Tumor budding in upper gastrointestinal carcinomas

Abstract

The basis of personalized medicine in oncology is the prediction of an individual's risk of relapse and death from disease. The presence of tumor budding (TB) at the tumor-host interface of gastrointestinal cancers has been recognized as a hallmark of unfavorable disease biology. TB is defined as the presence of dedifferentiated cells or small clusters of up to five cells at the tumor invasive front and can be observed in aggressive carcinomas of the esophagus, stomach, pancreas, ampulla, colon, and rectum. Presence of TB reproducibly correlates with advanced tumor stage, frequent lymphovascular invasion, nodal, and distant metastasis. The UICC has officially recognized TB as additional independent prognostic factor in cancers of the colon and rectum. Recent studies have also characterized TB as a promising prognostic indicator for clinical management of esophageal squamous cell carcinoma, adenocarcinoma of the gastro-esophageal junction, and gastric adenocarcinoma. However, several important issues have to be addressed for application in daily diagnostic practice: (1) validation of prognostic scoring systems for TB in large, multi-center studies, (2) consensus on the optimal assessment method, and (3) inter-observer reproducibility. This review provides a comprehensive analysis of TB in cancers of the upper gastrointestinal tract including critical appraisal of perspectives for further study.

Keywords: epithelial–mesenchymal transition; esophageal cancer; gastric cancer; gastrointestinal cancer; prognostic factor; tumor budding; tumor microenvironment.

Figure 1

Tumor budding. (A) High-power image (250×) of tumor budding at the invasive front of colorectal cancer as visualized by pancytokeratin (brown) immunohistochemistry. (B) Tumor buds as seen in a standard hematoxylin and eosin (H&E) stain (250×).

Figure 2

Tumor budding leads to vascular invasion and metastasis. The formation of tumor buds is thought to be the visible correlate of epithelial–mesenchymal transition (EMT) in the tumor microenvironment. Following tumor cell dissociation, lymphovascular invasion is frequently observed in high-grade budding tumors. TB could be a source of circulating cancer cells (CICs), leading to the establishment of metastasis at distant sites in the process of mesenchymal–epithelial transition (MET).

Figure 3

Tumor budding in Barrett’s carcinoma. (A) Poorly differentiated adenocarcinoma of the esophagus with signet cell component as seen in a pancytokeratin (top) and H&E (bottom) stain (250×). Tumor buds cannot be differentiated by morphology from the diffusely infiltrating tumor mass. (B) Intestinal type adenocarcinoma of the esophagus with presence of tumor buds at the invasive front as seen in a pancytokeratin (top) and H&E (bottom) stain (250×).