Clinical Significance of Tumor-Infiltrating Lymphocytes in Lung Neoplasms

doi:10.1016/j.athoracsur.2008.10.067

The Annals of Thoracic Surgery

Volume 87, Issue 2, February 2009, Pages 365-372

Presented at the Forty-fourth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 28–30, 2008.

https://doi.org/10.1016/j.athoracsur.2008.10.067 Get rights and content

Background

Tumor-infiltrating lymphocytes (TIL) are considered important in anticancer immunosurveillance, although their role has not been clearly established yet. We examined prevalence, correlations, and prognostic significance of TIL among our patient population of resected lung neoplasms.

Methods

From 1993 to 2006, the presence of TIL was retrospectively evaluated in 1,290 patients operated on for primary lung neoplasms. Tumor-infiltrating lymphocytes were defined as those intraepithelial lymphocytes located within the cancer cell nests.

Results

Tumor-infiltrating lymphocytes were detected in 294 patients (23%). A significant difference was found between prevalence in non–small cell lung carcinomas versus neuroendocrine tumors (290 of 1,208, 24% versus 4 of 82, 5%; p = 0.0001). Prevalence was similar in adenocarcinomas, squamous-cell carcinomas, and large-cell anaplastic carcinomas. Logistic regression analysis indicates that TIL correlate with grading (odds ratio, 1.27; 95% confidence interval, 1.04 to 1.55; p = 0.02), tumor dimension (odds ratio, 0.86; 95% confidence interval, 0.79 to 0.94; p = 0.0008), and vascular invasion (odds ratio, 1.62; 95% confidence interval, 1.21 to 2.16; p = 0.0009). A not significantly better survival in the presence of TIL was observed overall (p = 0.20), becoming significant in squamous-cell carcinomas (p = 0.03). In patients with stage I disease, TIL is associated with a significant survival advantage in squamous-cell carcinomas (p = 0.03). The survival advantage increases with the duration of follow-up and is more evident after 4 to 6 years.

Conclusions

Tumor-infiltrating lymphocytes are observed in about one fourth of resected lung neoplasms: they are rare in neuroendocrine tumors. Tumor-infiltrating lymphocytes are more frequent in poorly differentiated tumors and in tumors with microscopic vascular invasion. The presence of TIL correlates with an improved survival in squamous cell carcinomas, particularly at early stage. The survival advantage increases with the duration of follow-up.

Section snippets

Patients and Methods

Approval for this study was provided by our institutional review board, and patient consent was waived. A retrospective review was undertaken among our population of patients with primary lung neoplasms operated on at our institution between 1993 and 2006. In this period, of a total of 2,200 patients, 1,290 were evaluated for the presence of TIL on the surgical specimen. The remaining 910 were not considered for the analysis either as a result of fulfilling the exclusion criteria (see below) or

Results

Overall, TIL were detected on the surgical specimen in 294 patients (23%) operated on for primary lung neoplasms. The typical lymphocytic infiltration pattern around the tumor as emerged from our samples can be described as follows: (1) a peripheral lymphocytic infiltration composed of prevalent B lymphocytes (CD20+) organized in lymphoid follicles mixed with T lymphocytes (both CD3+ and CD4+); (2) a lymphocytic infiltration within cancer stroma (mainly CD3+ T lymphocytes); and (3)

Comment

The aim of the present study was to investigate the prevalence of TIL in our population of patients with lung neoplasms who underwent surgical resection, to examine possible correlations with other clinicopathologic variables, and to assess their prognostic significance. The retrospective nature of the study design represents a weakness and a limitation of the present study, and it has to be taken into account in interpretation of the results.

The results of our study indicate that (1) TIL are

References (21)

S. Vesalainen et al.
Histological grade, perineural infiltration, tumour-infiltrating lymphocytes and apoptosis as determinants of long-term prognosis in prostatic adenocarcinomas
Eur J Cancer
(1994)
P. Yu et al.
Tumor-infiltrating T lymphocytes: friends or foes?
Lab Invest
(2006)
I. Melero et al.
Costimulation, tolerance and ignorance of cytolytic T lymphocytes in immune responses to tumour antigens
Life Sci
(1997)
A. Jemal et al.
Cancer statistics, 2005
CA Cancer J Clin
(2005)
Y. Naito et al.
CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer
Cancer Res
(1998)
K. Schumacher et al.
Prognostic significance of activated CD8+ T cell infiltrations within esophageal carcinomas
Cancer Res
(2001)
O. Nakano et al.
Proliferative activity of intratumoral CD8+ T-lymphocytes as a prognostic factor in human renal cell carcinoma: clinicopathologic demonstration of antitumor immunity
Cancer Res
(2001)
A. Fukunaga et al.
CD8+ tumour-infiltrating lymphocytes together with CD4+ tumour-infiltrating lymphocytes and dendritic cells improve the prognosis of patients with pancreatic adenocarcinomas
Pancreas
(2004)
M. Mori et al.
Infiltration of CD8+ T cells in non-small cell lung cancer is associated with dedifferentiation of cancer cells, but not with prognosis
Tohoku J Exp Med
(2000)
K. Hiraoka et al.
Concurrent infiltration by CD8+ T cells and CD4+ T cells is a favourable prognostic factor in non-small cell carcinoma
Br J Cancer
(2006)

There are more references available in the full text version of this article.

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Original articleGeneral thoracicClinical Significance of Tumor-Infiltrating Lymphocytes in Lung Neoplasms

Background

Methods

Results

Conclusions

Section snippets

Patients and Methods

Results

Comment

Eur J Cancer

Lab Invest

Life Sci

Cancer statistics, 2005

CA Cancer J Clin

CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer

Cancer Res

Prognostic significance of activated CD8+ T cell infiltrations within esophageal carcinomas

Cancer Res

Proliferative activity of intratumoral CD8+ T-lymphocytes as a prognostic factor in human renal cell carcinoma: clinicopathologic demonstration of antitumor immunity

Cancer Res

CD8+ tumour-infiltrating lymphocytes together with CD4+ tumour-infiltrating lymphocytes and dendritic cells improve the prognosis of patients with pancreatic adenocarcinomas

Pancreas

Infiltration of CD8+ T cells in non-small cell lung cancer is associated with dedifferentiation of cancer cells, but not with prognosis

Tohoku J Exp Med

Concurrent infiltration by CD8+ T cells and CD4+ T cells is a favourable prognostic factor in non-small cell carcinoma

Br J Cancer

Original article
General thoracic
Clinical Significance of Tumor-Infiltrating Lymphocytes in Lung Neoplasms