Tumor Infiltrating Lymphocytes as Prognostic Factor of Early Recurrence and Poor Prognosis of Colorectal Cancer After Radical Surgical Treatment

Abstract

Background and Aims: The main medical problem of CRC is the high rate of recurrences after radically performed surgical therapy. Tumor infiltrating lymphocytes (TIL) have been described as a good prognostic factor for patients with a high risk of relapse. Their number, type and morphology of TIL cells determine resulting tumor prognosis. The aim of this study was to analyse the relationship of contemporary clinical and histopathological factors and TIL to determine patients with a high risk of poor overall survival and tendency to early recurrence of malignancy with shortened disease free interval (DFI) after radical surgery for CRC. Methods: We analysed 150 patients who underwent radical surgical procedure for CRC between the years 2004-2007. The following clinical parameters were statistically analysed in relation to the disease free interval (DFI) and the overall survival (OS): staging, grading, preoperative leukocytosis, type of surgical procedure (radical vs. palliative), postoperative complications and postoperative oncological treatment. We evaluated endovascular (VI), endolymphatic (LI) and perineural infiltration (PI) by cancer cells. Lymphocytic infiltration was detected as intratumoral (ITL - intratumoral lymphocytes), intrastromal (ISL - intrastromal lymphocytes), peritumoral (PTL - peritumoral lymphocytes) and Crohn-like reaction (Crohn-like PTL). Reactive histological changes in lymph nodes (LN reactions) were detected as follicular hyperplasia (LN-FH), sinus histiocytosis (LN-SH) and the presence of granulomas (LN-GR). We examined also the immunohistochemical positivity of lymphocytes for CD4 and CD8. Results: The Spearman rank correlation coefficient did not prove any stronger correlation than a moderate correlation at LI and lymph node infiltration by metastatic process (Spearman rank correlation coeffiecient 0.56, p<0.05). Statistical analysis proved lymph node infiltration by metastatic process as statistically significant for the prognosis of overall survival. VI was proved as a negative prognostic factor of shorter overall survival. The presence of PTL, Crohn-like PTL, LN-FH was proved as a positive prognostic factor of OS. The severity of CD8+ lymphocytic infiltration was proved as a positive prognostic factor prolonging OS. CD4+ lymphocytic infiltration was proved as a negative prognostic factor of OS. The Multivariate Cox Regression Hazard Model proved that the combination of the severity of lymph node infiltration by metastatic cells and LN-FH are the best prognostic factors for the prediction of the risk of short overall survival. PI was proved as a negative prognostic factor of an earlier recurrence. CD8+ lymphocytic infiltration was proved as a positive prognostic factor prolonging DFI. Lymph node infiltration by a metastatic decreased DFI. The Multivariate Cox Regression Hazard Model proved that the combination of the severity of the lymph node infiltration by metastatic cells and the severity of CD8 positivity of infiltrating lymphocytes are the best prognostic factors for the prediction of risk of early recurrence. Conclusion: Tumor infiltrating lymphocytes seem to be promising prognostic factors that could find their use in colorectal surgery and consecutive oncological treatment as an indicator of the type or combinations of therapies reflecting the risk of patients to early recurrence or poor overall survival. Regrettably, we don't understand the combination of types of tumor infiltrating lymphocytes and their mutually positive or negative influence. Future work has to be focused on the molecular-biological background of tumor infiltration by lymphocytes to understand their pathophysiological functions.