The role of tumor budding in colorectal adenocarcinoma: Possible involvement of the intestinal cancer stem cell marker Lgr5

ABSTRACT

Background: Tumor budding (TB) is a promising prognostic factor in colorectal cancer (CRC) that is independent of tumor-node-metastasis (TNM) staging. Leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5) is a stem cell marker and a member of the canonical Wnt-signaling cascade. It is involved in colorectal carcinogenesis. However, its role in CRC progression and TB needs to be clarified. Materials and Methods: TB was assessed in both H and E and CK immunostained sections of 92 CRC cases. Associations between TB grade and different clinicopathological parameters were evaluated. Lgr5 expression in CRC cases and its association with TB grade and other clinicopathological features was also evaluated. Results: H and E stained sections revealed low- and high-grade budding in 55 (59.8%) and 37 (40.2%) tumors, respectively, whereas Cytokeratin Immunohistochemistry (CK-IHC) showed low- and high-grade budding in 31 (33.7%) and 61 (66.3%) tumors, respectively. TB grade (in H and E and CK stained sections) was significantly associated with adverse pathological prognostic variables including vascular invasion (P = 0.03 and 0.001), lymph node metastasis (P = 0.001 and 0,001), advanced Dukes (P = 0.000 and 0.000), and TNM (P = 0.001 and 0.000) stages and inversely associated with Tumor infiltrating lymphocytes (TILS) (P = 0.02 and 0.0001) which is known to be a good prognostic indicator. Lgr5 protein was positively expressed in 52.2% (48/92) of the CRCs. Immunoreactivity of Lgr5 was significantly associated with histological grade (P = 0.01), lymph node metastasis (P = 0.002), vascular invasion (P = 0.02), TNM stage (P = 0.000), Dukes stage (P = 0.000), and TILS (P = 0.03). Furthermore, Lgr5 was found to be significantly associated with TB estimated in both H and E and CK stained tumors (P = 0.003 and 0.001 respectively). Conclusion: This study supported the relevance of TB in the assessment of CRC aggressiveness. It also revealed that Lgr5 expression is related to morphologic features in the invasive front of CRC. Lgr5 could have an important role in forming a morphologic feature at the invasive front associated with the aggressiveness of the tumor.