T cell infiltrate and outcome following resection of intermediate-grade primary neuroendocrine tumours and liver metastases

Abstract

Background: Tumour-infiltrating lymphocytes (TILs) have been shown to predict survival in numerous malignancies. The importance of TILs in primary pancreatic neuroendocrine tumours (NETs) and NET liver metastases (NETLMs) has not been defined.

Methods: We identified 87 patients with NETs and 39 with NETLMs who had undergone resection. Immunohistochemistry was performed to determine TIL counts. Recurrence-free survival (RFS) and overall survival (OS) were determined using the log-rank test.

Results: The median follow-up time was 62 months in NET patients and 48 months in NETLM patients. Vascular invasion and histologic grade were the only independent predictors of outcome for NETs and NETLMs, respectively. Analysis of intermediate-grade NETs indicated that a dense T cell (CD3+) infiltrate was associated with a median RFS of 128 months compared with 61 months for those with low levels of intratumoral T cells (P= 0.05, univariate analysis). Examination of NETLMs revealed that a low level of infiltrating regulatory T cells (Treg, FoxP3+) was a predictor of prolonged survival (P < 0.01, univariate analysis).

Conclusions: A robust T cell infiltrate is associated with improved RFS following resection of intermediate-grade NETs, whereas the presence of more Treg correlated with shorter OS after treatment of NETLMs. Further study of the immune response to intermediate-grade NETs and NETLMs is warranted.

Figure 1

Neuroendocrine tumours were stained with anti-CD3 to identify infiltrating T cells. Grading levels were assigned according to the following criteria per 10 highpower fields: grade 0 = < 10 cells; grade 1 = < 1% or 10–20 cells; grade 2 = 1–5% or 21–50 cells, and grade 3 = > 5% or >50 cells. (Haematoxylin and eosin stain; original magnification 400×)

Figure 2

Neuroendocrine tumours were stained with anti-CD3 (all T cells), anti-CD8 (cytotoxic T cells), anti-CD4 (helper T cells), and anti-FoxP3 (regulatory T cells) to quantify the numbers of various T cell subsets within the tumours. Kaplan–Meier analyses were performed to determine differences in recurrence-free survival among patients with high and low levels of T cell infiltration

Figure 3

Low- and intermediate-grade neuroendocrine tumours (NETs) were stained with anti-CD3 to quantify the numbers of various T cell subsets within the tumours. Kaplan–Meier analyses were performed to determine differences in recurrence-free survival among patients with high and low levels of T cell infiltration. Thirteen patients without documented grade information were excluded from this analysis

Figure 4

Neuroendocrine tumour liver metastases (NETLMs) were stained with anti-FoxP3 to quantify the numbers of regulatory T cells within the tumours. Kaplan–Meier analyses were performed to determine differences in overall survival among patients with high and low levels of T cell infiltration