Histologic and Immunohistochemical Alterations Associated with Cytoreductive Surgery and Heated Intraperitoneal Chemotherapy.

Abstract

Cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) are used to treat peritoneal carcinomatosis from a variety of primary tumor sites. Little is known about the in vivo effects of CRS and HIPEC. We examined tumor and non-neoplastic peritoneal tissue samples from 38 patients undergoing CRS and HIPEC for appendiceal or colorectal carcinomatosis, using conventional histologic analysis and immunohistochemical analysis for markers of early DNA damage (phosphorylated H2AX, γH2AX) and early necrosis (extracellular HMGB1). Findings were correlated with clinicopathologic features and oncologic outcome. Histologic findings corresponding with CRS and HIPEC included extensive submesothelial inflammatory infiltrate, endothelial activation, mesothelial karyolysis and surface fibrin deposition. Endothelial activation in submesothelial vessels exhibited high specificity for samples obtained following HIPEC relative to samples obtained following CRS but prior to HIPEC. Mesothelial nuclear γH2AX staining and submesothelial extracellular HMGB1 staining increased progressively following CRS and HIPEC, consistent with DNA damage and necrosis. No significant increase in tumor staining for markers was seen with CRS or HIPEC. Submesothelial HMGB1 staining was associated with increased progression-free survival on univariate analysis. The immediate histologic effects of CRS and HIPEC are defined and provide evidence that DNA damage and early steps of necrosis are underway in mesothelial tissues at the conclusion of the procedure. Further research will be necessary to investigate the impact of these findings on long-term oncologic outcome, and may provide insight into the downstream effects of CRS and HIPEC that could facilitate refinement of regional therapeutic regimens for carcinomatosis.