Domain generalization across tumor types, laboratories, and species - Insights from the 2022 edition of the Mitosis Domain Generalization Challenge.

Recognition of mitotic figures in histologic tumor specimens is highly relevant to patient outcome assessment. This task is challenging for algorithms and human experts alike, with deterioration of algorithmic performance under shifts in image representations. Considerable covariate shifts occur when assessment is performed on different tumor types, images are acquired using different digitization devices, or specimens are produced in different laboratories. This observation motivated the inception of the 2022 challenge on MItosis Domain Generalization (MIDOG 2022). The challenge provided annotated histologic tumor images from six different domains and evaluated the algorithmic approaches for mitotic figure detection provided by nine challenge participants on ten independent domains. Ground truth for mitotic figure detection was established in two ways: a three-expert majority vote and an independent, immunohistochemistry-assisted set of labels. This work represents an overview of the challenge tasks, the algorithmic strategies employed by the participants, and potential factors contributing to their success. With an F1 score of 0.764 for the top-performing team, we summarize that domain generalization across various tumor domains is possible with today's deep learning-based recognition pipelines. However, we also found that domain characteristics not present in the training set (feline as new species, spindle cell shape as new morphology and a new scanner) led to small but significant decreases in performance. When assessed against the immunohistochemistry-assisted reference standard, all methods resulted in reduced recall scores, with only minor changes in the order of participants in the ranking.

Automated diagnosis of 7 canine skin tumors using machine learning on H&E-stained whole slide images.

Microscopic evaluation of hematoxylin and eosin-stained slides is still the diagnostic gold standard for a variety of diseases, including neoplasms. Nevertheless, intra- and interrater variability are well documented among pathologists. So far, computer assistance via automated image analysis has shown potential to support pathologists in improving accuracy and reproducibility of quantitative tasks. In this proof of principle study, we describe a machine-learning-based algorithm for the automated diagnosis of 7 of the most common canine skin tumors: trichoblastoma, squamous cell carcinoma, peripheral nerve sheath tumor, melanoma, histiocytoma, mast cell tumor, and plasmacytoma. We selected, digitized, and annotated 350 hematoxylin and eosin-stained slides (50 per tumor type) to create a database divided into training, n = 245 whole-slide images (WSIs), validation (n = 35 WSIs), and test sets (n = 70 WSIs). Full annotations included the 7 tumor classes and 6 normal skin structures. The data set was used to train a convolutional neural network (CNN) for the automatic segmentation of tumor and nontumor classes. Subsequently, the detected tumor regions were classified patch-wise into 1 of the 7 tumor classes. A majority of patches-approach led to a tumor classification accuracy of the network on the slide-level of 95% (133/140 WSIs), with a patch-level precision of 85%. The same 140 WSIs were provided to 6 experienced pathologists for diagnosis, who achieved a similar slide-level accuracy of 98% (137/140 correct majority votes). Our results highlight the feasibility of artificial intelligence-based methods as a support tool in diagnostic oncologic pathology with future applications in other species and tumor types.

A comprehensive multi-domain dataset for mitotic figure detection.

The prognostic value of mitotic figures in tumor tissue is well-established for many tumor types and automating this task is of high research interest. However, especially deep learning-based methods face performance deterioration in the presence of domain shifts, which may arise from different tumor types, slide preparation and digitization devices. We introduce the MIDOG++ dataset, an extension of the MIDOG 2021 and 2022 challenge datasets. We provide region of interest images from 503 histological specimens of seven different tumor types with variable morphology with in total labels for 11,937 mitotic figures: breast carcinoma, lung carcinoma, lymphosarcoma, neuroendocrine tumor, cutaneous mast cell tumor, cutaneous melanoma, and (sub)cutaneous soft tissue sarcoma. The specimens were processed in several laboratories utilizing diverse scanners. We evaluated the extent of the domain shift by using state-of-the-art approaches, observing notable differences in single-domain training. In a leave-one-domain-out setting, generalizability improved considerably. This mitotic figure dataset is the first that incorporates a wide domain shift based on different tumor types, laboratories, whole slide image scanners, and species.

Pan-tumor T-lymphocyte detection using deep neural networks: Recommendations for transfer learning in immunohistochemistry.

The success of immuno-oncology treatments promises long-term cancer remission for an increasing number of patients. The response to checkpoint inhibitor drugs has shown a correlation with the presence of immune cells in the tumor and tumor microenvironment. An in-depth understanding of the spatial localization of immune cells is therefore critical for understanding the tumor's immune landscape and predicting drug response. Computer-aided systems are well suited for efficiently quantifying immune cells in their spatial context. Conventional image analysis approaches are often based on color features and therefore require a high level of manual interaction. More robust image analysis methods based on deep learning are expected to decrease this reliance on human interaction and improve the reproducibility of immune cell scoring. However, these methods require sufficient training data and previous work has reported low robustness of these algorithms when they are tested on out-of-distribution data from different pathology labs or samples from different organs. In this work, we used a new image analysis pipeline to explicitly evaluate the robustness of marker-labeled lymphocyte quantification algorithms depending on the number of training samples before and after being transferred to a new tumor indication. For these experiments, we adapted the RetinaNet architecture for the task of T-lymphocyte detection and employed transfer learning to bridge the domain gap between tumor indications and reduce the annotation costs for unseen domains. On our test set, we achieved human-level performance for almost all tumor indications with an average precision of 0.74 in-domain and 0.72-0.74 cross-domain. From our results, we derive recommendations for model development regarding annotation extent, training sample selection, and label extraction for the development of robust algorithms for immune cell scoring. By extending the task of marker-labeled lymphocyte quantification to a multi-class detection task, the pre-requisite for subsequent analyses, e.g., distinguishing lymphocytes in the tumor stroma from tumor-infiltrating lymphocytes, is met.

Mitosis domain generalization in histopathology images - The MIDOG challenge.

The density of mitotic figures (MF) within tumor tissue is known to be highly correlated with tumor proliferation and thus is an important marker in tumor grading. Recognition of MF by pathologists is subject to a strong inter-rater bias, limiting its prognostic value. State-of-the-art deep learning methods can support experts but have been observed to strongly deteriorate when applied in a different clinical environment. The variability caused by using different whole slide scanners has been identified as one decisive component in the underlying domain shift. The goal of the MICCAI MIDOG 2021 challenge was the creation of scanner-agnostic MF detection algorithms. The challenge used a training set of 200 cases, split across four scanning systems. As test set, an additional 100 cases split across four scanning systems, including two previously unseen scanners, were provided. In this paper, we evaluate and compare the approaches that were submitted to the challenge and identify methodological factors contributing to better performance. The winning algorithm yielded an F1 score of 0.748 (CI95: 0.704-0.781), exceeding the performance of six experts on the same task.

Pan-tumor CAnine cuTaneous Cancer Histology (CATCH) dataset.

Due to morphological similarities, the differentiation of histologic sections of cutaneous tumors into individual subtypes can be challenging. Recently, deep learning-based approaches have proven their potential for supporting pathologists in this regard. However, many of these supervised algorithms require a large amount of annotated data for robust development. We present a publicly available dataset of 350 whole slide images of seven different canine cutaneous tumors complemented by 12,424 polygon annotations for 13 histologic classes, including seven cutaneous tumor subtypes. In inter-rater experiments, we show a high consistency of the provided labels, especially for tumor annotations. We further validate the dataset by training a deep neural network for the task of tissue segmentation and tumor subtype classification. We achieve a class-averaged Jaccard coefficient of 0.7047, and 0.9044 for tumor in particular. For classification, we achieve a slide-level accuracy of 0.9857. Since canine cutaneous tumors possess various histologic homologies to human tumors the added value of this dataset is not limited to veterinary pathology but extends to more general fields of application.

Inter-species cell detection - datasets on pulmonary hemosiderophages in equine, human and feline specimens.

Pulmonary hemorrhage (P-Hem) occurs among multiple species and can have various causes. Cytology of bronchoalveolar lavage fluid (BALF) using a 5-tier scoring system of alveolar macrophages based on their hemosiderin content is considered the most sensitive diagnostic method. We introduce a novel, fully annotated multi-species P-Hem dataset, which consists of 74 cytology whole slide images (WSIs) with equine, feline and human samples. To create this high-quality and high-quantity dataset, we developed an annotation pipeline combining human expertise with deep learning and data visualisation techniques. We applied a deep learning-based object detection approach trained on 17 expertly annotated equine WSIs, to the remaining 39 equine, 12 human and 7 feline WSIs. The resulting annotations were semi-automatically screened for errors on multiple types of specialised annotation maps and finally reviewed by a trained pathologist. Our dataset contains a total of 297,383 hemosiderophages classified into five grades. It is one of the largest publicly available WSIs datasets with respect to the number of annotations, the scanned area and the number of species covered.

Fast whole-slide cartography in colon cancer histology using superpixels and CNN classification.

Purpose: Automatic outlining of different tissue types in digitized histological specimen provides a basis for follow-up analyses and can potentially guide subsequent medical decisions. The immense size of whole-slide-images (WSIs), however, poses a challenge in terms of computation time. In this regard, the analysis of nonoverlapping patches outperforms pixelwise segmentation approaches but still leaves room for optimization. Furthermore, the division into patches, regardless of the biological structures they contain, is a drawback due to the loss of local dependencies. Approach: We propose to subdivide the WSI into coherent regions prior to classification by grouping visually similar adjacent pixels into superpixels. Afterward, only a random subset of patches per superpixel is classified and patch labels are combined into a superpixel label. We propose a metric for identifying superpixels with an uncertain classification and evaluate two medical applications, namely tumor area and invasive margin estimation and tumor composition analysis. Results: The algorithm has been developed on 159 hand-annotated WSIs of colon resections and its performance is compared with an analysis without prior segmentation. The algorithm shows an average speed-up of 41% and an increase in accuracy from 93.8% to 95.7%. By assigning a rejection label to uncertain superpixels, we further increase the accuracy by 0.4%. While tumor area estimation shows high concordance to the annotated area, the analysis of tumor composition highlights limitations of our approach. Conclusion: By combining superpixel segmentation and patch classification, we designed a fast and accurate framework for whole-slide cartography that is AI-model agnostic and provides the basis for various medical endpoints.

Computer-assisted mitotic count using a deep learning-based algorithm improves interobserver reproducibility and accuracy.

The mitotic count (MC) is an important histological parameter for prognostication of malignant neoplasms. However, it has inter- and intraobserver discrepancies due to difficulties in selecting the region of interest (MC-ROI) and in identifying or classifying mitotic figures (MFs). Recent progress in the field of artificial intelligence has allowed the development of high-performance algorithms that may improve standardization of the MC. As algorithmic predictions are not flawless, computer-assisted review by pathologists may ensure reliability. In the present study, we compared partial (MC-ROI preselection) and full (additional visualization of MF candidates and display of algorithmic confidence values) computer-assisted MC analysis to the routine (unaided) MC analysis by 23 pathologists for whole-slide images of 50 canine cutaneous mast cell tumors (ccMCTs). Algorithmic predictions aimed to assist pathologists in detecting mitotic hotspot locations, reducing omission of MFs, and improving classification against imposters. The interobserver consistency for the MC significantly increased with computer assistance (interobserver correlation coefficient, ICC = 0.92) compared to the unaided approach (ICC = 0.70). Classification into prognostic stratifications had a higher accuracy with computer assistance. The algorithmically preselected hotspot MC-ROIs had a consistently higher MCs than the manually selected MC-ROIs. Compared to a ground truth (developed with immunohistochemistry for phosphohistone H3), pathologist performance in detecting individual MF was augmented when using computer assistance (F1-score of 0.68 increased to 0.79) with a reduction in false negatives by 38%. The results of this study demonstrate that computer assistance may lead to more reproducible and accurate MCs in ccMCTs.