Preoperative systemic chemotherapy alters the histopathological growth patterns of colorectal liver metastases

Pieter M.H. Nierop, Diederik J. Höppener, Florian E. Buisman, Eric P. van der Stok, Boris Galjart, Vinod P. Balachandran, William R. Jarnagin, T. Peter Kingham, Jinru Shia, Murielle Mauer, Bernard Nordlinger, Catherine Julié, Bas Groot Koerkamp, Michail Doukas, Peter B. Vermeulen, Dirk J. Grünhagen, Michael I. D'Angelica, Cornelis Verhoef*

*Corresponding author for this work

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Abstract

Histopathological growth patterns (HGPs) are a reliable, reproducible, and strong prognostic biomarker that can be assessed on haematoxylin and eosin-stained sections of resected colorectal liver metastases (CRLM). Assessment estimates the relative fraction of the tumour–liver interface for each of the three growth patterns; the desmoplastic HGP reflects good prognosis. Whether preoperative chemotherapy affects the HGP is currently unclear. The present international multicentre study evaluates this in an original cohort of 877 consecutive patients treated in the Netherlands, an external validation cohort of 1,203 consecutive patients treated in the USA, and a post hoc analysis from the phase III randomised controlled European Organization for Research and Treatment of Cancer (EORTC) 40983 trial (n = 70). All patients underwent resection of CRLM with or without preoperative systemic chemotherapy. Trial patients were randomised between perioperative chemotherapy and resection or resection alone. HGPs were determined according to consensus guidelines and compared for preoperative treatment status. Data from three separate tumour regression grading systems were available for the trial cohort. These were correlated with HGP stratified for treatment arm. In the original cohort, the average presence of desmoplastic HGP was 43% for chemo-naïve versus 67% for preoperatively treated patients (p < 0.001). A significant association between chemotherapy and desmoplastic HGP was found on multivariable analysis (β [95% confidence interval, CI]: 24.57 [18.28–30.87], p < 0.001). In the validation cohort, the average presence of desmoplastic HGP was 40% for chemo-naïve versus 63% for preoperatively treated patients (p < 0.001). This association remained on multivariable analysis (β [95% CI]: 24.18 [18.70–29.66], p < 0.001). In the EORTC 40983 trial, the average desmoplastic HGP presence was 33% in the resection arm versus 61% in the chemotherapy arm (p = 0.005). Chemotherapy was independently associated with an increase in desmoplastic HGP (β [95% CI]: 23.29 [1.78–44.79], p = 0.022). All three tumour regression gradings were significantly associated with the desmoplastic HGP in the chemotherapy arm (all p < 0.04). None were associated in the resection arm (all p > 0.11). Preoperative chemotherapy induces histopathological changes that alter the HGP of CRLM.

Original languageEnglish
Pages (from-to)48-64
Number of pages17
JournalJournal of Pathology: Clinical Research
Volume8
Issue number1
DOIs
Publication statusPublished - Jan 2022

Bibliographical note

Funding Information:
The data of the EORTC 40983 trial were kindly provided for the current study by the EORTC. We thank the investigators and all participating patients of the EORTC 40983 trial. All funding for this study was institutional. The EORTC 40983 trial was supported by grants from the Swedish Cancer Society (Sweden), Cancer Research UK (United Kingdom), the Ligue Nationale Contre le Cancer (France), and the National Cancer Institute (Bethesda, MD, USA; grants 5U10-CA11488-28 through 5U10 CA11488-37). The respective institutions and the funder of the EORTC 40983 trial had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

Funding Information:
The data of the EORTC 40983 trial were kindly provided for the current study by the EORTC. We thank the investigators and all participating patients of the EORTC 40983 trial. All funding for this study was institutional. The EORTC 40983 trial was supported by grants from the Swedish Cancer Society (Sweden), Cancer Research UK (United Kingdom), the Ligue Nationale Contre le Cancer (France), and the National Cancer Institute (Bethesda, MD, USA; grants 5U10‐CA11488‐28 through 5U10 CA11488‐37). The respective institutions and the funder of the EORTC 40983 trial had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

Publisher Copyright:
© 2021 The Authors. The Journal of Pathology: Clinical Research published by The Pathological Society of Great Britain and Ireland & John Wiley & Sons, Ltd.

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