| Aims:Perineural invasion (PNI) is the process of neoplastic invasion of nerves and is an under-recognized route of metastatic spread. Leibig defined PNI as the presence of cancer cells along nerves and/or within the spaces of the neuronal sheath, including cases in which the cells circumscribed at least33%of the nerve.The frequencies of perineural invasion reported in gastric cancer are different and there is no consensus about its prognostic role in gastric cancer. Thus, we reread the paraffin sections of surgical specimens in our hospital to understand PNI and its effect on overall survival (OS) of gastric cancer patients. Furthermore, we systematically reviewed the available published reports and estimated the pooled odds ratio (OR) using meta-analysis to evaluate the prognostic role of PNI in gastric cancer. A protocol was developed a priori from the research question-'Is PNI an independent prognostic factor affecting on OS of gastric cancer patients who undergo the curative gastric resection?'Methods:This study included gastric cancer patients who had undergone curative gastrectomy in the Department of Surgical Oncology of the First Hospital affiliated to Medical School of Zhejiang University from January2000to December2006. Pathological sections were stained with hematoxylin and eosin. Tumors were rereviewed for PNI by a pathologist blinded to the patients'outcomes. PNI was assessed as positive when cancer cells in close proximity to nerve and involving at least33%of its circumference or tumor cells within any of the3layers of the nerve sheath.The relationship between PNI positivity and other clinicopathological factors were analyzed using Chi-square test. Survival analysis and curves were established according to the Kaplan-Meier method and compared by the log-rank test. Multivariate analysis to assess the role of PNI and the other clinicopathological features as prognostic factors were performed by the Cox regression analysis. All P values were two-sided in tests, and P values less than.05were considered to be statistically significant.Reports from1993-2011investigating the prognostic effect of PNI on the overall survival of gastric cancer patients were selected for the meta-analysis using a search of PubMed, Web of Science, Google Scholar, Wanfang data resource system and China knowledge network. Homogeneity test was performed by using odds ratio q test. A fixed effect model was used to integrate the OR and CI when studies were homogeneous. A random effect model was used when studies were heterogeneous. Egger's and Begg's tests were used to check the publication bias.Results:The5-year survival rate was62.7%for the whole group. PNI was positive in121of the292patients (41.44%). pT stage, pN stage, TNM stage, tumor size, tumor differentiation, Borrmann classification and blood vessel invasion were closely associated with the presence of PNI. However, PNI was not related to age, sex, tumor location and D resection.The overall survival of the PNI-positive patients was45.151months (39.231,51.071), significantly shorter than that of the PNI-negative patients, which was70.049months (66.010,74.087),(P=0.000). And5-year survival rates were41.3%vs77.8%(P<0.05).For the node-negative gastric cancer patients, the overall survival of the PNI-positive patients was65.263months (51.735,78.790), significantly worse than that of PNI-negative patients, which was80.541months (77.788,83.294),(P=0.000). And 5-year survival rates were68.8%vs96.5%(P<0.05).Univariate analysis showed that overall survival was affected by age, lymph node metastasis, mural invasion depth, resection method, tumor size, tumor Differentiation Borrmann type, perinerual invasion and vessel invasion. However, in the multivariate Cox proportional hazards model analysis, age, lymph node metastasis, mural invasion depth, tumor size and D resection are independent factors that impact on overall survival while PNI had no independent prognostic significance.Univariate analysis indicated that the overall survival of node-negative patients was affected by sex, T stage, tumor size and perinerual invasion. However, all the above-mentioned were not independent prognostic factors in multivariate Cox proportional hazards model analysis.Meta-analysis included14reports, incorporating6742gastric cancer cases. OS was investigated unadjusted for other variables in eight studies incorporating3,401cases. The hazard estimates ranged from1.082to3.492with a pooled estimate of risk of1.897(95%CI1.536,2.343)(P=0.000). OS adjusted for other parameters was evaluated in ten series comprising4,147cases and the estimates for these studies ranged from0.709to3.230with a pooled estimate of1.582,(95%CI1.166,2.148)(P=0.003). Studies were heterogeneous. Begg's test and Egger's test showed no obvious publication bias in this research.Conclusions:Our single group findings suggest that PNI positive rate was41.44%in curative gastric cancer resection specimens. For the whole group of patients and node-negative patients, the overall survival of PNI positive patients were significantly shorter than those of PNI negative patients. PNI is an indicator of cancer aggressiveness. However, multivariate Cox proportional hazards model analysis did not show PNI was an independent prognostic factor for gastric cancer patients with curative gastrectomy.The meta-analysis strongly supports the prognostic role of perineural invasion in gastric cancer and shows that this effect is independent of lymph node status, tumor size and tumor grade as well as a range of other biological variables on multivariate analysis. PNI may be considered when stratifying gastric caner patients for adjuvant treatment. Large prospective studies are now needed to establish the clinical utility of perineural invasion as an independent prognostic marker. |
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