Mitotic activity is a crucial biomarker for diagnosing and predicting outcomes for different types of cancers, particularly breast cancer. However, manual mitosis counting is challenging and time-consuming for pathologists, with moderate reproducibility due to biopsy slide size, low mitotic cell density, and pattern heterogeneity. In recent years, deep learning methods based on convolutional neural networks (CNNs) have been proposed to address these limitations. Nonetheless, these methods have been hampered by the available data labels, which usually consist only of the centroids of mitosis, and by the incoming noise from annotated hard negatives. As a result, complex algorithms with multiple stages are often required to refine the labels at the pixel level and reduce the number of false positives. This article presents a novel weakly supervised approach for mitosis detection that utilizes only image-level labels on histological hematoxylin and eosin (H&E) images, avoiding the need for complex labeling scenarios. Also, an Uninformed Teacher-Student (UTS) pipeline is introduced to detect and distill hard samples by comparing weakly supervised localizations and the annotated centroids, using strong augmentations to enhance uncertainty. Additionally, an automatic proliferation score is proposed that mimicks the pathologist-annotated mitotic activity index (MAI). The proposed approach is evaluated on three publicly available datasets for mitosis detection on breast histology samples, and two datasets for mitotic activity counting in whole-slide images. The proposed framework achieves competitive performance with relevant prior literature in all the datasets used for evaluation without explicitly using the mitosis location information during training. This approach challenges previous methods that rely on strong mitosis location information and multiple stages to refine false positives. Furthermore, the proposed pipeline for hard-sample distillation demonstrates promising dataset-specific improvements. Concretely, when the annotation has not been thoroughly refined by multiple pathologists, the UTS model offers improvements of up to ∼4% in mitosis localization, thanks to the detection and distillation of uncertain cases. Concerning the mitosis counting task, the proposed automatic proliferation score shows a moderate positive correlation with the MAI annotated by pathologists at the biopsy level on two external datasets. The proposed Uninformed Teacher-Student pipeline leverages strong augmentations to distill uncertain samples and measure dissimilarities between predicted and annotated mitosis. Results demonstrate the feasibility of the weakly supervised approach and highlight its potential as an objective evaluation tool for tumor proliferation.

Background/Objectives: Breast cancer (BC) is the most commonly diagnosed cancer in women and the leading cause of cancer-related deaths globally. Molecular subtyping is crucial for prognosis and treatment planning, with immunohistochemistry (IHC) being the most commonly used method. However, IHC has limitations, including observer variability, a lack of standardization, and a lack of reproducibility. Gene expression profiling is considered the ground truth for molecular subtyping; unfortunately, this is expensive and inaccessible to many institutions. This study investigates the potential of an artificial intelligence (AI) model to predict BC molecular subtypes directly from hematoxylin and eosin (H&E)-stained whole-slide images (WSIs). Methods: A pretrained deep learning framework based on multiple-instance learning (MIL) was validated on the Stavanger Breast Cancer (SBC) dataset, consisting of 538 BC cases. Three classification tasks were assessed, including two-class [triple negative BC (TNBC) vs. non-TNBC], three-class (luminal vs. HER2-positive vs. TNBC), and four-class (luminal A vs. luminal B vs. HER2-positive vs. TNBC) groups. Performance metrics were used for the evaluation of the AI model. Results: The AI model demonstrated strong performance in distinguishing TNBC from non-TNBC (AUC = 0.823, accuracy = 0.833, F1-score = 0.824). However, performance declined with an increasing number of classes. Conclusions: The study highlights the potential of AI in BC molecular subtyping from H&E WSIs, offering an easily applicable and standardized method to IHC. Future improvements should focus on optimizing multi-class classification and validating AI-based methods against gene expression analyses for enhanced clinical applicability.

Mitotic activity is a crucial proliferation biomarker for the diagnosis and prognosis of different types of cancers. Nevertheless, mitosis counting is a cumbersome process for pathologists, prone to low reproducibility, due to the large size of augmented biopsy slides, the low density of mitotic cells, and pattern heterogeneity. To improve reproducibility, deep learning methods have been proposed in the last years using convolutional neural networks. However, these methods have been hindered by the process of data labelling, which usually solely consist of the mitosis centroids. Therefore, current literature proposes complex algorithms with multiple stages to refine the labels at pixel level, and to reduce the number of false positives. In this work, we propose to avoid complex scenarios, and we perform the localization task in a weakly supervised manner, using only image-level labels on patches. The results obtained on the publicly available TUPAC16 dataset are competitive with state-of-the-art methods, using only one training phase. Our method achieves an F1-score of 0.729 and challenges the efficiency of previous methods, which required multiple stages and strong mitosis location information.