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

Abstract

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 podoplanin-positive 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 podoplanin-negative 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.

Fig. 1

Immunohistochemical staining for CD204, Foxp3, and podoplanin in high-grade neuroendocrine carcinoma (HGNEC) of the lung. a A case with high CD204-positive tumor-associated macrophages (TAMs). b A case with low CD204-positive TAMs. c A case with high Foxp3-positive regulatory T cells (Tregs). d A case with low Foxp3-positive Tregs. e A case with podoplanin-positive cancer-associated fibroblasts (CAFs). f A case with podoplanin-negative CAFs

Fig. 2

Survival analysis of HGNEC patients with CD204-positive TAMs, Foxp3-positive Tregs, and podoplanin-positive CAFs. a Overall survival curves according to CD204 expression in TAMs. b Relapse-free survival curves according to CD204 expression in TAMs. c Overall survival curves according to Foxp3 expression in Tregs. d Relapse-free survival curves according to Foxp3 expression in Tregs. e Overall survival curves according to podoplanin expression in CAFs. f Relapse-free survival curves according to podoplanin expression in CAFs

Fig. 3

Survival analysis of HGNEC patients without postoperative chemotherapy. a Overall survival curves. b Relapse-free survival curves

Fig. 4

Subgroup analysis combining podoplanin expression in CAFs and other independent risk factors. Group A: ly (−)/podoplanin-positive CAFs; Group B: ly (+)/podoplanin-positive CAFs or ly (−)/podoplanin-negative CAFs; and Group C: ly (+)/podoplanin-negative CAFs)