Research ArticlesIntratumoral Budding and Tumor Microenvironment in Pretreatment Rectal Cancer Biopsies Predict the Response to Neoadjuvant ChemoradiotherapyWen, Xiaoyun MD, PhD; Zee, Sui Y. MD; Shroyer, Kenneth R. MD, PhD; Bandovic, Jela MD Author Information Department of Pathology, Stony Brook Medicine, Stony Brook, NY The authors declare no conflict of interest. Reprints: Xiaoyun Wen, MD, PhD, Department of Pathology, Stony Brook Medicine, 101 Nicolls Road, Stony Brook, NY 11794 (e-mail: [email protected]). Applied Immunohistochemistry & Molecular Morphology 30(1):p 1-7, January 2022. | DOI: 10.1097/PAI.0000000000000966 Buy Metrics Abstract Tumor budding at the invasive tumor front (peritumoral budding) is an established prognostic factor in colorectal cancer. However, the significance of intratumoral budding (ITB) in pretreatment biopsies is still uncertain. Our study aims to investigate the association of ITB and tumor microenvironment in pretreatment rectal cancer biopsies with pathologic response to neoadjuvant chemoradiotherapy. Pretreatment biopsies of low-grade rectal cancer from 37 patients who underwent resection after neoadjuvant chemoradiotherapy were retrospectively reviewed to evaluate ITB, type of tumor stroma, and intraepithelial lymphocytes. ITB was counted on a single hotspot in 1 HPF upon pan-keratin immunohistochemical staining. Intraepithelial lymphocytes was graded semiquantitatively as “absent” (≤2/HPF) or “present” (>2/HPF). The tumor stroma was classified as either immature type or maturing type. In pretreatment biopsies, ITB was observed in 34/37 patients (92%). High-grade ITB was significantly associated with a poor pathologic response to neoadjuvant chemoradiotherapy (tumor regression score 2 to 3, P<0.001; and higher posttreatment T stage, P=0.002). Immature type of stroma was significantly associated with both high-grade ITB in biopsies (P=0.02) and a poor pathologic response to neoadjuvant chemoradiotherapy (tumor regression score 2 to 3, P=0.005). In multivariate analysis, ITB and the type of stroma remained the significant parameters for prediction of response to neoadjuvant treatment. Our study indicates that ITB and tumor microenvironment in pretreatment biopsies are strong predictors of response to neoadjuvant chemoradiotherapy, which may assist risk stratification and clinical management in rectal cancer patients. Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.