Heterogeneity of immunohistochemical status of microsatellite instability in gastric cancer: clinical-pathological associations and prognostic significance

Objective. The investigation of the prevalence of heterogeneity in immunohistochemical staining of mismatch repair system markers (MMR heterogeneity) in gastric cancer (GC), search for correlations with clinical and morphological parameters, and analysis of the prognostic role of this phenomenon. Material and methods. Histological specimens stained immunohistochemically with antibodies to MMR markers (MSH2, MSH6, MLH1, PMS2; full-size surgical material from patients with GC, n=310) were analyzed. Two heterogeneous phenotypes were identified: 1) MMR-positive/heterogeneous — some tumor cells lose nuclear staining, while staining is preserved in other tumor cells and in the stroma, 2) MMR-negative/heterogeneous — in cases of MMR-negative tumors showing heterogeneous staining of preserved MMR markers. Statistical analysis was performed using IBM SPSS 26 software. Results. MMR-positive/heterogeneous tumors accounted for 11% of cases (n=34), MMR-negative/heterogeneous tumors — 2.3% (n=7). In MMR-positive/heterogeneous tumors, compared with MMR-positive tumors, there was a higher frequency of absence of signet ring cells (p<0.001), 1—2 macroscopic forms (p=0.046), papillary and tubular histological subtypes (p<0.001), intestinal histological subtype according to P. Lauren (p<0.001), higher differentiation grade (p<0.001), and earlier stage of disease (p=0.024). MMR-positive/heterogeneous status was associated with the tendency to longer overall survival (p=0.050; median 61 months vs. MMR-positive — 36 months). MMR-negative/heterogeneous and MMR-negative tumors did not differ statistically in terms of the parameters studied. Conclusion. MMR-heterogeneous tumors in GC, distinguished from MMR-positive, are characterized by a more favorable clinical and morphological profile and the tendency to longer survival compared to the latter. However, it is important to note the small number of cases in the MMR-negative/heterogeneous tumor group, as well as the heterogeneity of the clinical and morphological parameters among patients in the subgroups identified based on MMR status. This necessitates confirmation of the observed trends in survival differences in larger patient cohorts. Consequently, it is necessary to classify heterogeneous cases into separate subgroups, followed by a detailed study of their pathogenetic, predictive, and prognostic characteristics.