Xing Wang,Ping Han,Yan-Fang He＊

1North China University of Science and Technology Affiliated Hospital,Tangshan,Hebei 063000,China.

Abstract Background:To explore diagnostic value and clinical significance of preoperative neutrophil-to-lymphocyte ratio(NLR)and platelet-to-lymphocyte ratio(PLR)combined with serum carbohydrate antigen(CA),including CA125,CA153 and CA199,in endometrial cancer (EC).Methods:The clinical data of 135 patients who underwent endometrial pathology examination in our hospital from January 2014 to June 2019 were retrospectively analyzed,including 65 cases of EC,40 cases of proliferative endometrial lesions and 50 cases of normal endometrium.Blood routine analyzer and electrochemical luminescence method were used to detect 5 parameters of NLR,PLR,CA125,CA153 and CA199 in these patients.The study explored the relationship between the five indicators and different levels of endometrial lesions,and analyzed their relationship with clinical pathological characteristics of EC patients.The diagnostic efficacy of NLR,PLR,CA,NLR combined CA,PLR combined CA was evaluated by receiver operating curve (ROC) combined with logistic regression equation.Results: The expression of the five parameters was different in different levels of endometrial lesions,and the expression level increased with the increase of endometrial lesion level.The difference among the three groups was statistically significant(P ＜0.05).CA125 level was related to International Federation of Gynecology and Obstetrics (FIGO) stage,lymph node metastasis and ki-67 index.CA153 level was related to ki-67 index.CA199 was related to FIGO stage,tissue differentiation and lymph node metastasis.NLR was related to FIGO stage,pathological type,tissue differentiation,myometrial invasion and lymph node metastasis.PLR was correlated with tissue differentiation,and the differences were statistically significant(P ＜0.05).The diagnosis of NLR combined with CA was the largest area under ROC curve(0.940),and its accuracy,sensitivity and specificity were higher than those of individual parameters and NLR combined with CA.Conclusion:NLR,PLR,CA125,CA153 and CA199 were highly expressed in EC and were correlated with clinical pathological data of EC patients respectively.NLR and PLR combined with CA could significantly improve the diagnostic efficiency of EC,providing clinical reference value for EC screening,therapeutic effect evaluation and disease progression evaluation.

Keywords:Endometrial carcinoma;NLR;PLR;Carbohydrate antigen;Diagnosis

Background

Endometrial cancer (EC) is one of the most common gynecologic malignancies,with a incidence of 1.47/10,000 and a mortality of 2.3/100000 [1].With the increasing incidence of obesity and other metabolic diseases in society,the incidence and mortality of EC increased year by year,becoming the second most common gynecological malignant tumor after cervical cancer.Although 90% of EC patients have abnormal vaginal bleeding and other clinical symptoms in the early stage of the disease,early symptoms in women of childbearing age are not specific,and the disease is often delayed due to the lack of timely diagnosis [2].Therefore,improving early detection rates can improve overall survival.Currently,the gold standard for EC diagnosis is still endometrial sampling by diagnostic curettage,but this examination is invasive examination into the uterine cavity and cannot be used as an EC screening method for asymptomatic women [3].In clinical work,we aim to find a simple,inexpensive and non-invasive examination or test for screening endometrial lesions.This study analyzed the expression of neutrophil-to-lymphocyte ratio (NLR),platelet-to-lymphocyte ratio (PLR),carbohydrate antigen (CA)125,CA153,CA199 in patients with different levels of endometrial lesions and their relationship with clinical pathological characteristics of EC patients.Through the receiver operating characteristic (ROC) curve,the function of NLR,PLR and CA were evaluated in the diagnostic value of EC,providing a reference for EC screening and diagnostic significance.

Materials and methods

Patients

The study was approved by the ethics committee of our hospital.From January 2014 to June 2019,patients with endometrial lesions,who visited the gynecology department of North China University of Science and Technology Affiliated Hospital,were included in the study.Among them,patients with other systemic tumors,infections and immune diseases,were excluded.A total of 105 patients underwent endometrial examination,including 65 EC patients,40 endometrial hyperplasia patients,and 50 normal endometrial patients underwent endometrial pathological examination due to other benign diseases at the same time.All cases were diagnosed by pathological examination,and clinical,laboratory and pathological data of all cases were collected.

Data collection

The data of CA,neutrophils,lymphocytes and platelets in the blood routine within 1 week before surgery were collected,and the NLR (absolute number of neutrophils/absolute number of lymphocytes) and PLR(absolute number of platelets/absolute number of lymphocytes) were calculated.Five mL fasting venous blood was collected in the morning for the above data detection,and serum CA125,CA153,CA199 and other tumor markers were detected by chemiluminescence immunoanalyzer (the detection standard was consistent in the last five years).All blood cell tests were detected by the automatic five-classification blood analyzer (the test standard was consistent in the last five years).The postoperative pathology of the patients was collected,including surgical pathological staging,histological type,pathological grade,muscle layer infiltration,lymph node metastasis and ki-67 index.

Statistical analysis

SPSS 25.0 statistical software was used for statistical analysis of the data,and the normality test was performed on all the data.One-way analysis of variance was used for the comparison of mean value among groups if the data conforms to normal distribution.Otherwise,Kruskal-Wallis H test was used.Logistic regression analysis was used to analyse the correlation between the five indicators and EC.ROC curve and logistic regression equation were adopted to evaluate the diagnostic efficacy of the five indicators on EC.P＜0.05 was considered statistically significant.

Results

Clinical pathological results of EC group

Clinicopathological stages were stage I in 35 patients,stage Ⅱin 15 patients,and stage Ⅲ+Ⅳin 15 patients.There were 52 cases of endometrial adenocarcinoma and 13 cases of other types.High differentiation was in 25 cases,medium differentiation in 27 cases,low differentiation in 13 cases.The superficial and deep layers invaded 37 cases and 28 cases respectively.There were 15 cases with lymph node metastasis and 50 cases without lymph node metastasis.Ki-67 index was lower than 30%in 24 cases and ≥30%in 41 cases(Table 1).

Comparison of the five parameters among the three groups of patients

The differences of NLR,PLR,CA125,CA153 and CA199 in endometrial patients with different lesion levels were statistically significant (P＜0.05),and the expression of five indicators in EC group was significantly higher than that in the normal endometrial group(Table 2).

The relationship between the five parameters and the pathological characteristics of EC

The level of CA125 in the blood of EC patients was related to International Federation of Gynecology andObstetrics (FIGO) stage,lymph node metastasis and ki-67 index;CA153 level was related to ki-67 index.CA199 is related to FIGO staging,tissue differentiation and lymph node metastasis.NLR was associated with FIGO staging,pathological type,tissue differentiation,muscle infiltration and lymph node metastasis.PLR was correlated with tissue differentiation,and the differences were statistically significant(P＜0.05)(Table 3).

Table 1 Clinical pathological results of EC group

Correlation analysis of the five parameters with the diagnosis of EC

The correlation analysis of the five indicators with the diagnosis of EC was conducted by binary logistic regression model,which showed that the five indicators were all correlated with the diagnosis of EC,and the difference was statistically significant (P＜0.05)(Table 4).

Evaluation of the diagnostic efficacy of the five parameters on EC

ROC curve analysis showed that the area under the curve of NLR,PLR and CA was 0.914,0.645 and 0.811,respectively,all of which had high diagnostic value.The area under the curve of NLR combined with CA and PLR combined with CA was 0.940 and 0.833,respectively,which were both higher than the area under curve (AUC)of the diagnosis of EC when NLR,PLR and CA were detected separately,and the accuracy,sensitivity and specificity of the combined diagnosis were improved compared with that of the separate diagnosis,as shown in Figure 1.The diagnosis of NLR combined with CA was the largest under the ROC curve (0.940),and the accuracy,sensitivity and specificity were all higher than each single parameter and NLR combined with CA.The optimal diagnostic value,area under the curve,accuracy,sensitivity,specificity,Youden index,positive likelihood ratio,negative likelihood ratio,positive predictive value and negative predictive value corresponding to the other three indicators and joint indicators are shown in Table 5.

Table 3 Correlation between 5 test indicators and pathological characteristics of EC patients(median)

Table 4 Logistic regression analysis of EC diagnosis with 5 indicators

Table 5 Comparison of the diagnostic efficacy of NLR and PLR with CA125+CA153+CA199

Discussion

Recent years have witnessed a number of studies on the association between inflammatory microenvironment and EC [4].Many studies have shown that changes in levels of systemic inflammatory response biomarkers,such as NLR and PLR,are related to adverse clinical outcomes of various malignancies.The correlation of prognostic value in NLR and PLR with other malignant tumors,such as lung cancer [5],renal cancer [6],breast cancer [7],laryngeal cancer[8],cervical cancer[9],etc.have been proved by many scholars.However,there are few studies on the correlation between NLR,PLR and EC at home and abroad.M Cummings et al.retrospectively studied the relationship between NLR,PLR and EC,including clinicopathological relationship and prognostic relationship,suggesting that high NLR and PLR are correlated with the clinical stage,vascular invasion and lymph node metastasis of EC.The total survival time and tumor-specific survival time of patients with high NLR and PLR before surgery were significantly poor,indicating that NLR and PLR were independent factors affecting the prognosis of EC patients [10].Similar studies also proved the prognostic significance of NLR and PLR for EC patients [11].At present,there are few similar studies in China.By comparing the levels of NLR and PLR in peripheral blood of patients with different levels of endometrial lesions,this study analyzed the correlation between NLR,PLR and the clinicopathological characteristics of EC patients,and described the diagnostic value of NLR and PLR for EC.It was found that NLR and PLR increased as the level of endometrial lesions increased and that NLR was correlated with tumor staging,tissue differentiation,muscle layer infiltration and lymph node metastasis,which is similar to the above results.However,no conclusion has been drawn that PLR is also correlated with EC staging,vascular infiltration and lymph node metastasis.Further studies are needed to confirm the relationship between the two.This study found that NLR and PLR have strong diagnostic value for EC.The area under the curve of NLR and PLR was 0.914 and 0.645 respectively according to the ROC curve,indicating that NLR and PLR may become potential peripheral blood indicators to predict EC and provide certain reference significance for diseases screening of high-risk EC groups.

Currently,a serological method widely recognized for preoperative identification,efficacy evaluation and prognosis evaluation of malignant tumors is tumor marker series examination,which is the earliest and most widely used in the diagnosis and treatment of tumors.When cells become cancerous,substances on the surface of cells change,and sugar chain antigens,as glycoproteins on the surface of cells,change [13].The application of sugar chain antigen in tumor markers of gynecological tumors is relatively common,and the expressions of CA125,CA153 and CA199 in EC patients are discussed.CA125,CA153 and CA199 all have good clinical correlation with EC,and are of high early diagnostic value.Abnormal increase of them is also correlated with poor prognosis of EC [14,15].The role of CA125 in the diagnosis of ovarian epithelial tumors has been clarified and its expression in EC patients has a high clinical significance.Nithin Kumar U et al.reported that compared with the control group,the EC group had higher levels of both CA125 and CA135,In addition,they also argued that CA125 had diagnostic value of EC [16].Ying-Mei Wang et al.found that high preoperative CA125 level was strongly correlated with large EC lesions(≥2 cm),deep muscle layer infiltration,clinical stage,and lymph node metastasis,which indicated that the increase of CA125 was significantly associated with poor prognosis of EC[17].CA153,a specific tumor marker of breast cancer,plays an important role in the diagnosis and monitoring of postoperative recurrence and the observation of efficacy,but studies on the correlation between CA153 and EC are rare.

Baser E pointed out in the study that CA153 was an important marker for EC patients to predict the effect of adjuvant therapy.Tas EE et al.retrospectively analyzed the relationship between CA153 and the prognostic factors of EC patients.Then he found tha that high CA153 level was correlated with tumor staging,pathological classification,tumor grade,vascular infiltration,and lymph node metastasis,and concluded that CA153 level was significantly correlated with the prognostic factors of EC and could be used as one of the diagnostic indicators of EC [18].In earlier studies,some scholars found a close relationship between serum CA153 level (＞30 U/mL and ＞50 U/mL) and shorter survival rate (P= 0.0004 andP= 0.00025) [19].The role of CA199 in EC has been confirmed in similar studies [20,21].After comparing the relationship of CA125,CA153,and CA199 in different level endometrial lesions,this study found CA125,CA153,and CA199 were all associated with EC and they rose with the increase of level of endometrial lesions.At the same time,the difference was statistically significant (P＜ 0.05),which indicated the occurrence of EC is not only related to the tumor cells themselves,but also related to the inflammatory microenvironment in tumor microenvironment.In the correlation analysis of CA125,CA153 and CA199 with the clinicopathological characteristics of EC,it was found that CA125 was related to FIGO stage,lymph node metastasis,and ki-67 index;CA153 level was related to ki-67 index;and CA199 was related to FIGO stage,tissue differentiation,and lymph node metastasis.It indicates that CA125,CA153 and CA199 play important roles in the occurrence,development and metastasis of EC.In clinical diagnosis and treatment,treatment effect and prognosis can be detected through the level of sugar chain antigen series of EC patients.The specific mechanism of promoting the progression of malignant tumor remains to be confirmed by further studies.When evaluating the diagnostic value of CA125 + CA153 + CA199 combined by ROC curve,this study found that the AUC was 0.811,that the accuracy was 0.748,and that the sensitivity and specificity were 0.615 and 0.844,respectively.Therefore,the fact that CA has good clinical relevance and diagnostic value for EC has been proved again.

CA has been applied in clinical malignant tumor screening,therapeutic effect detection and prognosis evaluation,but there are still some defects in EC diagnosis due to the fact that it can be increased to different degrees in many benign gynecological diseases.As systemic inflammatory indicators,NLR and PLR are greatly affected by interfering factors.Although they are related to the diagnosis and progression of EC,they are still to be studied as EC markers.Therefore,this study further evaluated the diagnostic value of NLR and PLR combined with CA respectively by ROC curve.The results of this study showed that the accuracy,sensitivity and specificity of NLR,PLR and CA combined diagnosis of EC were all higher than the single index.In the diagnosis of NLR combined with CA,the area under the ROC curve was 0.940 at the maximum,and its sensitivity,specificity,positive likelihood ratio and positive predictive value were 0.862,0.922,11.077 and 0.889 respectively,which were significantly better than any single indicator and the diagnostic efficacy of PLR combined with CA.Therefore,NLR combined with CA can significantly improve the diagnostic efficacy,sensitivity and specificity of EC,and the two supplement each other to jointly improve the diagnostic efficacy of EC.

The significance of CA125,CA153,CA199,NLR and PLR to EC has been confirmed by a large number of studies which indicates that all three have certain value in the diagnosis and progression of EC.NLR combined with CA can effectively improve the accuracy,sensitivity and specificity of EC diagnosis.In addition,it also provides important clinical reference value for the screening of EC high-risk groups,the evaluation of treatment effect,disease progress,and prognosis of EC patients.In this study,the effect of NLR,PLR and CA on the prognosis of EC has not been discussed,and the sample size needs to be increased to further evaluate the correlation with the prognosis of EC.