| ObjectiveGastric neuroendocrine carcinoma(NEC)is a rare tumor with a poor prognosis.The response rate to standard chemotherapy is poor.Research in lung large cell neuroendocrine carcinoma revealed that the genetic alteration of TP53 and RB1 can be used to classify patients into different types,which had differences in prognosis and chemotherapy response.In gastric NEC,research on this classification method is still limited.On the other hand,immunotherapy has become one important branch of tumor treatment in recent years.Several biomarkers have been established to predict the response of immune checkpoint inhibitor treatment.However,there is still a lack of relevant research in gastric NEC.This study explored a potential classification method based on genetic alteration and expression of TP53 and RB1 and the expression of immunotherapy biomarkers in gastric NEC patients.MethodsWe retrospectively enrolled and followed up 41 cases with gastric NEC who underwent surgery or biopsy in Peking Union Medical College Hospital(PUMCH)from June 2013 to June 2021.Their clinical data were collected.Pathological paraffin-embedded specimens were obtained.RB1 and TP53 genetic alteration(including gene mutation and copy number loss),tumor mutation burden(TMB)and microsatellite instability(MSI)were detected by full whole-exon gene sequencing.Expression of Rb,p53,PD-L1 and CD8 were investigated by immunohistochemical staining.Samples were subtyped according to genetic alteration and expression of RB1 and TP53.Differences of clinicopathological features and expression of immunotherapy related biomarkers among different subtypes of gastric NEC were analyzed by Fisher exact test.Fisher exact test was also used to analyze the difference in clinicopathological features of patients with different immunotherapy related markers expression.Kaplan-Meier was used to plot the survival curve,log rank test was used for survival analysis,and multivariate Cox regression analysis was used to calculate independent survival predictors.Cases of gastric adenocarcinoma(25 cases),gastric neuroendocrine tumor(NET)(21 cases)and small cell lung cancer(SCLC)(29 cases)in PUMCH from January 2019 to June 2021 were retrospectively included with paraffin-embedded specimens.Sequencing data of these three tumors were obtained from cbioportal public database.Results41 cases with gastric NEC were included in this study,including 31 males and 10 females.The median age was 67 years(36-81 years).In terms of clinical stages,there were 9 cases(22.0%)in stage Ⅰ,19 cases(46.3%)in stage Ⅱ,12 cases(29.3%)in stageⅢ and 1 case(2.4%)in stage Ⅳ.28 cases with gastric NEC were sequenced.TP53 genetic alterations were detected in 14 cases(50.0%),RB1 genetic alterations were detected in 5 cases(17.9%),and TP53 and RB1 co-alteration were detected in 3 cases(10.7%).There was no significant overall survival difference between cases with co-alteration and the others.Immunohistochemical staining of p53 and Rb was performed in 41 cases,of which 39 cases were able to be interpreted the results.18 cases(46.2%)had loss of Rb expression,and 26 cases(66.7%)had abnormal p53 expression.Cases with both abnormal expression of p53 and Rb were defined as SCLC-like type,accounting for 38.5%.The remaining cases were defined as non-SCLC-like type,accounting for 61.5%.SCLC-like cases were more likely to have lymph node metastases(p=0.001)and higher TNM stage(p<0.001)with significantly lower overall survival time compared with non-SCLC-like cases(p=0.023).In multivariate Cox regression analysis,SCLC-like subtype was an independent predictor of overall survival(p=0.021)with a risk rate of 4.690,95%confidence interval(1.263,17.421)compared with non-SCLC-like type.Expression of Rb and p53 in gastric NEC was significantly different from that in gastric NET,gastric adenocarcinoma and SCLC;there were significant differences between gastric NEC and gastric NET(p=0.001)and gastric adenocarcinoma(p=0.002)on p53 and Rb expression based subtyping.Immunotherapy related biomarkers were investigated in 39 subtyped cases of gastric NEC.9 cases(23.1%)were PD-L1 positive;20 cases(51.3%)were CD8 T cells highly infiltrated.The median TMB was 4.9 muts/mb(0.1-42.2 muts/mb),and no MSI-H was detected.In survival analysis,there was no immunotherapy related biomarkers significantly related to the overall survival.There was no significant difference in the expression of immunotherapy related biomarkers among different subtypes.Conclusion:This study found that gastric NEC might be classified into two subtypes by p53 and Rb expression.These two subtypes may have differences in clinicopathological features and prognosis.Immunotherapy related biomarkers were expressed in part of gastric NEC cases.No significant difference in the expression of immunotherapy related biomarkers was found between the two subtypes. |
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