Interpretable deep learning model to predict the molecular classification of endometrial cancer from haematoxylin and eosin-stained whole-slide images

Autor: Sarah Fremond, Sonali Andani, Jurriaan Barkey Wolf, Jouke Dijkstra, Sinéad Melsbach, Jan J Jobsen, Mariel Brinkhuis, Suzan Roothaan, Ina Jurgenliemk-Schulz, Ludy C H W Lutgens, Remi A Nout, Elzbieta M van der Steen-Banasik, Stephanie M de Boer, Melanie E Powell, Naveena Singh, Linda R Mileshkin, Helen J Mackay, Alexandra Leary, Hans W Nijman, Vincent T H B M Smit, Carien L Creutzberg, Nanda Horeweg, Viktor H Koelzer, Tjalling Bosse
Přispěvatelé: Radiotherapie, RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, Targeted Gynaecologic Oncology (TARGON), Translational Immunology Groningen (TRIGR), Radiotherapy
Jazyk: angličtina
Rok vydání: 2023
Předmět:
Zdroj: The Lancet Digital Health, 5(2), e71-e82. Lancet Publishing Group
The Lancet Digital Health, 5(2), e71-e82. Elsevier
The Lancet Digital Health, 5(2), e71-e82. Elsevier Ltd.
ISSN: 2589-7500
Popis: Background: Endometrial cancer can be molecularly classified into POLEmut, mismatch repair deficient (MMRd), p53 abnormal (p53abn), and no specific molecular profile (NSMP) subgroups. We aimed to develop an interpretable deep learning pipeline for whole-slide-image-based prediction of the four molecular classes in endometrial cancer (im4MEC), to identify morpho-molecular correlates, and to refine prognostication. Methods: This combined analysis included diagnostic haematoxylin and eosin-stained slides and molecular and clinicopathological data from 2028 patients with intermediate-to-high-risk endometrial cancer from the PORTEC-1 (n=466), PORTEC-2 (n=375), and PORTEC-3 (n=393) randomised trials and the TransPORTEC pilot study (n=110), the Medisch Spectrum Twente cohort (n=242), a case series of patients with POLEmut endometrial cancer in the Leiden Endometrial Cancer Repository (n=47), and The Cancer Genome Atlas-Uterine Corpus Endometrial Carcinoma cohort (n=395). PORTEC-3 was held out as an independent test set and a four-fold cross validation was performed. Performance was measured with the macro and class-wise area under the receiver operating characteristic curve (AUROC). Whole-slide images were segmented into tiles of 360 μm resized to 224 × 224 pixels. im4MEC was trained to learn tile-level morphological features with self-supervised learning and to molecularly classify whole-slide images with an attention mechanism. The top 20 tiles with the highest attention scores were reviewed to identify morpho-molecular correlates. Predictions of a nuclear classification deep learning model serve to derive interpretable morphological features. We analysed 5-year recurrence-free survival and explored prognostic refinement by molecular class using the Kaplan-Meier method. Findings: im4MEC attained macro-average AUROCs of 0·874 (95% CI 0·856–0·893) on four-fold cross-validation and 0·876 on the independent test set. The class-wise AUROCs were 0·849 for POLEmut (n=51), 0·844 for MMRd (n=134), 0·883 for NSMP (n=120), and 0·928 for p53abn (n=88). POLEmut and MMRd tiles had a high density of lymphocytes, p53abn tiles had strong nuclear atypia, and the morphology of POLEmut and MMRd endometrial cancer overlapped. im4MEC highlighted a low tumour-to-stroma ratio as a potentially novel characteristic feature of the NSMP class. 5-year recurrence-free survival was significantly different between im4MEC predicted molecular classes in PORTEC-3 (log-rank pmut had an excellent prognosis, as do those with true POLEmut endometrial cancer. Interpretation: We present the first interpretable deep learning model, im4MEC, for haematoxylin and eosin-based prediction of molecular endometrial cancer classification. im4MEC robustly identified morpho-molecular correlates and could enable further prognostic refinement of patients with endometrial cancer. Funding: The Hanarth Foundation, the Promedica Foundation, and the Swiss Federal Institutes of Technology.
Databáze: OpenAIRE
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