Podoplanin-positive cancer-associated fibroblasts could have prognostic value independent of cancer cell phenotype in stage I lung squamous cell carcinoma: Usefulness of combining analysis of both cancer cell phenotype and cancer-associated fibroblast phenotype

Background: The prognostic significance of the tumor microenvironment, which is created by both cancer cells and cancer-associated fibroblasts (CAFs), has been increasingly recognized. The purpose of this study was to analyze the prognostic markers of stage I squamous cell carcinoma (SqCC), with special reference to the immunophenotypes of both cancer cells and CAFs. Methods: A total of 142 patients with stage I SqCC were included in this study. We examined the expressions of E-cadherin, laminin-5, podoplanin, c-MET, carbonic anhydrase IX (CA-IX), CD10, and CD44 in the cancer cells and those of podoplanin, CA-IX, CD10, and CD44 in the CAFs to evaluate their prognostic value. Results: Patients with low E-cadherin expression in the cancer cells showed a significantly poorer prognosis than those with high E-cadherin expression in the cancer cells (P <.001). On the other hand, high podoplanin expression in the CAFs was also associated with a significantly poorer prognosis (P <.001). A multivariate analysis identified low E-cadherin expression in the cancer cells and high podoplanin expression in the CAFs as significantly independent prognostic factors for overall survival (P =.013 and P =.0011, respectively). According to subgroup analyses combining E-cadherin expression in cancer cells and podoplanin expression in CAFs, 5-year overall survival of patients with low E-cadherin expression in the cancer cells and high podoplanin expression in the CAFs was 7.0% and showed a significantly poorer prognosis as compared with other groups (P <.001). Conclusions: The current study indicates that immunophenotypes of CAFs could have a prognostic value independent of those of the cancer cells in SqCC.