Microsatellite Instability Status in Gastric Cancer: A Reappraisal of Its Clinical Significance and Relationship with Mucin Phenotypes

Abstract

BackgroundGastric cancers with microsatellite instabilities (MSI) have been reported to be associated with favorable prognosis. However, the significance of the effect of MSI on the clinicopathological features, as well as its association with mucin phenotype, remains unclear.MethodsMSI status was assessed in 414 cases of gastric cancer using polymerase chain reaction analysis of five microsatellite loci, as recommended by National Cancer Institution criteria. The expression of mucins (MUC5AC, MUC6, MUC2, and CD10) was assessed.ResultsOut of 414 total cases of gastric cancer, 380 (91.7%), 11 (2.7%), and 23 (5.6%) were microsatellite stable (MSS), low-level MSI (MSI-L), and high-level MSI (MSI-H), respectively. Compared to MSS/MSI-L, MSI-H gastric cancers were associated with older age (p=0.010), tumor size (p=0.014), excavated gross (p=0.042), intestinal type (p=0.028), aggressive behaviors (increase of T stage [p=0.009]), perineural invasion [p=0.022], and lymphovascular emboli [p=0.027]). MSI-H gastric cancers were associated with tumor necrosis (p=0.041), tumor-infiltrating lymphocytes (≥2/high power field, p<0.001), expanding growth patterns (p=0.038), gastric predominant mucin phenotypes (p=0.028), and MUC6 expression (p=0.016). Tumor necrosis (≥10% of mass, p=0.031), tumor-infiltrating lymphocytes (p<0.001), intestinal type (p=0.014), and gastric mucin phenotypes (p=0.020) could represent independent features associated with MSI-H gastric cancers. MSI-H intestinal type gastric cancers had a tendency for poor prognosis in univariate analysis (p=0.054) but no association in Cox multivariate analysis (p=0.197).ConclusionsOur data suggest that MSI-H gastric cancers exhibit distinct aggressive biologic behaviors and a gastric mucin phenotype. This contradicts previous reports that describe MSI-H gastric cancer as being associated with favorable prognosis.

Genetic and histological subtypes of gastric cancer reviewed, particularly emphasising on microsatellite instability and E-cadherin gene mutation

“…Recent studies have demonstrated the predictive value of immunohistochemistry which includes analysing four proteins (MLH1, MSH2, MSH6 and PMS2) which is virtually equivalent to MSI testing (Fig. 2) [11,35,36]. Microsatellite analysis and immunohistochemical staining are in agreement in more than 90% of GCs [37].…”

“…The histological features which are not specific, but are commonly seen, include an intestinal type of tumour and prominent lymphoid cell infiltration with expanding borders [26,37,38]. The MSI-H phenotype was also associated with mucinous GC or MUC 6 positivity [26,35]. There exists a growing body of evidence that GC with MSI is associated with a better prognosis than MSS GC [39,40].…”

“…However, microsatellite analysis when using PCR is more sensitive and provides informative results in virtually all cancers [37]. Clinicopathological features displayed by high-level microsatellite instability GC with MSI-H are reported to be distinct both clinically and in molecular terms compared to microsatellite stable (MSS) GC [35]. In contrast to colorectal cancer, the clinical significance and role of MSI in GC however remain controversial [35].…”

“…Clinicopathological features displayed by high-level microsatellite instability GC with MSI-H are reported to be distinct both clinically and in molecular terms compared to microsatellite stable (MSS) GC [35]. In contrast to colorectal cancer, the clinical significance and role of MSI in GC however remain controversial [35]. MSI-H GCs tend to be associated with an older age, female gender, distal tumour location, rare lymph node involvement and a lesser propensity to invade the serosa.…”

“…MSI-H GCs tend to be associated with an older age, female gender, distal tumour location, rare lymph node involvement and a lesser propensity to invade the serosa. They often display distinct features at the histological level, which should raise suspicion of MSI and prompt further analysis [35]. The histological features which are not specific, but are commonly seen, include an intestinal type of tumour and prominent lymphoid cell infiltration with expanding borders [26,37,38].…”