Assessment of programmed death-ligand 1 expression in primary tumors and paired lymph node metastases of gastric adenocarcinoma

BACKGROUND Anti-programmed death-1/programmed death-ligand 1(PD-1/PD-L1)immuno-therapy has demonstrated promising results on gastric cancer(GC).However,PD-L1 can express differently between metastatic sites and primary tumors(PT).AIM To compare PD-L1 status in PT and matched lymph node metastases(LNM)of GC patients and to determine the correlation between the PD-L1 status and clinicopathological characteristics.METHODS We retrospectively reviewed 284 GC patients who underwent D2-gastrectomy.PD-L1 was evaluated by immunohistochemistry(clone SP142)using the com-bined positive score.All PD-L1+PT staged as pN+were also tested for PD-L1 expression in their LNM.PD-L1(-)GC with pN+served as the comparison group.RESULTS Among 284 GC patients included,45 had PD-L1+PT and 24 of them had pN+.For comparison,44 PD-L1(-)cases with pN+were included(sample loss of 4 cases).Of the PD-L1+PT,54.2%(13/24 cases)were also PD-L1+in the LNM.Regarding PD-L1(-)PT,9.1%(4/44)had PD-L1+in the LNM.The agreement between PT and LNM had a kappa value of 0.483.Larger tumor size and moderate/severe peritumoral inflammatory response were associated with PD-L1 positivity in both sites.There was no statistical difference in overall survival for PT and LNM according to the PD-L1 status(P=0.166 and P=0.837,respectively).CONCLUSION Intra-patient heterogeneity in PD-L1 expression was observed between the PT and matched LNM.This disagreement in PD-L1 status may emphasize the importance of considering different tumor sites for analyses to select patients for immunotherapy.

Prognostic implications of tumor-infiltrating lymphocytes in association with programmed cell death ligand 1 expression in remnant gastric cancer

Objective:Remnant gastric cancer(RGC)is usually associated with a worse prognosis.As they are less common and very heterogeneous tumors,new prognostic and reliable determinants are required to predict patients’clinical course for RGC.This study aimed to investigate the tumor-infiltrating lymphocytes(TILs)and programmed cell death ligand 1(PD-L1)status as prognostic biomarkers in a cohort of patients with RGC to develop an immunerelated score.Methods:Patients with gastric cancer(GC)who underwent curative intent gastrectomy were retrospectively investigated.RGC resections with histological diagnosis of gastric adenocarcinoma were enrolled in the study.The risk score based on immune parameters was developed using binary logistic regression analysis.RGCs were divided into high-risk(HR),intermediate-risk(IR),and low-risk(LR)groups based on their immune score.The markers(CD3+,CD4+/CD8+T cells and PD-L1)were selected for their potential prognostic,therapeutic value,and evaluated by immunohistochemistry(IHC).Results:A total of 42 patients with RGC were enrolled in the study.The score based on immune parameters exhibited an accuracy of 79%[the area under the receiver operating characteristic curve(AUC)=0.79,95%confidence interval(95%CI),0.63-0.94,P=0.002],and the population was divided into 3 prognostic groups:10(23.8%)patients were classified as LR,15(35.7%)as IR,and 17(40.5%)as HR groups.There were no differences in clinicopathological and surgical characteristics between the three groups.In survival analysis,HR and IR groups had worse disease-free survival and overall survival rates compared to the LR group.In the multivariate analysis,lymph node metastasis and the immune score risk groups were independent factors related to worse survival.Conclusions:A scoring system with immune-related markers was able to distinguish prognostic groups of RGC associated with survival.Accordingly,tumor-infiltrating immune lymphocytes and PD-L1 status may serve as a potential prognostic biomarker for patients with RGC.

Expression profiles of gastric cancer molecular subtypes in remnant tumors

BACKGROUND Remnant gastric cancer(RGC)is a carcinoma arising in the stomach remnant after previous gastric resection.It is frequently reported as a tumor with a poor prognosis and distinct biological features from primary gastric cancer(PGC).However,as it is less frequent,its profile regarding the current molecular classifications of gastric cancer has not been evaluated.AIM To evaluate a cohort of RGC according to molecular subtypes of GC using a panel of immunohistochemistry and in situ hybridization to determine whether the expression profile is different between PGC and RGC.METHODS Consecutive RGC patients who underwent gastrectomy between 2009 and 2019 were assessed using seven GC panels:Epstein-Barr virus in situ hybridization,immunohistochemistry for mismatch repair proteins(MutL homolog 1,MutS homolog 2,MutS homolog 6,and PMS1 homolog 2),p53 protein,and E-cadherin expression.Clinicopathological characteristics and survival of these patients were compared to 284 PGC patients.RESULTS A total of 40 RGC patients were enrolled in this study.Compared to PGC,older age(P<0.001),male(P<0.001),lower body mass index(P=0.010),and lower hemoglobin level(P<0.001)were associated with RGC patients.No difference was observed regarding Lauren’s type and pathologic Tumor Node Metastasis stage between the groups.Regarding the profiles evaluated,EBV-positive tumors were higher in RGC compared to PGC(P=0.039).The frequency of microsatellite instability,aberrant p53 immunostaining,and loss of E-cadherin expression were similar between RGC and PGC.Higher rates of simultaneous alterations in two or more profiles were observed in RGC compared to PGC(P<0.001).According to the molecular classification,the subtypes were defined as EBV in nine(22.5%)cases,microsatellite instability in nine(22.5%)cases,genomically stable in one(2.5%)case,and chromosomal instability in 21(52.5%)cases.There was no significant difference in survival between molecular subtypes in RGC patients.CONCLUSION RGC was associated with EBV positivity and higher rates of co-altered expression profiles compared to PGC.According to the molecular classification,there was no significant difference in survival between the subtypes of RGC.