Despite the incidence rate of the gastric cancer has been continuously decreasing during the past decade, it remains the third most common cancer type worldwide. With the rapid improvement of medical science, many indicators are established to calculate the aggressiveness and severity of gastric cancer. For example, as a critical method for prognosis of the gastric cancer patients after radical surgery, the TNM staging system, is widely acknowledged by clinical physicians. Nevertheless, the survival outcomes for patients with the advanced gastric cancer varies widely even in the same disease stage, similar situation can also be seen in pT2 stage. For one thing, the data about clinicopathological characteristics and survival outcomes for pT2 stage gastric cancer patients after radical surgery is limited. For another, it is obvious that cancer aggressiveness, distant metastasis risk and patient prognosis are nearly correlated to the tumor infiltration in gastric cancer, and the latest 8th TNM staging system does not define the detailed subclassification of the pT2 stage. Above all, it is necessary to investigate prognostic differences based on the depth tumor muscularis propria infiltration.
For all we know, this is the first study to evaluate differences in the clinicopathologic features and the prognoses of pT2 subclassification based on the depth of tumor muscularis propria infiltration in a large cohort of Chinese gastric cancer patients. Molecular markers and serum tumor markers also are firstly investigated in the pT2 subclassification.
Several studies that discussed the clinicopathological features and survival difference for pT2 stage GC used the older stage system, that contained tumors subserosa invasion stage[4, 9, 10]. On the contrary, our present study was based on the latest staging system that only included tumors invading the muscularis propria, patients were allocated into two groups, the sMP group and dMP group. For general characteristics, there were more regional lymph node metastases in patients of the dMP group than patients of the sMP group, which in line with the previous study[4, 11]. We also found that neural invasion and elevated initial AFP levels were more likely to appear in the dMP group than the sMP group.
In previous studies, Sun and colleagues demonstrated that patients in the sMP group had significantly better survival outcomes than patients in the dMP/SS group, whereas similar outcomes could be observed in the dMP group and the SS group. However, they did not analyze the prognosis differences among the sMP group and dMP group. We demonstrated that in N0 group, patients with sMP tumor had statistically longer survival than patients with dMP tumor, but not in N+ group. This result is consistent with the findings of Zhang and colleagues. In addition, when patients were grouped depending on the depth of tumor invasion and pN stage, we further found that the survival outcomes were not significantly different between patients with the dMPN0 stage and with the sMPN1-2 stage. After further comparison according to postoperative adjuvant chemotherapy status, we observed that significantly improved survival outcomes for patients who had received the adjuvant chemotherapy in the dMPN0 staging group, rather than in the sMPN1-2 staging group. We also observed that the dMPN0 patients with the adjuvant chemotherapy had a better postoperative survival compared to sMPN1-2 patients.
Depending on the latest 8th UICC/AJCC TNM staging system, sMPN0, dMPN0 patients and sMPN1-2 patients were classified as stage IB, IB and II, respectively, and patients with stage II, rather than with stage IB, should receive the adjuvant chemotherapy depending on therapy guideline. In the present study, however, significantly different survival could be seen between sMPN0 group (stage IB) and dMPN0 group (stage IB), but not dMPN0 group (stage IB) and sMPN1-2 group (stage II), and dMPN0 patients who received the adjuvant chemotherapy had obviously improved postoperative survival compared to sMPN1-2 patients. These results showed that the dMPN0 stage should be divided from stage IB as a special subclassification and the dMPN0 patients should receive appropriate adjuvant chemotherapy and follow-up strategy.
As the increase in the understanding of the molecular mechanism of tumorigenesis, it is currently believed that the molecular markers related with the tumorigenesis and disease progression may be potential prognostic factors. The mutated p53 gene subsequently causing inactivation of the p53 protein tumor-suppressor activity appear to constitute one of the commonest molecular steps in tumor development[12, 13]. It is reported that the gene mutation of p53 lead to an increased stability and prolonged half-life time of p53 protein, and result in a nuclear accumulation of protein where it is easily detectable by immunohistochemistry (IHC) using monoclonal antibodies. Although the p53 protein accumulation detected by IHC does not entirely indicate the mutation of gene, the high accordance (85%) could be seen in the p53 overexpression and an underlying mutation. Therefore, the p53 protein overexpression detected through IHC may be considered as a cheaper substitution of that gene mutation. Multiple studies also show the overexpression of the p53 protein as an indicator of poor prognosis in GC[5, 16, 17]. A previous meta-analysis, which collected 34 articles focusing on the prognostic value of p53 protein, suggested that positive/high p53 protein expression as a powerful biomarker to predict poorer survival outcomes for gastric cancer patients. Surprisingly, we found that almost all previous studies[5, 16, 17] that discussed the prognostic value of p53 had not performed subgroup analysis based on a certain TNM staging. In our study, we demonstrated that positive expression of p53 protein was a negative prognostic factor for the OS in the early stages of GC. Specifically, for patients with p53-positive, the sMPN0 group had better survival outcomes than dMPN0 group. Moreover, similar survival outcomes could be seen between the dMPN0 patients (stage IB) with p53-positive and T2N1-2 patients (stage II). The above results might unveil that dMPN0 patients (stage IB) with positive expression of p53 should accept suitable adjuvant chemotherapy like patients in stage II.
HER-2/neu as a predictive factor for the therapeutic effect of trastuzumab in the treatment of gastric cancer already has been confirmed by ToGA study. However, the prognostic value of HER-2/neu for GC was still debated. Several studies reported overexpression of HER-2/neu protein as a predictor for aggressive tumor behavior and poor prognosis[19, 20], while others were not[21, 22]. In a meta-analysis, Pyo and colleagues found that HER2 IHC was highly concordant with ISH in HER2 IHC score 0/1+ or 3+ (96.9%, 91.5%, respectively) and lowly concordant with ISH in HER2 IHC score 2+ (39.3%). In our study, overexpression of HER-2/neu protein was not an adverse prognostic predictor. That discrepancy may be partly blamed for the low specificity of immunohistochemical in HER2 IHC score 2+ and the evaluation standard that defined the IHC score of 2+ and 3+ as HER-2 positivity in our study.
Prognostic value of serologic tumor markers was also been investigated in pT2 GC patients. We demonstrated that the elevated maximal LDH level, elevated initial CA19-9 and AFP level were poor prognostic factors in the multivariable survival analysis, which was concordant with previous studies[3, 24, 25]. Petrelli et al. used a meta-analysis and confirmed that a high serum LDH concentration (>245 U/L) was associated with a poorer survival in the GC patients. Fanotto et al. found similar results. After further subgroup analysis, we noticed that patients with the sMPN0 had a higher overall survival than those with the dMPN0 in the elevated maximal LDH level group and there was similar OS between the dMPN0 patients with the elevated maximal LDH level and T2N1-2 patients. Similar results also were shown in the dMPN0 patients with elevated maximal CEA levels. According to the above conclusions, we confirmed that serologic tumor markers could be used to identify individual heterogeneity and improve the survival prediction ability of the TNM staging.
Despite some promising findings, our present study still has several limitations. On the one hand, although the sample size of this study is the largest amongst other studies focusing on the T2 subclassification to date, as a single center retrospective study, the results are susceptible to selection bias. Further multi-center, large-sample, prospective studies are therefore required to verify the findings of this study. On the other hand, IHC has been applied to detect molecular markers of cancer in our present study. However, the differences of the types of antibody, concentration and evaluation standard of positivity used in IHC might produce potential bias.