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Authors: Gulcin Yilmaz Gunesa, Mehmet Akif Cifcib,c,d
Abstract
Background
Mitotic activity is a recognized marker of tumor proliferation, yet its reproducible assessment across whole-slide images (WSIs) remains difficult. We developed a transfer-learning framework for lung squamous cell carcinoma (LUSC) and evaluated whether a patch-derived tumor-area mitosis proportion (TAMP) was associated with survival and molecular tumor characteristics.
Methods
The analysis combined MIDOG 2022 with TCGA-LUSC, including 478 patients and 512 diagnostic WSIs after quality control. Tumor regions and mitotic figures were reviewed by two pathologists with interobserver agreement of Cohen’s κ ≥ 0.85. A ResNet-50 model was trained on MIDOG and subsequently adapted to TCGA-LUSC using Focal Loss and stain-aware augmentation. Target-domain performance was evaluated using patient-level stratified 5-fold cross-validation and an additional WSI-level holdout analysis to address potential leakage from the initial patch-level partitioning. TAMP was calculated from patient-level out-of-fold predictions as the proportion of evaluable tumor patches classified as mitosis-positive. Associations with overall survival, immune and genomic features, transcriptomic programs, predicted drug response, and transcription-factor activity were subsequently examined. Multivariable Cox regression adjusted for age, sex, smoking status, tumor stage, and Eastern Cooperative Oncology Group performance status.
Results
The model achieved an area under the receiver operating characteristic curve (AUC) of 0.975 (95% confidence interval (CI): 0.965–0.980) on the held-out MIDOG test set. In TCGA-LUSC, fine-tuning increased the initial patch-level AUC from 0.82 to 0.92. Patient-level cross-validation yielded a mean AUC of 0.89 (95% CI: 0.86–0.90), and WSI-level holdout validation yielded an AUC of 0.90 (95% CI: 0.84–0.90). High TAMP was associated with poorer overall survival (log-rank p = 0.008; HR = 1.82, 95% CI: 1.18–2.81) and remained associated with mortality after multivariable adjustment (adjusted HR = 1.68, 95% CI: 1.08–2.62; p = 0.022). Higher TAMP was also associated with lower stromal fraction, selected immune-cell differences, greater indel-derived neoantigen load and indel burden, and enrichment of stem-cell proliferation, growth-factor-response, E2F-target, G2M-checkpoint, and MYC-target programs. Additional associations were observed with predicted sensitivity to selected cell-cycle-targeting compounds and with proliferation-related transcription-factor activity.
Conclusions
TAMP provides a patient-level, image-derived representation of mitosis-positive tumor regions that was associated with survival and several molecular features in TCGA-LUSC. Its association with overall survival persisted after adjustment for major clinical covariates. External multicenter validation, prespecified threshold evaluation, and prospective assessment are required before clinical use.
Read the full article: Tumor-area mitosis proportion as an image-derived mitotic phenotype in lung squamous cell carcinoma: Patient-level prognostic and multi-omics evaluation – ScienceDirect
- aDepartment of Pulmonology, Bandırma Training and Research Hospital, Bandirma, Turkey
- bInstitute of Research and Development, Duy Tan University, Da Nang, Viet Nam
- cSchool of Engineering and Technology, Duy Tan University, Da Nang, Viet Nam
- dDepartment of Computer Engineering, Bandırma Onyedi Eylül University, 10200 Balıkesir, Turkey
