| Research backgroundEndometrial Cancer(EC)is the most common gynecologic tumor in developed countries,and its incidence is on the rise.At present,the traditional 2-score method proposed by Bookman in 1983 is the most widely used typing method in clinical practice.However,the malignant tumor is a kind of highly heterogeneous diseases on molecular level,so even different tumors share the same histological appearance,the response to treatment and prognosis are different.As a result,the traditional pathomorphism diagnose can not adapt to the need of modern diagnosis and treatment of tumor,we need a more accurate way of typing.In 2013,The Cancer Genome Atlas(TCGA)proposed four types of endometrial Cancer in molecules based on The studies of genomics,transcriptology and proteomics--POLE supermutantation,Microsatellite unstable high mutation,low copy number type and high copy number type.Research objectivesIn this experiment,the clinical cases of endometrial carcinoma confirmed by pathology in Qilu Hospital of Shandong University were reviewed.According to the criteria of molecular typing proposed by TCGA,the available pathological data were re-divided into four categories.The purpose of this study was to investigate the epidemiological and clinicopathological features of different molecular types,to compare the effects of molecular typing and pathological classification on prognosis and to summarize and analyze the prognostic factors of endometrial carcinoma patients.Research methodsAccording to the molecular typing method proposed by TCGA,the currently available pathological sections were divided into four types by the department of pathology and the laboratory staff.The existence of POLE mutation was identified by PCR method,and the POLE mutation was classified as POLE supermutation.According to the immunohistochemical test results of mismatch repair protein(MLH1,MSH2,MSH6 and PMS2),paraffin-embedded specimens were analyzed,and the positive ones were classified as microsatellite unstable high mutant.According to the immunohistochemical test results of P53,the positive group was classified as high copy number type,and the negative group was classified as low copy number type.In light of the results of molecular typing,clinicopathological data of 662 patients with endometrial carcinoma from the year of 2010 to 2017 were collected,including age,medical history,clinical manifestation,previous history,menstrual and marriage history,family history,serum tumor marker level before operation.Tumor size,postoperative pathology,histological grade,surgical-pathological stages,possible risk factors,follow-up status and follow-up time.The clinical features,prognosis and prognostic factors of different molecular typing were analyzed by SPSS20.0 statistical analysis software.And it is also applied to compare the accuracy of pathological classification and molecular typing in predicting the prognosis of patients.Results1.Molecular typing resultsA total of 662 pathological sections were reviewed,including 23 cases(3.47%)in the POLE supermutation group,185 cases(27.95%)in the MSI high-mutation group,299 cases(45.16%)in the low-copy number,and 155 cases(23.41%)in the high-copy number.2.Clinical features2.1 Age of onsetAmong the 662 patients with endometrial carcinoma,the age of onset ranged from 83 years old to 28 years old,with an average age of onset of 53.39±9.331 years old and a median age of onset of 54 years old.There was no significant difference in the age of onset between the 4 groups(P=0.161).2.2 MenopauseAmong the 662 cases,411 cases had menopause(62.08%),and the menopause status with different molecular typing had statistical difference(P=0.012).The mean age of menopause was 50.56 3.925 years,and there was no statistical difference among different molecular types.2.3 Clinical manifestationsThe top three clinical manifestations were irregular vaginal bleeding,vaginal discharge and abdominal pain.There were no statistically significant differences between the clinical manifestations of different molecular types.2.4 ComplicationsAmong the 662 cases,the number of patients with hypertension was the highest,211 cases(31.87%).Patients with diabetes mellitus(88 cases,13.80%)and coronary heart disease(42 cases,6.34%)were next.Patients with different molecular typing had significant differences in stroke(P<0.05)and colorectal cancer(P=0.02).2.5 History of menstruation,marriage and pregnant-labor historyAmong the 662 patients,72(10.88%)had a history of menstrual irregularities,and there was no statistically significant difference in molecular typing among the 4 groups(P=0.180).There were no statistically significant differences in the number of pregnancies(P=0.354),number of births(P=0.603),and number of abortions(P=0.108).2.6 Family historyFamily history of malignant tumor was 25 cases(3.78%),and family history of hypertension was 176 cases(26.59%).There was no statistical difference in family history among different molecular typing.2.7 Tumor markersCA125 levels were elevated in 123(18.58%)of the 662 patients.In addition,CA199 level increased in 41 cases(6.19%),CA153 level increased in 12 cases(1.81%),Ca724 level increased in 20 cases(3.02%),and CEA level increased in 53 cases(8.00%).The proportion of patients with abnormal CA153 and CA724 in the high-copy number was significantly higher than that in the other three groups(P values<0.05 and=0.008,respectively).There was no significant difference.3.Pathological differences of different molecular typing3.1 Pathological typesThe types of cases in the POLE supermutation group were all type I endometrioid adenocarcinoma,while the majority of cases in the MSI group and low-copy number were type I endometrial carcinoma(182 cases,99.39%,298 cases,99.67%).The proportion of type II endometrial carcinoma in the high-copy number was significantly increased(96 cases,61.94%).There were significant differences between the pathological types of type 4 endometrial carcinoma(P<0.05).3.2 Pathological gradingAmong the MSI and low copy number,G1 had the absolute advantage(104 cases,99.39%,161 cases(94.23%),POLE group and high-copy number had the increasing number of low differentiation(respectively 12 cases,57.14%).In addition,the proportion of undifferentiated high-copy numbers was the highest(70 cases,44.90%).There were significant differences between the pathological grades of type 4 endometrial carcinoma(P<0.05).3.3 Pathological stagingEarly endometrial cancer in the POLE group accounted for the majority(15 cases in Ia1 stage,66.67%),and a small propor;tion of lb stage(4 cases,19.05%)and stage ?(3 cases,14.28%).Most of the patients in the MSI group and the low-copy number were early-stage endometrial carcinoma(stage Ia1,132 cases,71.49%respectively,213 cases,71.15%).The.proportion of late high copy number(stage ? and IV,47 cases,30.32%)was significantly higher.There was a significant difference between the pathological stages of type 4 endometrial carcinoma(P=0.001).3.4 Other pathological information3.4.1 Ascites/peritoneal lavage cytology:among the 662 patients,a total of 127 cases(19.18%)received ascites or peritoneal lavage cytology,among which 5 cases were positive,with a positive rate(3.94%).There was no significant difference in molecular typing.3.4.2 Lymph node metastasis:a total of 50 cases,with a positive rate of 7.55%,showed statistically significant differences among different molecular types of lymph node metastasis(P<0.05).3.4.3 Lymphatic vessel space involvement:a total of 47 cases(7.10%)showed statistically significant difference in LVSI with different molecular typing(P=0.013),and the high-copy number was significantly higher than the other three groups.3.4.4 Myometrial infiltration:only 63 patients(9.52%)were involved in the mucosal layer,433 patients(65.41%)were involved in the muscular layer infiltration 1/2,and 166 patients(25.98%)were involved in the muscular layer infiltration>1/2.There were statistically significant differences in the muscle infiltration depth among patients with different molecular types(P=0.004).3.4.5 Immunohistochemistry:PR positive 565 cases(85.35%),ER positive 568 cases(85.90%),P53 positive 514 cases(77.64%).There was no significant difference in PR,ER positive rate and negative rate(P= 0.838 and 0.944,respectively).The positive rate of P53 in the 4 groups was statistically significant(P<0.05).3.4.6 Tumor size:in addition to the unknown tumor area of 157 patients,the maximum diameter line of tumor area of 153 patients(30.29%)was less than 2.5cm,the maximum diameter line of tumor area of 259 patients(51.29%)was between 2.5cm and 5.0cm,and the maximum diameter line of tumor area of 92 patients(18.29%)was more than 5.0cm.There was no statistically significant difference in tumor area among patients with different molecular typing(P=0.748).4.The prognosis4.1 Prognosis of different types of molecular typingThe median follow-up time was 56 months.Among the 662 patients,a total of 35(5.39%)were lost to follow-up,and 40(6.04%)died,among which 31(77.5%)died due to this disease,and 58(8.76%)relapsed.There was no statistical difference in the loss of follow-up among different molecular types(P=0.730),and there was a statistical difference in the number of deaths due to the disease(P=0.02),and a statistical difference in the recurrence rate(P<0.05).After excluding the patients who were lost to follow-up and the non-fatal cases(other diseases,car accidents,etc.),the Log rank method was used to compare the four molecular types,P=0.01.According to the kaplan-meier survival curve,it can be seen that the survival curve of the high-copy number is significantly lower than that of the other three groups,and the prognosis is significantly worse.4.2 Pathological classification and prognosis analysisAmong the 662 patients,564 were type I endometrial carcinoma(85.20%)and 98 were type II endometrial carcinoma(14.80%).There was no statistically significant difference between the two groups in the number of patients who lost follow-up due to different case types(P=0.566),and there were statistically significant differences in the number of deaths and relapses due to the disease(P<0.05).After excluding the patients who were lost to follow-up and the patients who died of the disease(other diseases,car accidents,etc.),the Log rank method was used to compare the four molecular types,P=0.01.According to the kaplan-meier survival curve,it can be seen that the survival curve of type II endometrial cancer is significantly lower than that of type I endometrial cancer,with poor prognosis.4.3 Comparison of prognosis between high-copy number and non-high-copy number for type I endometrial cancerAmong the patients with type I endometrial carcinoma,59(10.46%)had a high copy number and 505(89.54%)had a non-high copy number.There was no statistically significant difference in the number of recurrence of high copy number and non-high copy number type I endometrial cancer(P=0.001),no statistically significant difference in the number of deaths(P=0.112),and no statistically significant difference in the number of lost patients(P=0.101).After excluding the lost patients and non-fatal cases(other diseases,car accidents,etc.),the Log rank method was used to compare the four molecular types,P=0.027.According to the kaplan-meier survival curve,it can be seen that the high-copy number survival curve of patients with type I endometrial cancer is lower than that of non-high-copy number,and the prognosis is poor.4.4 Analysis of other prognostic factorsAccording to the foregoing,both molecular typing and pathological typing can affect the prognosis of patients(both P values were 0.01).In addition,still the Kaplan-rank analysis method and the Log rank method was carried out on the factors affecting the prognosis of patients with endometrial cancer survival analysis of single factor,the results showed:the degree of differentiation(P = 0.005),pathological staging(P = 0.018),muscular infiltration(P = 0.001),LVSI(P = 0.046),CA153(P = 0.023),the ER(P =0.003),PR(P = 0.006),tumor volume(P = 0.022)and prognosis of endometrial carcinoma was significant.COX proportional regression risk model was used to analyze the multivariate survival of significant factors in the univariate analysis,and the results showed that molecular typing,muscle invasion depth and tumor volume were independent risk factors affecting the prognosis of endometrial cancer(P<0.05).Conclusion:1.In this study,662 cases of endometrial carcinoma were divided into the POLE group,the MSI group,the low-copy number and the high-copy number.The MSI group had the proportion of 185 cases(27.95%),followed by the high-copy number(155 cases,23.41%)and the low-copy number(299 cases,45.16%),and the POLE group had the lowest proportion(23 cases,3.47%).2.The high-copy number was significantly different from the other three groups,with a large number of postmenopausal patients;Tumor markers CA153 and CA724 were abnormal.The main pathological type was type II endometrial carcinoma,with high histological grade,late surgical-pathological stage,high lymph node metastasis rate,deep muscle infiltration and high P53 positive rate.The prognosis was significantly worse than that of the other three groups.3.This study showed that the main factors affecting the prognosis were molecular typing,pathological typing,degree of differentiation,pathological staging,muscular invasion,LVSI,CA153,ER,PR and tumor volume.Molecular typing,muscle invasion depth and tumor volume were independent risk factors for endometrial cancer prognosis. |
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