Prognostic impact of peripheral blood neutrophil to lymphocyte ratio in advanced-stage pulmonary large cell neuroendocrine carcinoma and its association with the immune-related tumour microenvironment

Abstract

Background: The prognostic value of the neutrophil-to-lymphocyte ratio (NLR) with large cell neuroendocrine carcinoma (LCNEC) patients remains unclear. Thus, we performed a retrospective study to examine the relationship between the pretreatment NLR and clinical outcome in advanced LCNEC patients and the impact of the immune-related tumour microenvironment (TME).

Methods: This retrospective study included 63 advanced LCNEC patients who had received chemotherapy. We collected clinical data and investigated the TME status (CD4, CD8, CD20 and FOXP3).

Results: The overall survival of the patients with a low NLR (<5) was significantly longer than those with a high NLR (≥5) (14.9 vs. 5.2 months; p < 0.001). A multivariate analysis identified a high NLR as a predictor of a poor prognosis (HR, 3.43; 95% CI, 1.73-6.79; p < 0.001). The NLR was inversely correlated with tumoural and stromal CD8-positive tumour-infiltrating lymphocytes (tumoural: r = -0.648, p = 0.005, stromal: r = -0.490, p = 0.046).

Conclusions: A high NLR was associated with a poor prognosis in advanced LCNEC patients. Our study revealed that the NLR can reflect the TME, at least in part, suggesting that the NLR plays an important role not only as a clinical outcome predictor but also as a tumour immune status indicator.

Fig. 1. Kaplan–Meier analysis of PFS and OS according to NLR value (n = 67).

a PFS and b OS in all patients with a low NLR (blue) vs. patients with a high NLR (red). P values were determined using the log-rank test; the number of individuals in each group and the median survival time (95% CI) are indicated.

Fig. 2. Overview of pathology slides in two patients.

Representative images of pathology slides showed a high-density positive TILs tumour (upper) and a low-density positive TILs tumour (lower) in patients with LCNEC. HE-positive (a and f), CD4-positive (b and g), CD8-positive (c and h), FOXP3-positive (d and i) and CD20-positive (e and j) TILs in the tumour nest and stroma area are visible (Bar = 50 μm).

Fig. 3. Relation between the NLR in preoperative blood tests and the TILs status in the TME.

Relation between the NLR value in preoperative blood tests and the density of tumoural and stromal CD8-positive (a and b), CD4-positive (c and d), CD20-positive (e and f) and FOXP3-positive (g and h) cells in the TME.