Identification of prognostic immunophenotypic features in cancer stromal cells of high-grade neuroendocrine carcinomas of the lung

Purpose The immunophenotypes of cancer stromal cells have been recognized as prognostic factors of cancer. The purpose of this study was to analyze the prognostic markers of high-grade neuroendocrine carcinomas of the lung (HGNEC; both small cell carcinoma and large cell neuroendocrine carcinoma) by examining the immunophenotypes of cancer stromal cells. Materials and methods One hundred and fifteen patients who underwent a complete resection of HGNEC were included in this study. We examined the presence of CD204-positive tumor-associated macrophages (TAMs), Foxp3-positive regulatory T cells (Tregs), and podoplaninpositive cancer-associated fibroblasts (CAFs) to evaluate the prognostic values of these markers. Results The number of CD204-positive TAMs and Foxp3-positive Tregs did not influence the overall survival (OS) or the relapse-free survival (RFS) of the patients. However, patients with podoplanin-positive CAFs had a significantly better prognosis than those with podoplaninnegative CAFs [OS: p = 0.002, RFS: p = 0.002, 5-year overall survival (5YR): 74 vs. 45 %]. According to subgroup analyses, patients with podoplanin-positive CAFs displayed a better prognosis for both small cell carcinoma (OS: p = 0.046, 5YR: 74 vs. 46 %) and large cell neuroendocrine carcinoma (OS: p = 0.020, 5YR: 74 vs. 45 %). Moreover, in multivariate analyses, the podoplanin status of the CAFs was shown to be a statistically significant independent predictor of recurrence. Conclusion The presence of podoplanin-positive CAFs had a favorable prognostic value, suggesting that the evaluation of podoplanin expression by CAFs would lead to a novel risk classification of patients.