P. J. van Diest

Yoni Schirris, Rosie Voorthuis, Mark Opdam et al.

The level of tumour-infiltrating lymphocytes (TILs) is a prognostic factor for patients with (triple-negative) breast cancer (BC). Computational TIL assessment (CTA) has the potential to assist pathologists in this labour-intensive task, but current CTA models rely heavily on many detailed annotations. We propose and validate a fundamentally simpler deep learning based CTA that can be trained in only ten minutes on hundredfold fewer pathologist annotations. We collected whole slide images (WSIs) with TILs scores and clinical data of 2,340 patients with BC from six cohorts including three randomised clinical trials. Morphological features were extracted from whole slide images (WSIs) using a pathology foundation model. Our label-efficient Computational stromal TIL assessment model (ECTIL) directly regresses the TILs score from these features. ECTIL trained on only a few hundred samples (ECTIL-TCGA) showed concordance with the pathologist over five heterogeneous external cohorts (r=0.54-0.74, AUROC=0.80-0.94). Training on all slides of five cohorts (ECTIL-combined) improved results on a held-out test set (r=0.69, AUROC=0.85). Multivariable Cox regression analyses indicated that every 10% increase of ECTIL scores was associated with improved overall survival independent of clinicopathological variables (HR 0.86, p<0.01), similar to the pathologist score (HR 0.87, p<0.001). We demonstrate that ECTIL is highly concordant with an expert pathologist and obtains a similar hazard ratio. ECTIL has a fundamentally simpler design than existing methods and can be trained on orders of magnitude fewer annotations. Such a CTA may be used to pre-screen patients for, e.g., immunotherapy clinical trial inclusion, or as a tool to assist clinicians in the diagnostic work-up of patients with BC. Our model is available under an open source licence (https://github.com/nki-ai/ectil).

Hong Liu, Haosen Yang, Paul J. van Diest et al.

The Segment Anything Model (SAM) marks a significant advancement in segmentation models, offering robust zero-shot abilities and dynamic prompting. However, existing medical SAMs are not suitable for the multi-scale nature of whole-slide images (WSIs), restricting their effectiveness. To resolve this drawback, we present WSI-SAM, enhancing SAM with precise object segmentation capabilities for histopathology images using multi-resolution patches, while preserving its efficient, prompt-driven design, and zero-shot abilities. To fully exploit pretrained knowledge while minimizing training overhead, we keep SAM frozen, introducing only minimal extra parameters and computational overhead. In particular, we introduce High-Resolution (HR) token, Low-Resolution (LR) token and dual mask decoder. This decoder integrates the original SAM mask decoder with a lightweight fusion module that integrates features at multiple scales. Instead of predicting a mask independently, we integrate HR and LR token at intermediate layer to jointly learn features of the same object across multiple resolutions. Experiments show that our WSI-SAM outperforms state-of-the-art SAM and its variants. In particular, our model outperforms SAM by 4.1 and 2.5 percent points on a ductal carcinoma in situ (DCIS) segmentation tasks and breast cancer metastasis segmentation task (CAMELYON16 dataset). The code will be available at https://github.com/HongLiuuuuu/WSI-SAM.

Mitko Veta, Yujing J. Heng, Nikolas Stathonikos et al.

Tumor proliferation is an important biomarker indicative of the prognosis of breast cancer patients. Assessment of tumor proliferation in a clinical setting is highly subjective and labor-intensive task. Previous efforts to automate tumor proliferation assessment by image analysis only focused on mitosis detection in predefined tumor regions. However, in a real-world scenario, automatic mitosis detection should be performed in whole-slide images (WSIs) and an automatic method should be able to produce a tumor proliferation score given a WSI as input. To address this, we organized the TUmor Proliferation Assessment Challenge 2016 (TUPAC16) on prediction of tumor proliferation scores from WSIs. The challenge dataset consisted of 500 training and 321 testing breast cancer histopathology WSIs. In order to ensure fair and independent evaluation, only the ground truth for the training dataset was provided to the challenge participants. The first task of the challenge was to predict mitotic scores, i.e., to reproduce the manual method of assessing tumor proliferation by a pathologist. The second task was to predict the gene expression based PAM50 proliferation scores from the WSI. The best performing automatic method for the first task achieved a quadratic-weighted Cohen's kappa score of $κ$ = 0.567, 95% CI [0.464, 0.671] between the predicted scores and the ground truth. For the second task, the predictions of the top method had a Spearman's correlation coefficient of r = 0.617, 95% CI [0.581 0.651] with the ground truth. This was the first study that investigated tumor proliferation assessment from WSIs. The achieved results are promising given the difficulty of the tasks and weakly-labelled nature of the ground truth. However, further research is needed to improve the practical utility of image analysis methods for this task.

Mitko Veta, Paul J. van Diest, Josien P. W. Pluim

The size of nuclei in histological preparations from excised breast tumors is predictive of patient outcome (large nuclei indicate poor outcome). Pathologists take into account nuclear size when performing breast cancer grading. In addition, the mean nuclear area (MNA) has been shown to have independent prognostic value. The straightforward approach to measuring nuclear size is by performing nuclei segmentation. We hypothesize that given an image of a tumor region with known nuclei locations, the area of the individual nuclei and region statistics such as the MNA can be reliably computed directly from the image data by employing a machine learning model, without the intermediate step of nuclei segmentation. Towards this goal, we train a deep convolutional neural network model that is applied locally at each nucleus location, and can reliably measure the area of the individual nuclei and the MNA. Furthermore, we show how such an approach can be extended to perform combined nuclei detection and measurement, which is reminiscent of granulometry.

Mitko Veta, Paul J. van Diest, Stefan M. Willems et al.

The proliferative activity of breast tumors, which is routinely estimated by counting of mitotic figures in hematoxylin and eosin stained histology sections, is considered to be one of the most important prognostic markers. However, mitosis counting is laborious, subjective and may suffer from low inter-observer agreement. With the wider acceptance of whole slide images in pathology labs, automatic image analysis has been proposed as a potential solution for these issues. In this paper, the results from the Assessment of Mitosis Detection Algorithms 2013 (AMIDA13) challenge are described. The challenge was based on a data set consisting of 12 training and 11 testing subjects, with more than one thousand annotated mitotic figures by multiple observers. Short descriptions and results from the evaluation of eleven methods are presented. The top performing method has an error rate that is comparable to the inter-observer agreement among pathologists.