Prognostic Effect of Epithelial and Stromal Lymphocyte Infiltration in Non–Small Cell Lung Cancer

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Abstract
Purpose: The major value of prognostic markers in potentially curable non-small cell lung cancer (NSCLC) should be to guide therapy after surgical resection. In this regard, the patients' immune status at the time of resection may be important and also measurable. The immune system has paradoxical roles during cancer development. However, the prognostic significance of tumor-infiltrating lymphocytes is controversial. The aim of this study is to elucidate the prognostic significance of epithelial and stromal lymphocyte infiltration in NSCLC. Experimental Design: Tissue microarrays from 335 resected NSCLC, stage I to IIIA were constructed from duplicate cores of viable and representative neoplastic epithelial and stromal areas. Immunohistochemistry was used to evaluate the epithelial and stromal CD4+, CD8+, and CD20+ lymphocytes. Results: In univariate analyses, increasing numbers of epithelial CD8+ (P = 0.023), stromal CD8+ (P = 0.002), epithelial CD20+ (P = 0.023), stromal CD20+ (P < 0.001), and stromal CD4+ (P < 0.001) lymphocytes correlated significantly with an improved disease-specific survival. No such relation was noted for epithelial CD4+ cells. Furthermore, a low level of stromal CD8+ lymphocyte infiltration was associated with an increased incidence of angiolymphatic invasion (P = 0.032). In multivariate analyses, a high number of stromal CD8+ (P = 0.043) and CD4+ (P = 0.002) cells were independent positive prognostic factors for disease-specific survival. Conclusions: High densities of CD4+ and CD8+ lymphocytes in the stroma are independent positive prognostic indicators for resected NSCLC patients. This may suggest that these cells are mediating a strong antitumor immune response in NSCLC.