Relevance of shrinkage versus fragmented response patterns in rectal cancer

Sonay Kus Ozturk*, Cristina Graham Martinez, Kieran Sheahan, Desmond C. Winter, Susan Aherne, Éanna J. Ryan, Cornelis J.H. van de Velde, Corrie A.M. Marijnen, Geke A.P. Hospers, Annet G.H. Roodvoets, Michail Doukas, David Mens, Cornelis Verhoef, Rachel S. van der Post, Iris D. Nagtegaal

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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. 


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.

Original languageEnglish
Pages (from-to)870-879
Number of pages10
Issue number6
Early online date23 Aug 2023
Publication statusPublished - Dec 2023

Bibliographical note

Funding Information:
This study was supported by a KWF programme grant (KWF 2016‐2‐10602).

Publisher Copyright:
© 2023 The Authors. Histopathology published by John Wiley & Sons Ltd.


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