Intratumoral Budding and Tumor Microenvironment in Pretreatment Rectal Cancer Biopsies Predict the Response to Neoadjuvant Chemoradiotherapy

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.

Clinicopathological Significances and Prognostic Role of Intratumoral Budding in Colorectal Cancers

“…However, the definitive evidence for the correlation was not described in those recommendations. In previous studies, ITB was significantly correlated with lymph node metastasis [ 16 , 17 , 18 , 19 , 21 , 23 ]. The present meta-analysis elucidated the significant correlations between ITB and aggressive tumor behaviors, including lymph node metastasis.…”

“…We compared the high ITB rates between good and poor response subgroups against neoadjuvant therapy in rectal cancers. In the present meta-analysis, all of them included the results of evaluating ITB in biopsy specimens [ 13 , 15 , 21 , 23 ]. However, surgical specimens after neoadjuvant therapy have a limitation in interpreting the result.…”

“…In the search and review, 13 eligible studies were finally included [ 4 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ]. The extracted data from the eligible studies were the author’s information, publication year, study location, number of patients analyzed, the prevalence and the clinicopathological characteristics of ITB, the correlation with various markers, and the information for disease-free survival.…”

Prognostic Implications of Intratumoral Budding in Colorectal Cancer: Detailed Analysis Based on Tumor-Infiltrating Lymphocytes

“…In the previous meta-analysis, ITB was significantly correlated with tumor grading, histologic subtype, lymphatic invasion, perineural invasion, pT stage, and lymph node metastasis [ 2 ]. The rate of ITB was significantly higher in CRCs with lymph node metastasis than in those without [ 7 , 8 , 9 , 10 ]. CRCs with higher pT stage (pT3–4) had higher rates of ITB than those with a lower pT stage (pT1–2) [ 2 ].…”