Date Published: April 26, 2018
Publisher: Public Library of Science
Author(s): Yasuhito Iseki, Masatsune Shibutani, Kiyoshi Maeda, Hisashi Nagahara, Tatsunari Fukuoka, Shinji Matsutani, Shinichiro Kashiwagi, Hiroaki Tanaka, Kosei Hirakawa, Masaichi Ohira, Masaru Katoh.
Numerous reports indicate that tumor-infiltrating lymphocytes (TILs) are a prognostic factor in various cancers and that they must be good biomarkers. However, the methods of evaluating TILs differ in each study; thus, there is not yet a standardized methodology for evaluating TILs. The purpose of this study is to evaluate the prognostic significance of tumor-infiltrating lymphocytes (TILs) in patients with colorectal cancer (CRC) using the new method proposed by the International TILs Working Group in breast cancer and to standardize the method of evaluating TILs in CRC.
We retrospectively reviewed a database of 160 patients with Stage II or III CRC. The density of TILs was assessed by measuring the area occupied by mononuclear cells over the stromal area on hematoxylin and eosin (H-E)-stained sections. We set 42% as the cut-off percentage of the area occupied by TILs according to the receiver operating characteristic curve, and we classified patients into the high-TILs and the low-TILs groups.
The rates of relapse-free survival (RFS) and overall survival (OS) in the high-TILs group were significantly higher than those in the low-TILs group. A multivariate analysis showed that the density of TILs was independently associated with RFS and OS. Moreover, the density of TILs assessed by an observer was significantly associated with the density of TILs assessed by the automated imaging software program.
The new method for evaluating TILs, which was recommended by the International TILs Working Group in breast cancer, might be a useful predictive factor in colorectal cancer patients.
Colorectal cancer (CRC) is the third most common cancer in the world . Although the surgical approach and chemotherapy for CRC have improved, the prognosis remains poor, as one-third of patients who undergo curative resection die within five years after surgery . Thus, it is necessary to provide individualized therapy according to the risk stratification and to find biomarkers that can predict the prognosis in order to improve the prognosis. In addition to tumor factors, the local tumor environment (i.e., extracellular matrix, immune cells, and cytokines) has an important role in tumor growth, invasion, metastasis and proliferation. Thus, these are considered to be prognostic factors in patients with colorectal cancer [3–8].
The extent of lymphocytic invasion in the tumor tissue reflects the immune status of the host and TILs play a pivotal role in tumor progression . Some reports have shown that TILs are a good prognostic factor in CRC [3–6]. Although TILs are correlated with the prognosis in CRC, various methods have been applied to their evaluation. These include immunohistochemical or H-E staining; the evaluation of the tumor center or invasion front; and the percentage of the area occupied by TILs or the absolute number of TILs. [4–6, 8, 11–17]. Klintrup et al.  and Huh et al.  reported that a greater number of inflammatory cells was correlated with a good prognosis in CRC in a study in which TILs were assessed using a 4-degree scale. Canna et al.  showed that the loss of CD4+ T-lymphocytes was correlated with poor survival in a study in which immunohistochemical staining for CD4 was performed. Funada et al.  showed that a high level of CD8+T lymphocytes was significantly correlated with a good prognosis. Chiba et al. measured the number of TILs , on the other hand Klintrup et al. measured TILs by using a four-degree scale . Nosho et al. measured the TILs in tumor center , whereas Menon et al. measured the TILs in invasive margin . Although it is clear that TILs are associated with the prognosis of CRC, there is no standardized methodology for evaluating the density of TILs.