Prognostic Value Of Signet-Ring Cell Histology In Gastric Cancer:A Meta-Analysis And And Clinical Study

Research BackgroundGastric cancer is one of the most common malignancies around the world,with high morbidity and mortality.In China,the incidence of gastric cancer is only lower than that of lung cancer and ranked second in all malignancies.In recent years,although the global incidence of gastric cancer showed a steady decline,diffuse gastric cancer,especially Signet-ring cell gastric(SRC)was reported to increase substantially,which made it attract more and more attention.SRC is a histological pattern of gastric cancer with unique pathological features and biological behavior:patients including more young people and women;infiltration growth in the stomach;higher ratio of signet-ring cancer cell in early stage;less lymph node metastasis;prone to peritoneal and ovarian metastasis for tumor invasiveness.However,the prognosis of SRC still remains controversial.For a long time,it is thought that the prognosis of SRC was poor due to the characteristics mentioned above and the SRC type is considered as an important factor for recurrence or metastasis of gastric cancer.However,in recent years,some studies suggested that SRC was not associated with prognosis of gastric cancer.Moreover,several reports indicated that its prognosis might be related to tumor stages.So we performed this systematic review and meta-analysis to assess the prognostic significance of SRC.The histological types of gastric cancer is largely gastric adenocarcinoma(GA).According to the 2010 WHO criteria,GA includes four major histological types:papillary adenocarcinoma(PAC),tubular adenocarcinoma(TAC),mucinous adenocarcinoma(MAC)and SRC.Each type has its own morphological characteristics and biological behavior.So whether different gastric cancer subtypes needing individualized treatment is worth to be further studied.In Part 2,we retrospectively analyzed the data of GA in the SEER(Surveillance Epidemiology and End Results)database from 2004 to 2011 to study the clinicopathologic characteristic of SRC.Meanwhile we used SRC as a reference to access the prognostic value of different histological GA subtypes,mainly SRC,which would improve our understanding of gastric cancer and guide the treatment of gastric cancer.Partl Prognostic Value of Signet-Ring Cell Histology in Gastric Cancer:A Systematic Review and Meta-AnalysisObjectiveA systematic review and meta-analysis was performed to assess the prognostic significance of SRC in gastric cancer,in order to improving our understanding of signet ring cell gastric cancer.MethodsA comprehensive literature search for relevant reports was performed mainly using PubMed,Embase and Web of Science.The upper date was limited to January 10,2017 and no language limit was set.All publications related to the prognosis of SRC were included according to the inclusion and exclusion criteria for analysis.The primary outcome was over survival(OS)and recurrence-free survival(RFS)?disease-free survival(DFS)were adopted as the secondary outcome.Information of published articles,basic characteristics of gastric cancer patients,clinicopathological data of tumor,prognosis assessment and follow-up information were acquired from individual studies.Statistics analysis was performed by the software of Revman5.2 and Stata11.0 in our study.ResultsA total of 27 English articles,about 60000 gastric cancer patients,were included in our meta-analysis.Among all included articles,20 studies were conducted in Asia while the remaining 7 were from European countries and the United States.The pooled HR for OS was 1.04(95%CI:0.89-1.21,I2 = 96%,P = 0.63)and for RFS/DFS was 1.17(95%CI:0.50-2.75,I2 = 83%,P=0.73).Both the two results were of no statistically significance.Owing to the large heterogeneity of included studies,subgroup analysis was then performed,which showed that the subgroup of European countries and America might somewhat result in the heterogeneity(HR= 1.08,95%CI:1.02-1.14,I2 = 34%,P=0.01),but the subgroups of radical surgery done or not?different tumor staging(early and advanced stage)and the proportion of patients with signet ring cell gastric carcinoma were both of no statistically significance.However,national area was not enough to explain the heterogeneity existed.It had been previously reported that the prognosis of SRC(vs NSRC)was influenced by tumor stage(early and advanced stage).So we decided to analyze the data about the early and advanced gastric cancers separately.Additionally,the HRs was pooled according to different analytical methods of univariate or multivariate analysis to further reduce the heterogeneity.In the group of early gastric cancer(univariate analysis),a better survival in SRC(vs NSRC)was demonstrated(HR=0.54,95%CI:0.42-0.69,P<0.00001,I2=33%)and in the group of multivariate analysis,pooled HR for OS was 0.86(95%CI:0.42-1.76,I2=92%,P=0.68).The conclusion that SRC is not independent prognostic factors in the early stage of gastric cancer could be obtained.SRC of advanced stage survived worse(HR=1.42,95%CI:1.22-1.65,I2=65%,P<0.00001),but SRC is also not independent prognostic factors in advanced stage(HR=1.11,95%CI:0.85-1.45,I2 = 83%P = 0.43).Although literature heterogeneity decreased by removing individual study one by one for sensitivity analysis,the final conclusions did not change.What is more,there was no publication bias existing in the literature.ConclusionIn comparison to NSRC,the SRC type survives better in early stage of gastric cancer and it has a worse survival in advanced stage conversely.Meanwhile,SRC morphologic subtype is not a prognostic factor for gastric cancer regardless of tumor stage.Part2 Prognostic significance of different histological types of gastric adenocarcinoma:a retrospective study on SEER databaseObjectiveWe extracted the information of GA patients from SEER database from 2004 to 2011.The clinicopathologic characteristic and prognosis of different histological types of GA,especially SRC were analyzed to provide some reference for the diagnosis and treatment of gastric cancer.MethodsWe extracted information for patients pathologically diagnosed with gastric cancer between 2004 and 2011 from the SEER database.According to the inclusion and exclusion criteria,the four main GA subtypes were screened for patients' basic information?tumor data and follow-up results.What's more,the data of patients'recurrence and metastasis were collected from 2010 to 2011.SPSS 20 software and GraphPad Prism 6 software were used for statistics analysis and graphs in our study.Results1.A total of 6937 patients diagnosed with GA were finally included in our study,including 5247 patients from 2004 to 2009 and 1690 patients from 2010 to 2011.The median follow-up time was 10(9.5-10.5)months.2.Comparison of clinical pathology and prognosis among the four GA subtypes:age,gender(TAC VS SRC;MAC VS SRC),tumor location,tumor diameter,tumor infiltration depth,distant metastasis,TNM stage and tumor differentiation were all of remarkable difference(P<0.05),while the other three types(TAC,MAC,GAC)compared to SRC.SRC were more frequently in young women and with deeper tumor infiltration(T3+T4),more lymph node metastasis(N2+N3)and higher TNM stage(III+IV).3.Comparison of organ metastasis among the four GA subtypes:SRC were prone to metastasize to bone,liver and lung and brain metastasis were more likely occurred compared to other subtypes;TA also had a high probability of metastasis in our study and liver metastasis were mostly found;Liver and lung were the major organs found with metastasis for MA;PA was diagnosed with less metastasis,but the conclusion might be influenced by too small number of PA cases.4.Comparison of prognosis among the four GA subtypes:(1)Prognostic analysis in early and advanced stage:1)univariate analysis:there was no statistically difference between SRC and MAC,PAC(p = 0.078,p?0.605)in early stage of GA,but significant difference existed while compared with GA(P = 0.015).In advanced stage of GA,SRC had a worse survival than the other three subtypes(p = 0.001,p= 0.014,p<0.001);2)multivariate analysis:regardless of early or advanced stage,age,race,lymph node status were all independent prognostic factors for GA while histological type and tumor location were just for advanced GA.MAC survived better than SRC(HR = 0.765,95%CI 0.647-0.903,p=0.002)in advanced stage.(2)The prognosis of four GA subtypes was of no statistically differences in subgroups of poorly differentiated or lymph node-negative GAConclusion1.Clinicopathological characteristics of GA subtypes were of significant differences.Signet ring cell carcinoma were predominantly female with younger age?deeper tumor infiltration,more lymph node metastasis and higher TNM stage.Gastric antrum and body of stomach were the most common location for SRC.2.Histological type was an independent prognostic factor for advanced GA,but not for early GA.The prognosis of MAC was better that SRC in advanced stage.3.Both in poorly differentiated and lymph node biopsy negative subgroups,gastric adenocarcinoma pathological type did not influence the prognosis of GA.