The presence of tumor budding (TuB) at the invasive front of rectal cancers is a valuable indicator of tumor aggressiveness. Tumor buds, typically identified as single cells or small tumor cell clusters detached from the main tumor body, are characterized by loss of cell adhesion, increased migratory, and invasion potential and have been referred to as malignant stem cells. The adverse clinical outcome of patients with a high-grade TuB phenotype has consistently been demonstrated. TuB is a category IIB prognostic factor; it has yet to be investigated in the prospective setting. The value of TuB in oncological and pathological practice goes beyond its use as a simple histomorphological marker of tumor aggressiveness. In this paper, we outline three situations in which the assessment of TuB may have direct implications on treatment within the multidisciplinary management of patients with rectal cancer: (a) patients with TNM stage II (i.e., T3/T4, N0) disease potentially benefitting from adjuvant therapy, (b) patients with early submucosally invasive (T1, sm1-sm3) carcinomas at a high risk of nodal positivity and (c) the role of intratumoral budding assessed in preoperative biopsies as a marker for lymph node and distant metastasis thus potentially aiding the identification of patients suitable for neoadjuvant therapy. 1. Introduction Tumor budding (TuB) refers to the presence of detached single tumor cells or clusters of up to 5 cells scattered within the stroma at the invasive tumor front of many different solid cancers [1]. TuB as a histomorphological feature is best described in gastrointestinal tumors and was first comprehensively investigated by Jass in the mid 1980s in patients with rectal cancer [2]. TuB can be evaluated at high magnification using regular H&E staining but its visualization is markedly facilitated with the use of pan-cytokeratin stains (Figure 1). Figure 1: Immunohistochemical analysis highlighting the presence of peritumoral buds at the invasion front of rectal cancer (pancytokeratin stain: CK22, 40x magnification). It is hypothesized that tumor buds, or at least a subpopulation of these cells, have undergone a process similar to epithelial mesenchymal transition (EMT) and have acquired the ability to act as malignant stem cells [3]. Immunohistochemical staining of tumor buds in colorectal cancers shows a clear overexpression of markers involved in extracellular matrix degradation, angiogenesis, migration, and invasion and decreased Ki67 staining indicative of a low proliferation rate [4]. An overexpression of nuclear beta-catenin
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