PanNuke Dataset Extension, Insights and Baselines

The emerging area of computational pathology (CPath) is ripe ground for the application of deep learning (DL) methods to healthcare due to the sheer volume of raw pixel data in whole-slide images (WSIs) of cancerous tissue slides. However, it is imperative for the DL algorithms relying on nuclei-level details to be able to cope with data from `the clinical wild', which tends to be quite challenging. We study, and extend recently released PanNuke dataset consisting of $\sim$200,000 nuclei categorized into 5 clinically important classes for the challenging tasks of segmenting and classifying nuclei in WSIs \cite{gamper_pannuke:_2019}. Previous pan-cancer datasets consisted of only up to 9 different tissues and up to 21,000 unlabeled nuclei \cite{kumar2019multi} and just over 24,000 labeled nuclei with segmentation masks \cite{graham2019hover}. PanNuke consists of 19 different tissue types that have been semi-automatically annotated and quality controlled by clinical pathologists, leading to a dataset with statistics similar to `the clinical wild' and with minimal selection bias. We study the performance of segmentation and classification models when applied to the proposed dataset and demonstrate the application of models trained on PanNuke to whole-slide images. We provide comprehensive statistics about the dataset and outline recommendations and research directions to address the limitations of existing DL tools when applied to real-world CPath applications.

CGC-Net: Cell Graph Convolutional Network for Grading of Colorectal Cancer Histology Images

Colorectal cancer (CRC) grading is typically carried out by assessing the degree of gland formation within histology images. To do this, it is important to consider the overall tissue micro-environment by assessing the cell-level information along with the morphology of the gland. However, current automated methods for CRC grading typically utilise small image patches and therefore fail to incorporate the entire tissue micro-architecture for grading purposes. To overcome the challenges of CRC grading, we present a novel cell-graph convolutional neural network (CGC-Net) that converts each large histology image into a graph, where each node is represented by a nucleus within the original image and cellular interactions are denoted as edges between these nodes according to node similarity. The CGC-Net utilises nuclear appearance features in addition to the spatial location of nodes to further boost the performance of the algorithm. To enable nodes to fuse multi-scale information, we introduce Adaptive GraphSage, which is a graph convolution technique that combines multi-level features in a data-driven way. Furthermore, to deal with redundancy in the graph, we propose a sampling technique that removes nodes in areas of dense nuclear activity. We show that modeling the image as a graph enables us to effectively consider a much larger image (around 16$\times$ larger) than traditional patch-based approaches and model the complex structure of the tissue micro-environment. We construct cell graphs with an average of over 3,000 nodes on a large CRC histology image dataset and report state-of-the-art results as compared to recent patch-based as well as contextual patch-based techniques, demonstrating the effectiveness of our method.

XY Network for Nuclear Segmentation in Multi-Tissue Histology Images

Nuclear segmentation within Haematoxylin & Eosin stained histology images is a fundamental prerequisite in the digital pathology work-flow, due to the ability for nuclear features to act as key diagnostic markers. The development of automated methods for nuclear segmentation enables the quantitative analysis of tens of thousands of nuclei within a whole-slide pathology image, opening up possibilities of further analysis of large-scale nuclear morphometry. However, automated nuclear segmentation is faced with a major challenge in that there are several different types of nuclei, some of them exhibiting large intra-class variability such as the tumour cells. Additionally, some of the nuclei are often clustered together. To address these challenges, we present a novel convolutional neural network for automated nuclear segmentation that leverages the instance-rich information encoded within the vertical and horizontal distances of nuclear pixels to their centres of mass. These distances are then utilised to separate clustered nuclei, resulting in an accurate segmentation, particularly in areas with overlapping instances. We demonstrate state-of-the-art performance compared to other methods on four independent multi-tissue histology image datasets. Furthermore, we propose an interpretable and reliable evaluation framework that effectively quantifies nuclear segmentation performance and overcomes the limitations of existing performance measures.

Methods for Segmentation and Classification of Digital Microscopy Tissue Images

High-resolution microscopy images of tissue specimens provide detailed information about the morphology of normal and diseased tissue. Image analysis of tissue morphology can help cancer researchers develop a better understanding of cancer biology. Segmentation of nuclei and classification of tissue images are two common tasks in tissue image analysis. Development of accurate and efficient algorithms for these tasks is a challenging problem because of the complexity of tissue morphology and tumor heterogeneity. In this paper we present two computer algorithms; one designed for segmentation of nuclei and the other for classification of whole slide tissue images. The segmentation algorithm implements a multiscale deep residual aggregation network to accurately segment nuclear material and then separate clumped nuclei into individual nuclei. The classification algorithm initially carries out patch-level classification via a deep learning method, then patch-level statistical and morphological features are used as input to a random forest regression model for whole slide image classification. The segmentation and classification algorithms were evaluated in the MICCAI 2017 Digital Pathology challenge. The segmentation algorithm achieved an accuracy score of 0.78. The classification algorithm achieved an accuracy score of 0.81.

Leveraging Unlabeled Whole-Slide-Images for Mitosis Detection

Mitosis count is an important biomarker for prognosis of various cancers. At present, pathologists typically perform manual counting on a few selected regions of interest in breast whole-slide-images (WSIs) of patient biopsies. This task is very time-consuming, tedious and subjective. Automated mitosis detection methods have made great advances in recent years. However, these methods require exhaustive labeling of a large number of selected regions of interest. This task is very expensive because expert pathologists are needed for reliable and accurate annotations. In this paper, we present a semi-supervised mitosis detection method which is designed to leverage a large number of unlabeled breast cancer WSIs. As a result, our method capitalizes on the growing number of digitized histology images, without relying on exhaustive annotations, subsequently improving mitosis detection. Our method first learns a mitosis detector from labeled data, uses this detector to mine additional mitosis samples from unlabeled WSIs, and then trains the final model using this larger and diverse set of mitosis samples. The use of unlabeled data improves F1-score by $\sim$5\% compared to our best performing fully-supervised model on the TUPAC validation set. Our submission (single model) to TUPAC challenge ranks highly on the leaderboard with an F1-score of 0.64.

Predicting breast tumor proliferation from whole-slide images: the TUPAC16 challenge

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 $\kappa$ = 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.

MILD-Net: Minimal Information Loss Dilated Network for Gland Instance Segmentation in Colon Histology Images

The analysis of glandular morphology within colon histopathology images is a crucial step in determining the stage of colon cancer. Despite the importance of this task, manual segmentation is laborious, time-consuming and can suffer from subjectivity among pathologists. The rise of computational pathology has led to the development of automated methods for gland segmentation that aim to overcome the challenges of manual segmentation. However, this task is non-trivial due to the large variability in glandular appearance and the difficulty in differentiating between certain glandular and non-glandular histological structures. Furthermore, within pathological practice, a measure of uncertainty is essential for diagnostic decision making. For example, ambiguous areas may require further examination from numerous pathologists. To address these challenges, we propose a fully convolutional neural network that counters the loss of information caused by max-pooling by re-introducing the original image at multiple points within the network. We also use atrous spatial pyramid pooling with varying dilation rates for resolution maintenance and multi-level aggregation. To incorporate uncertainty, we introduce random transformations during test time for an enhanced segmentation result that simultaneously generates an uncertainty map, highlighting areas of ambiguity. We show that this map can be used to define a metric for disregarding predictions with high uncertainty. The proposed network achieves state-of-the-art performance on the GlaS challenge dataset, as part of MICCAI 2015, and on a second independent colorectal adenocarcinoma dataset.

Micro-Net: A unified model for segmentation of various objects in microscopy images

Object segmentation and structure localization are important steps in automated image analysis pipelines for microscopy images. We present a convolution neural network (CNN) based deep learning architecture for segmentation of objects in microscopy images. The proposed network can be used to segment cells, nuclei and glands in fluorescence microscopy and histology images after slight tuning of its parameters. It trains itself at multiple resolutions of the input image, connects the intermediate layers for better localization and context and generates the output using multi-resolution deconvolution filters. The extra convolutional layers which bypass the max-pooling operation allow the network to train for variable input intensities and object size and make it robust to noisy data. We compare our results on publicly available data sets and show that the proposed network outperforms the state-of-the-art.