Lymph node metastases and recurrence in pT1 colorectal cancer: Prediction with the International Budding Consortium Score-A retrospective, multi-centric study.

BACKGROUND: The International Collaboration on Cancer Reporting proposes histological tumour type, lymphovascular invasion, tumour grade, perineural invasion, extent, and dimensions of invasion as risk factors for lymph node metastases and tumour progression in completely endoscopically resected pT1 colorectal cancer (CRC). OBJECTIVE: The aim of the study was to propose a predictive and reliable score to optimise the clinical management of endoscopically resected pT1 CRC patients. METHODS: This multi-centric, retrospective International Budding Consortium (IBC) study included an international pT1 CRC cohort of 565 patients. All cases were reviewed by eight expert gastrointestinal pathologists. All risk factors were reported according to international guidelines. Tumour budding and immune response (CD8+ T-cells) were assessed with automated models using artificial intelligence. We used the information on risk factors and least absolute shrinkage and selection operator logistic regression to develop a prediction model and generate a score to predict the occurrence of lymph node metastasis or cancer recurrence. RESULTS: The IBC prediction score included the following parameters: lymphovascular invasion, tumour buds, infiltration depth and tumour grade. The score has an acceptable discrimination power (area under the curve of 0.68 [95% confidence intervals (CI) 0.61-0.75]; 0.64 [95% CI 0.57-0.71] after internal validation). At a cut-off of 6.8 points to discriminate high-and low-risk patients, the score had a sensitivity and specificity of 0.9 [95% CI 0.8-0.95] and 0.26 [95% 0.22, 0.3], respectively. CONCLUSION: The IBC score is based on well-established risk factors and is a promising tool with clinical utility to support the management of pT1 CRC patients.

Relevance of shrinkage versus fragmented response patterns in rectal cancer.

AIMS: Partial response to neoadjuvant chemoradiotherapy (CRT) presents with one of two main response patterns: shrinkage or fragmentation. This study investigated the relevance of these response patterns in rectal cancer, correlation with other response indicators, and outcome. METHODS AND RESULTS: The study included a test (n = 197) and a validation cohort (n = 218) of post-CRT patients with rectal adenocarcinoma not otherwise specified and a partial response. Response patterns were scored by two independent observers using a previously developed three-step flowchart. Tumour regression grading (TRG) was established according to both the College of American Pathologists (CAP) and Dworak classifications. In both cohorts, the predominant response pattern was fragmentation (70% and 74%), and the scoring interobserver agreement was excellent (k = 0.85). Patients with a fragmented pattern presented with significantly higher pathological stage (ypTNM II-IV, 78% versus 35%; P < 0.001), less tumour regression with Dworak (P = 0.004), and CAP TRG (P = 0.005) compared to patients with a shrinkage pattern. As a predictor of prognosis, the shrinkage pattern outperformed the TRG classification and stratified patients better in overall (fragmented pattern, hazard ratio [HR] 2.04, 95% confidence interval [CI] 1.19-3.50, P = 0.008) and disease-free survival (DFS; fragmented pattern, HR 2.50, 95% CI 1.23-5.10, P = 0.011) in the combined cohorts. The multivariable regression analyses revealed pathological stage as the only independent predictor of DFS. CONCLUSIONS: The heterogeneous nature of tumour response following CRT is reflected in fragmentation and shrinkage. In rectal cancer there is a predominance of the fragmented pattern, which is associated with advanced stage and less tumour regression. While not independently associated with survival, these reproducible patterns give insights into the biology of tumour response.

Patterns and Grading of Gastrointestinal Graft-Versus-Host Disease: A Clinicopathologic Correlation Study.

BACKGROUND: The present study investigated gastrointestinal involvement patterns of acute graft-versus-host disease and assessed the correlation of pathologic severity with clinical grading. METHODS: Pathology reports of gastrointestinal (GI) endoscopic biopsies taken from 164 post-hematopoietic stem cell transplant patients with at least 1 endoscopic gastrointestinal biopsy diagnosed as "consistent with acute graft-versus-host disease" between 2005 and 2019 were retrieved from the automated hospital database. Endoscopic, pathologic and clinical gradings were performed using Freiburg criteria, Lerner and modified Seattle-Glucksberg grading systems, respectively. RESULTS: The majority of the patients (n = 140, 85.4%) were investigated with more than one biopsy from various gastrointestinal sites with a total of 479 biopsies: 44 (9.2%) esophagus, 90 (18.8%) stomach, 91 (19.0%) duodenum, 20 (4.2%) terminal ileum, 32 (6.7%) right colon, 87 (18.2%) left colon and, 115 (23.9%) rectum. Overall, lower gastrointestinal (n = 118/126, 93.6%) and upper gastrointestinal (n = 91/97, 93.8%) involvements were similar (P = .3). While the most severely affected site was duodenum (P = .021) in upper gastrointestinal, pathologic grades were similar in lower gastrointestinal sites, though more severe than upper gastrointestinal (P = .003). Pathologic grading had a low positive correlation with both clinical (r = 0.308, P = .001) and endoscopic grading (coefficient: 0.261, P = .003). CONCLUSION: Considering the similar graft-versus-host disease frequency of upper and lower gastrointestinal tract, distal colon evaluation with rectosigmoidoscopy seems to be a practical approach in patients with suspected gastrointestinal graft-versus-host disease. As it was positively correlated with both endoscopic and clinical grade, pathologic grading should be performed in these patients to assess gastrointestinal involvement patterns.

The immune microenvironment landscape shows treatment-specific differences in rectal cancer patients.

Neoadjuvant therapy is the cornerstone of modern rectal cancer treatment. Insights into the biology of tumor responses are essential for the successful implementation of organ-preserving strategies, as different treatments may lead to specific tumor responses. In this study, we aim to explore treatment-specific responses of the tumor microenvironment. Patients with locally advanced adenocarcinoma of the rectum who had received neo-adjuvant chemotherapy (CT), neo-adjuvant radiochemotherapy (RCT), neo-adjuvant radiotherapy with a long-interval (LRT) or short-interval (SRT) or no neoadjuvant therapy (NT) as control were included. Multiplex-immunofluorescence was performed to determine the presence of cytotoxic T-cells (T-cyt; CD3+CD8+), regulatory T-cells (T-reg; CD3+FOXP3+), T-helper cells (T-helper; CD3+CD8-FOXP3-), B cells (CD20+), dendritic cells (CD11c+) and tumor cells (panCK+). A total of 80 rectal cancer patients were included. Treatment groups were matched for gender, tumor location, response to therapy, and TNM stage. The pattern of response (shrinkage vs. fragmentation) was, however, different between treatment groups. Our analyses reveal that RCT-treated patients exhibited lower stromal T-helper, T-reg, and T-cyt cells compared to other treatment regimens. In conclusion, we demonstrated treatment-specific differences in the immune microenvironment landscape of rectal cancer patients. Understanding the underlying mechanisms of this landscape after a specific therapy will benefit future treatment decisions.

Shrinkage versus fragmentation response in neoadjuvantly treated oesophageal adenocarcinoma: significant prognostic relevance.

AIMS: No consensus exists on the clinical value of tumour regression grading (TRG) systems for therapy effects of neoadjuvant chemoradiotherapy (nCRT) in oesophageal adenocarcinoma. Existing TRG systems lack standardization and reproducibility, and do not consider the morphological heterogeneity of tumour response. Therefore, we aim to identify morphological tumour regression patterns of oesophageal adenocarcinoma after nCRT and their association with survival. METHODS AND RESULTS: Patients with oesophageal adenocarcinoma, who underwent nCRT followed by surgery and achieved a partial response to nCRT, were identified from two Dutch upper-gastrointestinal (GI) centres (2005-18; test cohort). Resection specimens were scored for regression patterns by two independent observers according to a pre-defined three-step flowchart. The results were validated in an external cohort (2001-17). In total, 110 patients were included in the test cohort and 115 in the validation cohort. In the test cohort, two major regression patterns were identified: fragmentation (60%) and shrinkage (40%), with an excellent interobserver agreement (κ = 0.87). Here, patients with a fragmented pattern had a significantly higher pathological stage (stages III/IV: 52 versus 16%; P < 0.001), less downstaging (48 versus 91%; P < 0.001), a higher risk of recurrence [risk ratio (RR) = 2.9, 95% confidence interval (CI) = 1.5-5.6] and poorer 5-year overall survival (30 versus 80% respectively, P = 0.001). CONCLUSIONS: The validation cohort confirmed these findings, although had more advanced cases (case-stages = III/IV 91 versus 73%, P = 0.005) and a higher prevalence of fragmented-pattern cases (80 versus 60%, P = 0.002). When combining the cohorts in multivariate analysis, the pattern of response was an independent prognostic factor [hazard ratio (HR) = 1.76, 95% CI = 1.0-3.0]. In conclusion, we established an externally validated, reproducible and clinically relevant classification of tumour response.