Clinical application of red cell distribution width, mean platelet volume, and cancer antigen 125 detection in endometrial cancer

Abstract Background Red cell distribution width (RDW) and mean platelet volume (MPV) are considered to be associated with tumors. We investigated the diagnostic value of RDW, MPV, and cancer antigen 125 (CA125), alone or in combination, in the diagnosis of endometrial cancer and endometrial hyperplasia. Methods This study included 144 patients with endometrial cancer (stage I: 32; II: 42; III: 48; and IV: 22), 104 patients with endometrial hyperplasia, and 80 healthy control subjects. The whole blood cell parameters were analyzed by a Mindray Blood Cell Analyzer (CAL8000), whereas CA125 was analyzed using an Architect i2000 Analyzer (Abbott). Results Significant differences in RDW, MPV, and CA125 level were observed in the endometrial cancer, endometrial hyperplasia, and control groups (P < .05). Red cell distribution width was positively correlated (r = .735) whereas MPV was negatively correlated with (r = −.736) endometrial cancer staging. The area under the receiver operating characteristic curve of the combined diagnosis of endometrial cancer based on RDW, MPV, and CA125 was 0.924 (95% CI: 0.881‐0.955). The sensitivity and specificity of the combined diagnosis were larger than those of the independent detections involving RDW, MPV, and CA125. Conclusions The combination of RDW, MPV, and CA125 can improve the differential diagnosis of endometrial cancer and endometrial hyperplasia.

and their 5-year overall survival rates range from 47% to 69% (stage III) and from 15% to 17% (stage 4). 2 Obesity is a risk factor for endometrial cancer; in fact, several bioactive molecules produced by adipose tissue, such as insulin-like growth factors, insulin, sex steroids, and their activation signals, promote the progression of endometrial cancer. 3 Most endometrial cancer cases are believed to be caused by excessive estrogen exposure due to the absence of the balancing effect of progesterone, inducing endometrial proliferation and subsequently endometrial hyperplasia and cancer. 4 Endometrial hyperplasia (EH) is a common endocrine disease in women, and it is mainly characterized by irregular vaginal bleeding, infertility, and even malignant transformation. Endometrial atypical hyperplasia, which has a certain tendency to develop into cancer, is recognized as a precancerous lesion of endometrial cancer. In fact, 29% of untreated complex atypical hyperplasia develops into cancer, and 46% of preoperative patients have adenocarcinoma in their hysterectomy specimens. 5 The development of inflammation is an important factor in the progression and promotion of the pathology of endometrial hyperplasia; it is also a risk factor for the progression of endometrial hyperplasia into malignant tumors. 6 Hematological parameters in routine blood tests are considered inflammatory markers. Red blood cell distribution width (RDW) is an important indicator of consistency in size of red blood cells, and mean platelet volume (MPV) is the main parameter used to assess platelet activation. Red cell distribution width and MPV play an important role in cancer progression, and they are associated with tumor stage and metastasis; for instance, they are associated with poor tumor prognosis in esophageal squamous cell carcinoma 7 and breast cancer. 8 However, the role of these parameters in endometrial cancer and endometrial hyperplasia has not yet been fully understood; therefore, this study aimed to investigate the role of RDW, MPV, and serum cancer antigen (CA) 125 (alone or in combination) in the diagnosis of endometrial cancer and endometrial hyperplasia.

| Patients
We performed a retrospective study involving patients with endometrial cancer diagnosed at the Liuzhou Traditional Chinese Medical Hospital, China, from December 2017 to August 2019. The patients included in this study were pathologically diagnosed with endometrial cancer, and they did not receive any treatment before diagnosis.
Blood samples were taken from the patients with the complaint of abnormal uterine bleeding, and all samples were taken before the endometrial biopsy performed. 9 The following patients were excluded: those with blood disease, diabetes mellitus, kidney disease, acute inflammation, anemia, and cardiovascular disease; those who have recently undergone iron therapy and blood transfusion (within the last 3 months); and those with venous thrombosis for >6 months.

| Method
Venous blood samples (2 mL) were obtained from all subjects in the morning and placed in EDTA-K2 anticoagulation tubes and drying tubes. Whole blood cell parameters were determined using a CAL8000 Automated Hematology Analyzer (Mindray). White blood cell count, absolute neutrophil count, absolute lymphocyte count, hemoglobin concentration, blood platelet count, platelet distribution width (PDW), and red blood cell distribution width (RDW) were obtained directly by the hematology analyzer. In our hospital, the RDW ranged from 11.0% to 14.0%. CA125 concentrations were measured using an ARCHITECT analyzer and its commercial kit (Abbott Diagnostics). The CA125 cutoff value was 35 U/mL according to the manufacturer.
Continuous variables are presented as mean ± standard deviation, non-normally distributed data are expressed as median and quartile, and categorical variables are expressed as whole numbers and percentage. One-way ANOVA was used to evaluate the differences in baseline data of the three groups. Tukey's test was performed to compare the indicator-related differences between two groups.
Correlations of cancer stage with RDW and MPV in endometrial cancer patients were analyzed by Spearman's correlation. The areas under curve (AUCs) were measured using the MedCalc Statistical Software (MedCalc Software bvba, Ostend, Belgium), which can reveal the sensitivity and specificity of a single diagnosis or a combined diagnosis. ROC curves were compared to test the statistical significance of the difference between areas. In all statistical tests, P-values of <.05 (two-tailed) indicated statistical significance.

| RE SULTS
A total of 144 patients with endometrial cancer (age range: 24-77 years) were included in this study. According to the classifi- 80 healthy control subjects (age range: 22-62 years) were also included in this study. These three groups did not significantly differ in terms of white blood cell count, absolute neutrophil count, absolute lymphocyte count, and platelet count. In terms of hemoglobin levels, a significant difference was observed between the endometrial cancer group and the endometrial hyperplasia group (P < .01) but not between the endometrial hyperplasia group and the control group (P > .05). Compared with the PDW measurements in the control group, that in the endometrial cancer group and in the endometrial hyperplasia group significantly increased; however, no significant difference in PDW measurement was observed between the endometrial cancer group and the endometrial hyperplasia group (P > .05).
Moreover, significant differences were observed among the three groups in terms of RDW, MPV, and CA125 level (Table 1).
Correlation analysis results showed that RDW in endometrial cancer patients was positively correlated with cancer stage, whereas MPV was negatively associated with cancer stage (Figures 1 and 2).
The ROC curve was used to analyze the diagnostic value of MPV, RDW, CA125, and their combination to diagnose endometrial  Figure 3 and

| D ISCUSS I ON
Many studies have already reported on the identification of endometrial cancer and endometrial hyperplasia and on the diagnosis of endometrial cancer. The use of many new markers or some scoring systems has been instrumental in the identification and diagnosis of endometrial cancer and endometrial hyperplasia. 10,11 In this study, in rheumatoid arthritis, suggesting that RDW is a potential adjunct marker that reflects an inflammatory process. 12 In addition, it has been reported in the literature that RDW is a sensitive marker of inflammation and is an important and independent predictor of low proliferation, angiogenesis, metastasis, and metabolism. 19 In turn, tumors promote platelet production and activation via the IL-6 pathway. Megakaryocytic maturation, platelet production, and platelet size are regulated by cytokines, such as macrophage colony-stimulating factor, granulocyte colony-stimulating factor, and IL-6. 20 Therefore, the increase in MPV may be related to cancer occurrence and progression.
CA125 is a relatively classic tumor marker and is often used in combination with epididymal protein 4 to improve the effectiveness of ovarian cancer diagnosis. CA125 plays an important role in the differential diagnosis of abnormal uterine bleeding and endometrial cancer. 21 Wang et al 22 combined the use of the serum tumor markers carcinoembryonic antigen, CA15-3, CA125, CA19-9, and tissue polypeptide-specific antigen to improve the efficiency of metastatic breast cancer diagnosis. Our study shows that CA125 combined with RDW and MPV increases the AUC and improves the diagnostic efficiency.
There are some limitations in our research. This retrospective study on endometrial cancer and endometrial hyperplasia involved a relatively small sample size. Therefore, a large-scale, multi-center, forward-looking study is needed to validate our conclusions. In addition, this study included Chinese participants only, so our conclusions are not applicable to other populations. Nonetheless, this study was the first to determine the clinical value of RDW, MPV, and CA125 in endometrial cancer and endometrial hyperplasia and in their combined use for improved efficiency of endometrial cancer diagnosis.

CO N FLI C T O F I NTE R E S T
All authors declare that they have no conflict of interest.

DATA AVA I L A B I L I T Y S TAT E M E N T
Some or all data used during the study are available.