Pseudomyxoma Peritonei: Inflammatory Responses in the Peritoneal Microenvironment

Abstract

Pseudomyxoma peritonei (PMP), a peritoneal mucinous neoplasm of appendiceal origin, is associated with inflammation and fibrosis, which is central to its biology. The significance of the microenvironment in PMP has not been well characterized. Immunoassays were used to measure cytokines and C-reactive protein (CRP). Forty-two cytokines were initially measured in 23 PMP ascites and 10 PMP peritoneal washings. On the basis of these results, matching serum and ascites samples were analyzed for ten relevant cytokines (n = 32) and CRP (n = 28). Immunohistochemistry was performed on formalin-fixed tissue sections. Statistical analysis was by Wilcoxon signed rank test, Mann-Whitney U-test, and bivariate analysis. Serum CRP was elevated in PMP and correlated to CRP level in ascites. Interleukin (IL)-6, IL-8 (CXCL8), interferon gamma-induced protein 10 (IP-10), (CXCL10), monocyte chemotactic protein (MCP)-1 (CCL2), and macrophage inflammatory protein (MIP)-1α (CCL3) levels were grossly elevated in ascites but did not correlate with serum levels. Cytokines normally associated with infection or tissue injury (e.g., IL-1, IL-2, interferon gamma) were not elevated. Immunohistochemistry localized IL-6 to stroma, IP-10, and MCP-1 to tumor cells and IL-8 to adipose tissue. There were complex interactions among cytokines. IL-6, in particular, had many significant correlations in ascites. Serum IL-8, MIP-1β, and CRP were higher in PMP compared to controls. The pattern of cytokines in PMP is distinct from infection- or injury-associated inflammation. The results support peritoneal synthesis for cytokines. CRP, IL-8, and MIP-1β are potential serum markers for PMP. IL-6 appears to play a central role in PMP biology. This study provides new details about PMP tumor biology and identifies possible therapeutic targets.