The Role Of Microenvironment In The Progression Of Pancreatic Ductal Adenocarcinoma: A Clinicopathological Study

Background Environment may has a dual action in tumors, with both pro-tumor and anti-tumor activities. It is very important to know the elements of environment and their roles in tumor invasion and metastasis. As one of the most malignant tumor, pancreatic ductal adenocarcinoma(PDAC) is characterized by a rich stroma. Recently the tumor microenvironment in other adenocarcinomas has been determined to be an important mediator of cancer cell behavior; however, few studies have elucidated the tumor-stroma interactions in pancreatic cancer. The present study is aimed to evaluate the common inflammatory reaction in PDAC by analysizing the elements of tumor environment and their clinicopathological significance. The present study would be helpful to further study about mechanism of tumor-stroma interaction.Methods First, we identified four areas:the non-invasion areas included two parts, peritumoral border and central zones; the invasion front was the intratumoral border zone; and the complete tumor area was the intratumoral central zone. HE staining, masson staining, immunohistochemistry staining were performed to evaluate the inflammatory cells infiltration, fibrosis formation, angiogenesis and lymphoangiogenesis. Second, according to the anatomic localization, zone-specific distribution of mast cells was assessed to explore their prognostic value with cox-hazard ratio model.Results At intratumor border zone the percentage of inflammatory cell infiltration, stromal fibrosis, angiogenesis and lymphoangiogenesis was 94.4%,91.6%,41.6% and 74.7%, respectively. At intratumor center zone the percentage of inflammatory cell infiltration, stromal fibrosis, angiogenesis and lymphoangiogenesis was 74.2%,93.3%, 5.1% and 52.2%, respectively. At peritumor border zone/center zone the above percentage was 90.4%/86.5%,88.7%/85.4%,36.0%/46.6%,69.7%/41.0%, respectively. Lymphocyte and neutrophil were dominant cell.Mast cell and macrophage cell were also common. Statistical analyses indicated that more inflammatory cells, less fibrosis and more microvessels significantly correlated with microvascular invasion(P<0.0005, P=0.0008 and P=0.014). And lymphoangiogenesis was associated with lymph node metastasis(P=0.010). In contrast, at peritumor border zone severe fibrosis was associated with less tumor diameter(P=0.003). In addition, mast cells at intratumor border zone were obviously more than that of other zones. Moreover, they were correlated with the number of microvessel(r=0.842, P<0.001;). Multivariate analyses suggested that count of mast cells at intratumor border zone was an independent risk factor for PDAC(HR=2.896, P<0.001).Conclusions The most obvious region of inflammatory reaction is the boundary area between tumor and peritumor tissues. Angiogenesis and lymphoangiogenesis at intratumor border zone may promote the progression of PDAC. However, fibrosis at peritumor border zone may restrict the progression of PDAC. In addition, the mast cell count at intratumoral border zone has been identified as a novel independent predictor for PDAC. Tumor associated angiogenesis may be a important protumor factor for stromal mast cell. Therefore, the intratumoral border zone microenvironment is important in understanding the mechanism of progression of PDAC.