Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by an extensive stroma being also present in chronic pancreatitis (CP). Using immunohistochemistry, the stroma of CP and PDAC was comprehensively analyzed and correlated with epithelial/carcinoma-related alterations and clinicopathological patient characteristics. While there were no significant differences between CP and PDAC regarding the distribution of CD3+ T cells and α-SMA+ fibroblasts, proportions of CD4+ and CD8+ T cells were significantly lower and numbers of CD25+(CD4+) and FoxP3+(CD4+) regulatory T cells were greater in PDAC compared with CP. Macrophages were more prevalent in CP, but localized more closely to carcinoma cells in PDAC, as were γδ-T cells. Duct-related FoxP3 and L1CAM expression increased from CP to PDAC, while vimentin expression was similarly abundant in both diseases. Moreover, stromal and epithelial compartments of well-differentiated tumors and CPs shared considerable similarities, while moderately and poorly differentiated tumors significantly differed from CP tissues. Analysis of 27 parameters within each pancreatic disease revealed a significant correlation of i) CD4+ and FoxP3+CD4+ T cells with FoxP3 expression in PDAC cells, ii) α-SMA+ fibroblasts with L1CAM expression and proliferation in PDAC cells, iii) CD3 and CD8 expression with γδ-TCR expression in both pancreatic diseases and iv) CD68+ and CD163+ macrophages with vimentin expression in PDAC cells. High expression of FoxP3, vimentin and L1CAM in PDAC cells as well as a tumor-related localization of macrophages each tended to correlate with higher tumor grade. Multivariate survival analysis revealed a younger age at time of surgery as a positive prognostic marker for PDAC patients with the most frequently operated disease stage T3N1M0. Overall this study identified several interrelationships between stroma and epithelial/carcinoma cells in PDACs but also in CP, which in light of previous experimental data strongly support the view that the inflammatory stroma contributes to malignancy-associated alterations already in precursor cells during CP.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is the 4th most lethal tumor disease with an overall 5-year-survival rate of,2% [1]
Cd-T cells within or adjacent to the ductal/tumoral epithelium were localized in 67% of the chronic pancreatitis (CP) as well as in 44% of the PDAC patients (Figure 3+4)
Cd-T cells accumulated more intensively within the ductal/tumoral epithelium in PDAC patients compared to CP patients (Figure 3+4)
Summary
Pancreatic ductal adenocarcinoma (PDAC) is the 4th most lethal tumor disease with an overall 5-year-survival rate of ,2% [1]. It is commonly diagnosed in an advanced stage, limiting curative therapeutic options to ,20% of the patients. Besides intraductal papillary mucinous neoplasias (IPMN), mucinous cystic neoplasias (MCN) and atypical flat lesions (AFL), pancreatic intraepithelial neoplasias (PanIN) are the most frequent and best characterized precursor lesions of PDAC [3]. Since PDAC is characterized by an extensive desmoplastic reaction accounting for up to 80% of the whole tumor mass, the tumor microenvironment has been regarded as a promising target to improve diagnosis and
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