T1  19 (8.4)  23 (9.9)    15 (6.6)  27 (11.8)     T2  41 (18.2)  33 (14.2)    39 (17.0)  35 (15.4)     T3  147 (65.4)  160 (69.0)    155 (67.7)  152 (66.7)     T4  18 (8.0)  16 (6.9)    20 (8.7)  14 (6.1)    Lymph node involvement      0.458      0.954   N0  121 (53.8)  121 (52.2)    118 (51.5)  124 (54.4)     N1  60 (26.7)  59 (25.4)    61 (26.7)  58 (25.4)     N2  32 (14.2)  44 (19.0)    36 (15.7)  40 (17.5)     N3  12 (5.3)  8 (3.4)    14 (6.1)  6 (2.6)    TNM stage      0.948      0.066   I  19 (8.4)  21 (9.1)    13 (5.7)  27 (11.8)     II  107 (47.6)  112 (48.3)    114 (49.8)  105 (46.1)     III  99 (44.0)  99 (42.6)    102 (44.5)  96 (42.1)    Alcohol consumption      0.890      0.742   No  147 (65.3)  153 (65.9)    152 (66.4)  148 (64.9)     Yes  78 (34.7)  79 (34.1)    77 (33.6)  80 (35.1)    Smoking      0.068      0.314   No  72 (32.0)  96 (41.4)    79 (34.5)  89 (39.0)     Yes  153 (68.0)  136 (58.6)    150 (65.5)  139 (61.0)    *P < 0.05. View Large Discussion As a platelet volume index and an indicator of platelet activation, MPV has been comprehensively investigated in diverse disorders, including malignant tumors.13–22 Several studies have demonstrated that elevated MPV was closely related with the severity and prognosis of cerebro- and cardiovascular events.15–17 Results from Khode et al. showed that MPV level was significantly higher in patients with acute myocardial infarction than in healthy controls.17 Besides, the elevation of MPV has also been reported in various malignancies. Li et al. suggested that patients with colon cancer had significantly higher MPV levels compared with controls, and MPV was found to be independently associated with the presence of colon cancer.19 In addition, Kilincalp et al. found that MPV was significantly elevated in preoperative gastric cancer patients and that changes in MPV might serve as an easily available biomarker for monitoring the healthy subjects for gastric cancer risk and might prompt physicians to make an early diagnosis.20 Furthermore, Baldane et al. showed that preoperative MPV levels in patients with papillary thyroid carcinomas (PTC) were significantly higher when compared with benign goiter patients and healthy controls, changes in MPV levels could be used as an easily available biomarker for monitoring the risk of PTC in patients with thyroid nodules, enabling early diagnosis of PTC.22 However, contrary to the above findings, Mutlu et al. did not detect MPV elevation at the time of diagnosis in various cancer patients.24 Additionally, a significant decrease of MPV was observed at the time of thrombotic events compared to those at diagnosis. Moreover, Aksoy et al. suggested that MPV was significantly decreased in various cancer patients with metastasis to the bone marrow in comparison with control patients.25 Furthermore, Inagaki et al. demonstrated that MPV and MPR were significantly decreased in the NSCLC group compared to the comparator group.23 These results strongly supported our own. We found that MPV and MPR were significantly decreased in newly diagnosed locally advanced ESCC patients compared to healthy controls. In addition, patients with advanced tumor length tended to have lower MPV levels, while there was no difference between other subgroups. Moreover, MPR was strongly correlated with advanced tumor length. To the best of our knowledge, this is the first report presenting a decrease in the MPV and MPR in patients with locally advanced ESCC. Accordingly, as two main indicators of platelet activation, the clinical implications of PLT and MPV in subjects with ESCC have drawn increasing attention. Aminian and his colleagues found that PLT did not correlate with prognostic factors in EC. However, it was significantly different between ESCC and EAC.26 In addition, results from Wang et al. demonstrated that the incidence of thrombocytosis (PLT >300 × 109/L) was 20.2% in resectable ESCC, and was more frequently seen in male and nonsmokers. Unfortunately, thrombocytosis failed to be associated with disease-free survival (DFS) or overall survival (OS) in univariate analysis.27 Most recently, Zhang et al. showed that the combination of the preoperative PLT and MPV (COP-MPV) was an independent prognostic factor for DFS and OS, thus, it could serve as a promising predictor for postoperative survival in ESCC patients.28 There might underlie several potential contributing factors. First, it has been confirmed that malignant cells could produce cytokines such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and other growth factors, which could stimulate the production of platelets.29 Besides, a locally advanced tumor originated from esophagus could easily evoke a status of chronic inflammation due to malignant serositis or necrosis, resulting in an extraordinary secretion of various proinflammatory cytokines including TNF-α, IL-1, and IL-6.30 They could strongly induce acceleration of thrombopoiesis in the bone marrow, leading to a striking increase of the circulating platelet count.31 Furthermore, ESCC cell derived microparticles such as P-selectin and tissue factors could also accelerate the platelet activation, resulting in disseminated microthrombosis.23 Since larger platelets are more reactive in response to stimulus, plenty of larger platelets would be selectively consumed in the background of locally advanced ESCC. Thus, leading to the decrease of MPV.32 The main limitations of this study were the retrospective single-center design and lack of measurement of other inflammatory parameters such as C-reactive protein levels. Despite these limitations, our study demonstrated that decreased MPV and MPV levels were significantly associated with locally advanced ESCC. Thus, they might be helpful in screening and risk stratification for locally advanced ESCC in combination with other approaches, including endoscopy. Further larger prospective studies are warranted to validate this finding and to access their prognostic value in ESCC. Notes Funding: None. Specific author contributions: Shu-yan Sun and Jie He conceived and designed the study. Bai-qiu Zhao and Jie Wang collected the data. Shu-yan Sun and Zheng-xia Mo wrote the manuscript. Yi-nuo Zhao and Yu Wang performed the statistical analysis and prepared the figures and tables. Shu-yan Sun and Jie He revised the manuscript. Shu-yan Sun, Bai-qiu Zhao, Jie Wang, Zheng-xia Mo, Yi-nuo Zhao, Yu Wang, and Jie He reviewed the manuscript. References 1 Siegel R L, Miller K D, Jemal A. Cancer statistics. CA Cancer J Clin  2015; 65: 5– 29. Google Scholar CrossRef Search ADS PubMed  2 Ferlay J, Shin H R, Bray F, Forman D, Mathers C, Parkin D M. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer  2010; 127: 2893– 917. Google Scholar CrossRef Search ADS PubMed  3 Arnold M, Soerjomataram I, Ferlay J, Forman D. Global incidence of oesophageal cancer by histological subtype in 2012. Gut  2015; 64: 381– 7. Google Scholar CrossRef Search ADS PubMed  4 Lin Y, Totsuka Y, He Y et al.   Epidemiology of esophageal cancer in Japan and China. J Epidemiol  2013; 23: 233– 42. Google Scholar CrossRef Search ADS PubMed  5 Rustgi A K, El-Serag H B. Esophageal carcinoma. N Engl J Med  2014; 371: 2499– 509. Google Scholar CrossRef Search ADS PubMed  6 Chen M, Huang J, Zhu Z, Zhang J, Li K. Systematic review and meta-analysis of tumor biomarkers in predicting prognosis in esophageal cancer. BMC Cancer  2013; 13: 539. Google Scholar CrossRef Search ADS PubMed  7 Dutta S, Crumley A B, Fullarton G M, Horgan P G, McMillan D C. Comparison of the prognostic value of tumour- and patient-related factors in patients undergoing potentially curative resection of oesophageal cancer. World J Surg  2011; 35: 1861– 6. Google Scholar CrossRef Search ADS PubMed  8 Coussens L M, Werb Z. Inflammation and cancer. Nature  2002; 420: 860– 7. Google Scholar CrossRef Search ADS PubMed  9 Diakos C I, Charles K A, McMillan D C, Clarke S J. Cancer-related inflammation and treatment effectiveness. Lancet Oncol  2014; 15: e493– 503. Google Scholar CrossRef Search ADS PubMed  10 George J N. Platelets. Lancet  2000; 355: 1531– 9. Google Scholar CrossRef Search ADS PubMed  11 Park Y, Schoene N, Harris W. Mean platelet volume as an indicator of platelet activation: methodological issues. Platelets  2002; 13: 301– 6. Google Scholar CrossRef Search ADS PubMed  12 Jagroop I A, Tsiara S, Mikhailidis D P. Mean platelet volume as an indicator of platelet activation: methodological issues. Platelets  2003; 14: 335– 6. Google Scholar CrossRef Search ADS PubMed  13 Sen N, Basar N, Maden O et al.   Increased mean platelet volume in patients with slow coronary flow. Platelets  2009; 20: 23– 8. Google Scholar CrossRef Search ADS PubMed  14 Yuksel O, Helvaci K, Basar O et al.   An overlooked indicator of disease activity in ulcerative colitis: Mean platelet volume. Platelets  2009; 20: 277– 81. Google Scholar CrossRef Search ADS PubMed  15 Azab B, Torbey E, Singh J et al.   Mean platelet volume/platelet count ratio as a predictor of long-term mortality after non-ST-elevation myocardial infarction. Platelets  2011; 22: 557– 66. Google Scholar CrossRef Search ADS PubMed  16 Slavka G, Perkmann T, Haslacher H et al.   Mean platelet volume may represent a predictive parameter for overall vascular mortality and ischemic heart disease. Arterioscler Thromb Vasc Biol  2011; 31: 1215– 8. Google Scholar CrossRef Search ADS PubMed  17 Khode V, Sindhur J, Kanbur D, Ruikar K, Nallulwar S. Mean platelet volume and other platelet volume indices in patients with stable coronary artery disease and acute myocardial infarction: a case control study. J Cardiovasc Dis Res  2012; 3: 272– 5. Google Scholar CrossRef Search ADS PubMed  18 Kurt M, Onal I K, Sayilir A Y et al. The role of mean platelet volume in the diagnosis of hepatocellular carcinoma in patients with chronic liver disease. Hepatogastroenterology  2012; 59: 1580– 2. Google Scholar PubMed  19 Li J Y, Li Y, Jiang Z, Wang R T, Wang X S. Elevated mean platelet volume is associated with presence of colon cancer. Asian Pac J Cancer Prev  2014; 15: 10501– 4. Google Scholar CrossRef Search ADS PubMed  20 Kilincalp S, Ekiz F, Basar O et al. Mean platelet volume could be possible biomarker in early diagnosis and monitoring of gastric cancer. Platelets  2014; 25: 592– 4. Google Scholar CrossRef Search ADS PubMed  21 Cho S Y, Yang J J, You E et al. Mean platelet volume/platelet count ratio in hepatocellular carcinoma. Platelets  2013; 24: 375– 7. Google Scholar CrossRef Search ADS PubMed  22 Baldane S, Ipekci S H, Sozen M, Kebapcilar L. Mean platelet volume could be a possible biomarker for papillary thyroid carcinomas. Asian Pac J Cancer Prev  2015; 16: 10501– 4. Google Scholar CrossRef Search ADS   23 Inagaki N, Kibata K, Tamaki T, Shimizu T. Prognostic impact of the mean platelet volume/platelet count ratio in terms of survival in advanced non-small cell lung cancer. Lung Cancer  2014; 83: 97– 101. Google Scholar CrossRef Search ADS PubMed  24 Mutlu H, Artis T A, Erden A, Akca Z. Alteration in mean platelet volume and platicrit values in patients with cancer that developed thrombosis. Clin Appl Thromb Hemost  2013; 19: 331– 3. Google Scholar CrossRef Search ADS PubMed  25 Aksoy S, Kilickap S, Hayran M et al. Platelet size has diagnostic predictive value for bone marrow metastasis in patients with solid tumors. Int J Lab Hematol  2008; 30: 214– 9. Google Scholar CrossRef Search ADS PubMed  26 Aminian A, Karimian F, Mirsharifi R et al. Significance of platelet count in esophageal carcinomas. Saudi J Gastroenterol  2011; 17: 134– 7. Google Scholar CrossRef Search ADS PubMed  27 Wang J B, Liu H, Shao N et al. The clinical significance of preoperative plasma fibrinogen level and platelet count in resectable esophageal squamous cell carcinoma. World J Surg Oncol  2015; 13: 157. Google Scholar CrossRef Search ADS PubMed  28 Zhang F, Chen Z L, Wang P, Hu X D, Gao Y B, He J. Combination of platelet count and mean platelet volume (COP-MPV) predicts postoperative prognosis in both resectable early and advanced stage esophageal squamous cell cancer patients. Tumor Biol  2016; 37: 9323– 31. Google Scholar CrossRef Search ADS   29 Sierko E, Wojtukiewicz M Z. Platelets and angiogenesis in malignancy. Semin Thromb Hemost  2004; 30: 95– 108. Google Scholar CrossRef Search ADS PubMed  30 Gasparyan A Y, Ayvazyan L, Mikhailidis D P, Kitas G D. Mean platelet volume: a link between thrombosis and inflammation? Curr Pharm Des  2011; 17: 47– 58. Google Scholar CrossRef Search ADS PubMed  31 Kaushansky K. The molecular mechanisms that control thrombopoiesis. J Clin Invest  2005; 115: 3339– 47. Google Scholar CrossRef Search ADS PubMed  32 Thomas G M, Panicot-Dubois L, Lacroix R, Dignat-George F, Lombardo D, Dubois C. Cancer cell-derived microparticles bearing P-selectin glycoprotein ligand 1 accelerate thrombus formation in vivo. J Exp Med  2009; 206: 1913– 27. Google Scholar CrossRef Search ADS PubMed  © The Authors 2017. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Diseases of the Esophagus Oxford University Press

The clinical implications of mean platelet volume and mean platelet volume/platelet count ratio in locally advanced esophageal squamous cell carcinoma

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10.1093/dote/dox125
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Abstract

SUMMARY As a hallmark of platelet activation, mean platelet volume (MPV) has been identified to be associated with various malignancies. However, the correlation between MPV, mean platelet volume/platelet count ratio (MPR), and esophageal squamous cell carcinoma (ESCC) remains unclear. The aim of this study is to clarify the relevance of MPV and MPR in patients with locally advanced ESCC. Four hundred and fifty-seven cases with newly diagnosed locally advanced ESCC followed by radical surgery and 240 healthy subjects matched for age and gender were included in this study. We retrospectively compared various hematological variables between groups and analyzed the correlation between MPV, MPR, and patients’ clinicopathologic characteristics. Preoperative MPV and MPR were found to be significantly decreased in locally advanced ESCC when compared to healthy controls, they were (8.14 ± 1.09 fL vs. 10.23 ± 0.78 fL, P < 0.0001) and (0.03875 ± 0.02645 vs. 0.04463 ± 0.00972, P = 0.001), respectively. In addition, patients with advanced tumor length (≥4 cm) tended to have lower MPV levels (8.03 ± 1.11 fL versus 8.33 ± 1.21 fL, P = 0.005), while there was no difference between other subgroups. Moreover, decreased MPR was significantly correlated with advanced tumor length (P < 0.001) when divided at a median of 0.03420. Decreased MPV and MPR were significantly associated with locally advanced ESCC. Thus, they might be helpful in screening and risk stratification for locally advanced ESCC in combination with other approaches. INTRODUCTION Esophageal cancer is the eighth most common cancer and fourth cause of cancer-related death worldwide, with more than 480 000 new cases and 400 000 deaths each year, half of which occur in China.1,2 The main pathological subtypes include esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). EAC remains the major subtype in some Western countries, whereas ESCC is the predominant histological type in certain regions of Asian countries.3,4 Although great progress has been made in the early diagnosis of ESCC in last decades, only 25% of ESCC patients can undergo a potentially radical resection and the prognosis still remains poor.5 Thus, identification of promising markers contributing to the screening and risk stratification of locally advanced ESCC might improve their long-term survival.6,7 Systemic inflammation response and the proinflammatory cytokines have been confirmed to be involved in the process of tumor invasion, progression, distant metastasis, and suppression of adaptive immunity.8,9 With their secretions of proinflammatory factors, chemokines and growth factors, activated platelets play an important role in the pathophysiology of various disorders, including malignant tumors.10–22 As indicators of platelet activation, mean platelet volume (MPV) and mean platelet volume/platelet count ratio (MPR) have attracted serious attention in the past few decades with numerous studies assessing the correlation between them and diverse malignancies. Several studies have demonstrated that MPV levels were significantly higher in colon cancer, gastric cancer, hepatocellular carcinoma and papillary thyroid carcinomas than healthy subjects. In addition, MPV could serve as an easily available biomarker for screening and monitoring the healthy populations for such malignancies and might prompt physicians to make early diagnosis.19–22 Whereas one research showed that MPV and MPR were significantly decreased in the nonsmall cell lung cancer (NSCLC) group and MPR was closely associated with patients’ survival.23 However, the roles of MPV and MPR in patients with ESCC have not yet been comprehensively investigated. Therefore, the aim of this study is to clarify the relevance of them in patients with locally advanced ESCC. PATIENTS AND METHODS Patients and healthy populations We selected a consecutive cohort of 510 patients who underwent radical esophagectomy and histopathologically diagnosed with locally advanced ESCC at the Department of Thoracic Surgery, Anhui Cancer Hospital and Anhui Provincial Hospital between January 2006 and December 2012. Exclusion criteria were as follows: patients with synchronous or metachronous cancer other than ESCC, patients who had received preoperative chemotherapy and/or radiotherapy, patients who had concurrent disease that would affect the hemostatic system (e.g., liver disease and blood coagulation disorders), those who received anticoagulants, corticosteroids, estrogen, or aspirin treatment within 1 month before the surgery. Additionally, to eliminate the influences of noncancer diseases on hematological indices, patients with a history of hypertension, renal disease, heart attack or stroke, chronic inflammatory diseases including autoimmune disorder and infection were also excluded. Therefore, a group of 457 cases met the inclusion and exclusion criteria and were included in our finial analysis. The 240 age- and sex-matched healthy controls were randomly selected from those who had undergone regular medical examination in our physical examination center. Clinical and laboratory parameters Patients’ baseline characteristics including demographic parameters, tumor histology and stage, and laboratory variables including the complete blood count (CBC) were retrospectively reviewed and collected from the electronic medical records. The AJCC/UICC TNM staging system (the 7th ed.) was applied to classify the tumor stage. The tumor length was defined as the long diameter measured with the general postoperative pathological specimens. The tumor locations were classified into upper esophagus, middle esophagus, and lower esophagus. And the degree of differentiation was categorized into poorly/not differentiated, moderately differentiated and well differentiated. CBC and various parameters were measured using ethylenediaminetetraacetic acid (EDTA)-treated blood in Advia 2120 (Siemens Healthcare Diagnostics Inc., Tarrytown, NY, USA) within 2 hours. Ethics statement All included patients and healthy controls were asked to provide written informed consent for their information to be recorded and used in our cancer registry. The study was approved by independent ethics committees at Sun Yat-sen University Cancer Center and was performed in accordance with the ethical standards of the World Medical Association Declaration of Helsinki. Statistical analysis Continuous and categorical variables were presented as the mean ± standard deviation, the frequency and proportion (%), respectively. Independent t-test was performed to compare the parameters of preoperative locally advanced ESCC patients and healthy controls, as well as MPV levels between subgroups. Chi-square or Fisher's exact test was utilized to access the correlation between MPV and clinicopathologic parameters. All statistical analyses were conducted with SPSS 17.0 (SPSS Inc., Chicago, IL, USA). And a two-sided P value of less than 0.05 was considered to be statistically significant. RESULTS Baseline characteristics The baseline clinicopathologic characteristics, laboratory tests of patients, and control groups were demonstrated in Table 1. No statistically significant difference was found between the groups regarding age and gender. Preoperative MPV and MPR levels were significantly decreased in locally advanced ESCC patients when compared to the comparator group, they were (8.14 ± 1.09 fL vs. 10.23 ± 0.78 fL, P < 0.0001) and (0.03875 ± 0.02645 vs. 0.04463 ± 0.00972, P = 0.001), respectively (Fig. 1), as well as the hemoglobin (HB) and mean corpuscular hemoglobin concentration (MCHC). On contrary, the white blood cell (WBC), neutrophil cell (NEC), monocyte (MNC), mean corpuscular volume (MCV), and mean corpuscular hemoglobin (MCH) were significantly elevated in locally advanced ESCC than in the control group. However, the platelet count (PLT) and lymphocyte (LYM) did not differ significantly between groups. Fig. 1 View largeDownload slide Dot plot analyses of the mean platelet volume (MPV), mean platelet volume/platelet count ratio (MPR) between locally advanced ESCC and healthy controls. Fig. 1 View largeDownload slide Dot plot analyses of the mean platelet volume (MPV), mean platelet volume/platelet count ratio (MPR) between locally advanced ESCC and healthy controls. Table 1 Baseline characteristics of localized ESCC patients and healthy controls Variables  ESCC patients  Healthy controls  P value    N = 457  N = 240    Age, years      0.911   Median (range)  59 (22–88)  59 (23–87)    Gender         Male  344  169     Female  113  71    PC (109/L)  238.0 ± 68.8  237.0 ± 39.8  0.838  MPV (fL)  8.14 ± 1.09  10.23 ± 0.78  <0.0001  MPR  0.03875 ± 0.02645  0.04463 ± 0.00972  0.001  WBC (109/L)  7.43 ± 2.36  6.15 ± 1.18  <0.001  NEC (109/L)  4.54 ± 2.03  3.49 ± 0.95  <0.001  LYM (109/L)  2.08 ± 0.65  2.13 ± 0.53  0.333  MNC (109/L)  0.56 ± 0.22  0.37 ± 0.12  <0.001  HB (g/L)  135.8 ± 15.5  142.1 ± 11.1  <0.001  MCV (fL)  90.84 ± 8.12  89.28 ± 3.00  0.004  MCH (pg)  30.84 ± 3.18  30.40 ± 1.40  0.043  MCHC (g/L)  337.8 ± 19.1  341.1 ± 8.0  0.011  Variables  ESCC patients  Healthy controls  P value    N = 457  N = 240    Age, years      0.911   Median (range)  59 (22–88)  59 (23–87)    Gender         Male  344  169     Female  113  71    PC (109/L)  238.0 ± 68.8  237.0 ± 39.8  0.838  MPV (fL)  8.14 ± 1.09  10.23 ± 0.78  <0.0001  MPR  0.03875 ± 0.02645  0.04463 ± 0.00972  0.001  WBC (109/L)  7.43 ± 2.36  6.15 ± 1.18  <0.001  NEC (109/L)  4.54 ± 2.03  3.49 ± 0.95  <0.001  LYM (109/L)  2.08 ± 0.65  2.13 ± 0.53  0.333  MNC (109/L)  0.56 ± 0.22  0.37 ± 0.12  <0.001  HB (g/L)  135.8 ± 15.5  142.1 ± 11.1  <0.001  MCV (fL)  90.84 ± 8.12  89.28 ± 3.00  0.004  MCH (pg)  30.84 ± 3.18  30.40 ± 1.40  0.043  MCHC (g/L)  337.8 ± 19.1  341.1 ± 8.0  0.011  Data are presented as mean ± standard deviation. ESCC, esophageal squamous cell carcinoma; HB, hemoglobin; LYM, lymphocyte; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration; MCV, mean corpuscular volume; MNC, monocyte; MPR, mean platelet volume-platelet count ratio; MPV, mean platelet volume; NEC, neutrophil cell; PC, platelet count; WBC, white blood cell. View Large MPV and MPR levels between subgroups Furthermore, we conducted additional analyses to investigate if the preoperative MPV and MPR levels varied between subgroups. The results indicated that patients with advanced tumor length (≥4 cm) tended to have lower MPV levels (8.03 ± 1.11 fL vs. 8.33 ± 1.21 fL, P = 0.005). Whereas MPV and MPR levels did not differ significantly between subgroups regarding age, gender, degree of tumor differentiation, depth of invasion or other variables (Table 2). Table 2 MPV and MPR levels between subgroups of ESCC patients Parameters  Patients  MPV (fL)  P value  MPR  P value    N (%)          Age (years)      0.115    0.558   <60  242 (53.0)  8.21 ± 1.11    0.03938 ± 0.03318     ≥60  215 (47.0)  8.05 ± 1.06    0.03804 ± 0.01581    Gender      0.301    0.656   Male  344 (75.3)  8.11 ± 1.07    0.03907 ± 0.02901     Female  113 (24.7)  8.23 ± 1.15    0.03779 ± 0.01643    Tumor length (cm)      0.005*    0.180   <4  155 (33.9)  8.33 ± 1.21    0.04107 ± 0.01686     ≥4  302 (66.1)  8.03 ± 1.11    0.03756 ± 0.03017    Differentiation      0.625    0.501   Poor/undifferentiated  104 (22.8)  8.09 ± 0.94    0.03920 ± 0.02933     Moradate/Well  353 (77.2)  8.15 ± 1.13    0.03721 ± 0.01241    Depth of invasion      0.527    0.748   T1–T2  116 (25.4)  8.19 ± 1.08    0.03807 ± 0.01458     T3–T4  341 (74.6)  8.12 ± 1.09    0.03898 ± 0.02943    Lymph node involvement      0.929    0.799   Negative  242 (53.0)  8.14 ± 1.10    0.03846 ± 0.01629     Positive  215 (47.0)  8.13 ± 1.08    0.03909 ± 0.03459    TNM stage      0.729    0.500   I–II  259 (56.7)  8.15 ± 1.05    0.03802 ± 0.01486     III  198 (43.3)  8.12 ± 1.13    0.03971 ± 0.03645    Alcohol consumption      0.850    0.374   No  300 (65.6)  8.14 ± 1.06    0.03955 ± 0.03061     Yes  157 (34.4)  8.12 ± 1.14    0.03723 ± 0.01566    Smoking      0.224    0.920   No  168 (36.8)  8.22 ± 1.06    0.03859 ± 0.01544     Yes  289 (63.2)  8.09 ± 1.10    0.03885 ± 0.03114    Parameters  Patients  MPV (fL)  P value  MPR  P value    N (%)          Age (years)      0.115    0.558   <60  242 (53.0)  8.21 ± 1.11    0.03938 ± 0.03318     ≥60  215 (47.0)  8.05 ± 1.06    0.03804 ± 0.01581    Gender      0.301    0.656   Male  344 (75.3)  8.11 ± 1.07    0.03907 ± 0.02901     Female  113 (24.7)  8.23 ± 1.15    0.03779 ± 0.01643    Tumor length (cm)      0.005*    0.180   <4  155 (33.9)  8.33 ± 1.21    0.04107 ± 0.01686     ≥4  302 (66.1)  8.03 ± 1.11    0.03756 ± 0.03017    Differentiation      0.625    0.501   Poor/undifferentiated  104 (22.8)  8.09 ± 0.94    0.03920 ± 0.02933     Moradate/Well  353 (77.2)  8.15 ± 1.13    0.03721 ± 0.01241    Depth of invasion      0.527    0.748   T1–T2  116 (25.4)  8.19 ± 1.08    0.03807 ± 0.01458     T3–T4  341 (74.6)  8.12 ± 1.09    0.03898 ± 0.02943    Lymph node involvement      0.929    0.799   Negative  242 (53.0)  8.14 ± 1.10    0.03846 ± 0.01629     Positive  215 (47.0)  8.13 ± 1.08    0.03909 ± 0.03459    TNM stage      0.729    0.500   I–II  259 (56.7)  8.15 ± 1.05    0.03802 ± 0.01486     III  198 (43.3)  8.12 ± 1.13    0.03971 ± 0.03645    Alcohol consumption      0.850    0.374   No  300 (65.6)  8.14 ± 1.06    0.03955 ± 0.03061     Yes  157 (34.4)  8.12 ± 1.14    0.03723 ± 0.01566    Smoking      0.224    0.920   No  168 (36.8)  8.22 ± 1.06    0.03859 ± 0.01544     Yes  289 (63.2)  8.09 ± 1.10    0.03885 ± 0.03114    *P < 0.05. TNM, tumor-node-metastasis. View Large Correlation between MPV, MPR levels, and clinicopathologic parameters We then analyzed the correlation between MPV (<8.00 fL/≥8.00 fL), MPR (<0.03420/≥0.03420) and the clinicopathological characteristics (Table 3). MPR levels were found to be significantly correlated with advanced tumor length (P < 0.001), but not other parameters. Table 3 Correlation between MPV, MPR, and clinicopathologic parameters in 457 ESCC patients Clinicopathologic  MPV (N, %)  P value  MPR (N, %)  P value  characteristics  <8.00 fL  ≥8.00 fL    <0.03420  ≥0.03420    Age (years)      0.057      0.96   <60  109 (48.4)  133 (57.3)    121 (52.8)  121 (53.1)     ≥60  116 (51.6)  99 (42.7)    108 (47.2)  107 (46.9)    Gender      0.098      0.343   Male  177 (78.7)  167 (72.0)    168 (73.4)  176 (77.2)     Female  48 (21.3)  65 (28.0)    61 (26.6)  52 (22.8)    Tumor lacation      0.187      0.609   Upper  23 (10.2)  16 (6.9)    17 (7.4)  22 (9.6)     Middle  144 (64.0)  141 (60.8)    147 (64.2)  138 (60.6)     Lower  58 (25.8)  75 (32.3)    65 (28.4)  68 (29.8)    Tumor length (cm)      0.394      <0.001*   <4  72 (32.0)  83 (35.8)    60 (26.2)  95 (41.7)     ≥4  153 (68.0)  149 (64.2)    169 (73.8)  133 (58.3)    Differentiation      0.766      0.387   Well  55 (24.4)  62 (26.7)    53 (23.1)  64 (28.1)     Moradate  116 (51.6)  120 (51.7)    125 (54.6)  111 (48.7)     Poor/undifferentiated  54 (24.0)  50 (21.6)    51 (22.3)  53 (23.2)    T stage      0.613      0.193   T1  19 (8.4)  23 (9.9)    15 (6.6)  27 (11.8)     T2  41 (18.2)  33 (14.2)    39 (17.0)  35 (15.4)     T3  147 (65.4)  160 (69.0)    155 (67.7)  152 (66.7)     T4  18 (8.0)  16 (6.9)    20 (8.7)  14 (6.1)    Lymph node involvement      0.458      0.954   N0  121 (53.8)  121 (52.2)    118 (51.5)  124 (54.4)     N1  60 (26.7)  59 (25.4)    61 (26.7)  58 (25.4)     N2  32 (14.2)  44 (19.0)    36 (15.7)  40 (17.5)     N3  12 (5.3)  8 (3.4)    14 (6.1)  6 (2.6)    TNM stage      0.948      0.066   I  19 (8.4)  21 (9.1)    13 (5.7)  27 (11.8)     II  107 (47.6)  112 (48.3)    114 (49.8)  105 (46.1)     III  99 (44.0)  99 (42.6)    102 (44.5)  96 (42.1)    Alcohol consumption      0.890      0.742   No  147 (65.3)  153 (65.9)    152 (66.4)  148 (64.9)     Yes  78 (34.7)  79 (34.1)    77 (33.6)  80 (35.1)    Smoking      0.068      0.314   No  72 (32.0)  96 (41.4)    79 (34.5)  89 (39.0)     Yes  153 (68.0)  136 (58.6)    150 (65.5)  139 (61.0)    Clinicopathologic  MPV (N, %)  P value  MPR (N, %)  P value  characteristics  <8.00 fL  ≥8.00 fL    <0.03420  ≥0.03420    Age (years)      0.057      0.96   <60  109 (48.4)  133 (57.3)    121 (52.8)  121 (53.1)     ≥60  116 (51.6)  99 (42.7)    108 (47.2)  107 (46.9)    Gender      0.098      0.343   Male  177 (78.7)  167 (72.0)    168 (73.4)  176 (77.2)     Female  48 (21.3)  65 (28.0)    61 (26.6)  52 (22.8)    Tumor lacation      0.187      0.609   Upper  23 (10.2)  16 (6.9)    17 (7.4)  22 (9.6)     Middle  144 (64.0)  141 (60.8)    147 (64.2)  138 (60.6)     Lower  58 (25.8)  75 (32.3)    65 (28.4)  68 (29.8)    Tumor length (cm)      0.394      <0.001*   <4  72 (32.0)  83 (35.8)    60 (26.2)  95 (41.7)     ≥4  153 (68.0)  149 (64.2)    169 (73.8)  133 (58.3)    Differentiation      0.766      0.387   Well  55 (24.4)  62 (26.7)    53 (23.1)  64 (28.1)     Moradate  116 (51.6)  120 (51.7)    125 (54.6)  111 (48.7)     Poor/undifferentiated  54 (24.0)  50 (21.6)    51 (22.3)  53 (23.2)    T stage      0.613      0.193   T1  19 (8.4)  23 (9.9)    15 (6.6)  27 (11.8)     T2  41 (18.2)  33 (14.2)    39 (17.0)  35 (15.4)     T3  147 (65.4)  160 (69.0)    155 (67.7)  152 (66.7)     T4  18 (8.0)  16 (6.9)    20 (8.7)  14 (6.1)    Lymph node involvement      0.458      0.954   N0  121 (53.8)  121 (52.2)    118 (51.5)  124 (54.4)     N1  60 (26.7)  59 (25.4)    61 (26.7)  58 (25.4)     N2  32 (14.2)  44 (19.0)    36 (15.7)  40 (17.5)     N3  12 (5.3)  8 (3.4)    14 (6.1)  6 (2.6)    TNM stage      0.948      0.066   I  19 (8.4)  21 (9.1)    13 (5.7)  27 (11.8)     II  107 (47.6)  112 (48.3)    114 (49.8)  105 (46.1)     III  99 (44.0)  99 (42.6)    102 (44.5)  96 (42.1)    Alcohol consumption      0.890      0.742   No  147 (65.3)  153 (65.9)    152 (66.4)  148 (64.9)     Yes  78 (34.7)  79 (34.1)    77 (33.6)  80 (35.1)    Smoking      0.068      0.314   No  72 (32.0)  96 (41.4)    79 (34.5)  89 (39.0)     Yes  153 (68.0)  136 (58.6)    150 (65.5)  139 (61.0)    *P < 0.05. View Large Discussion As a platelet volume index and an indicator of platelet activation, MPV has been comprehensively investigated in diverse disorders, including malignant tumors.13–22 Several studies have demonstrated that elevated MPV was closely related with the severity and prognosis of cerebro- and cardiovascular events.15–17 Results from Khode et al. showed that MPV level was significantly higher in patients with acute myocardial infarction than in healthy controls.17 Besides, the elevation of MPV has also been reported in various malignancies. Li et al. suggested that patients with colon cancer had significantly higher MPV levels compared with controls, and MPV was found to be independently associated with the presence of colon cancer.19 In addition, Kilincalp et al. found that MPV was significantly elevated in preoperative gastric cancer patients and that changes in MPV might serve as an easily available biomarker for monitoring the healthy subjects for gastric cancer risk and might prompt physicians to make an early diagnosis.20 Furthermore, Baldane et al. showed that preoperative MPV levels in patients with papillary thyroid carcinomas (PTC) were significantly higher when compared with benign goiter patients and healthy controls, changes in MPV levels could be used as an easily available biomarker for monitoring the risk of PTC in patients with thyroid nodules, enabling early diagnosis of PTC.22 However, contrary to the above findings, Mutlu et al. did not detect MPV elevation at the time of diagnosis in various cancer patients.24 Additionally, a significant decrease of MPV was observed at the time of thrombotic events compared to those at diagnosis. Moreover, Aksoy et al. suggested that MPV was significantly decreased in various cancer patients with metastasis to the bone marrow in comparison with control patients.25 Furthermore, Inagaki et al. demonstrated that MPV and MPR were significantly decreased in the NSCLC group compared to the comparator group.23 These results strongly supported our own. We found that MPV and MPR were significantly decreased in newly diagnosed locally advanced ESCC patients compared to healthy controls. In addition, patients with advanced tumor length tended to have lower MPV levels, while there was no difference between other subgroups. Moreover, MPR was strongly correlated with advanced tumor length. To the best of our knowledge, this is the first report presenting a decrease in the MPV and MPR in patients with locally advanced ESCC. Accordingly, as two main indicators of platelet activation, the clinical implications of PLT and MPV in subjects with ESCC have drawn increasing attention. Aminian and his colleagues found that PLT did not correlate with prognostic factors in EC. However, it was significantly different between ESCC and EAC.26 In addition, results from Wang et al. demonstrated that the incidence of thrombocytosis (PLT >300 × 109/L) was 20.2% in resectable ESCC, and was more frequently seen in male and nonsmokers. Unfortunately, thrombocytosis failed to be associated with disease-free survival (DFS) or overall survival (OS) in univariate analysis.27 Most recently, Zhang et al. showed that the combination of the preoperative PLT and MPV (COP-MPV) was an independent prognostic factor for DFS and OS, thus, it could serve as a promising predictor for postoperative survival in ESCC patients.28 There might underlie several potential contributing factors. First, it has been confirmed that malignant cells could produce cytokines such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and other growth factors, which could stimulate the production of platelets.29 Besides, a locally advanced tumor originated from esophagus could easily evoke a status of chronic inflammation due to malignant serositis or necrosis, resulting in an extraordinary secretion of various proinflammatory cytokines including TNF-α, IL-1, and IL-6.30 They could strongly induce acceleration of thrombopoiesis in the bone marrow, leading to a striking increase of the circulating platelet count.31 Furthermore, ESCC cell derived microparticles such as P-selectin and tissue factors could also accelerate the platelet activation, resulting in disseminated microthrombosis.23 Since larger platelets are more reactive in response to stimulus, plenty of larger platelets would be selectively consumed in the background of locally advanced ESCC. Thus, leading to the decrease of MPV.32 The main limitations of this study were the retrospective single-center design and lack of measurement of other inflammatory parameters such as C-reactive protein levels. Despite these limitations, our study demonstrated that decreased MPV and MPV levels were significantly associated with locally advanced ESCC. Thus, they might be helpful in screening and risk stratification for locally advanced ESCC in combination with other approaches, including endoscopy. Further larger prospective studies are warranted to validate this finding and to access their prognostic value in ESCC. Notes Funding: None. Specific author contributions: Shu-yan Sun and Jie He conceived and designed the study. Bai-qiu Zhao and Jie Wang collected the data. Shu-yan Sun and Zheng-xia Mo wrote the manuscript. Yi-nuo Zhao and Yu Wang performed the statistical analysis and prepared the figures and tables. Shu-yan Sun and Jie He revised the manuscript. Shu-yan Sun, Bai-qiu Zhao, Jie Wang, Zheng-xia Mo, Yi-nuo Zhao, Yu Wang, and Jie He reviewed the manuscript. References 1 Siegel R L, Miller K D, Jemal A. Cancer statistics. CA Cancer J Clin  2015; 65: 5– 29. Google Scholar CrossRef Search ADS PubMed  2 Ferlay J, Shin H R, Bray F, Forman D, Mathers C, Parkin D M. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer  2010; 127: 2893– 917. Google Scholar CrossRef Search ADS PubMed  3 Arnold M, Soerjomataram I, Ferlay J, Forman D. Global incidence of oesophageal cancer by histological subtype in 2012. Gut  2015; 64: 381– 7. Google Scholar CrossRef Search ADS PubMed  4 Lin Y, Totsuka Y, He Y et al.   Epidemiology of esophageal cancer in Japan and China. J Epidemiol  2013; 23: 233– 42. Google Scholar CrossRef Search ADS PubMed  5 Rustgi A K, El-Serag H B. Esophageal carcinoma. N Engl J Med  2014; 371: 2499– 509. Google Scholar CrossRef Search ADS PubMed  6 Chen M, Huang J, Zhu Z, Zhang J, Li K. 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Google Scholar CrossRef Search ADS PubMed  © The Authors 2017. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

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Published: Feb 1, 2018

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