Prognostic impact of tumor microenvironment characteristics in intrahepatic cholangiocarcinoma: A systematic review and meta-analysis.

Abstract

<h4>Introduction</h4>Intrahepatic cholangiocarcinoma (ICC) is a rare and aggressive cancer. Histologic characterization of ICC and the tumor microenvironment (TME) may be associated with prognosis and response to treatment. The objective of the current study was to systematically review and conduct a meta-analysis to identify various elements of the TME that impact prognosis among patients with ICC.<h4>Methods</h4>A systematic search was performed using the PubMed, Embase and Scopus databases that employed a Boolean search strategy using Medical Subject Headings (MeSH) terms for: bile duct neoplasms, intrahepatic cholangiocarcinoma and tumor microenvironment. A random effect meta-analysis was conducted to assess the impact of TME elements on overall survival (OS) and disease free survival (DFS).<h4>Results</h4>Twenty-five studies (4162 patients, 56.1 % male) met inclusion criteria. On pooled meta-analysis, stromal factors associated with improved patient outcomes included mature stroma (HR = 0.38; 95 %CI, 0.26-0.56-OS). In contrast, alpha-smooth muscle actin fibroblasts in the TME were associated with worse OS (HR = 1.48; 95 %CI, 1.22-1.80); micro vessel density did not correlate with patient prognosis (HR = 0.73; 95 %CI, 0.31-1.70). High peritumoral and intra tumoral CD8⁺ T cells (HR = 0.57; 95 %CI, 0.45-0.71) and CD 4+ T-cells (HR = 0.48; 95 %CI, 0.37-0.62) were associated with improved OS. Epithelial-mesenchymal transition characterized by positive E-Cadherin expression was also associated with improved OS. In contrast, lack of cholangiocellular differentiation and large duct type ICC were associated with a worse OS among patients with ICC.<h4>Conclusion</h4>Elements of the TME had a variable impact on the prognosis of patients and may have differential implications for potential treatment of patients with ICC.