Topology and attention in computational pathology

Histopathology serves as the gold standard in the process of cancer diagnosis and unravelling the disease heterogeneity. In routine practice, a trained histopathologist performs visual examination of tissue glass slides under the microscope. The objective of the visual examination is to observe the morphological appearance of tissue sections, analyse the density of tumour rich areas, spatial arrangement, and architecture of diferent types of cells. However, careful visual examination of tissue slides is a demanding task especially when workloads are high, and the subjective nature of the histological grading inevitably leads to inter- and even intra-observer variability. Attaining high accuracy and objective quantification of tissue specimens in cancer diagnosis are some of the ongoing challenges in modern histopathology. With the recent advent of digital pathology, tissue glass slides can now be scanned with digital slides scanners to produce whole slide images (WSIs). A WSI contains a high-resolution pixel representation of tissue slide, stored in a pyramidal structure and typically containing 1010 pixels. Automated algorithms are generally based on the concepts of digital image analysis which can analyse WSIs to improve the precision and reproducibility in cancer diagnostics. The reliability of the results of an algorithm can be objectively measured and improved against an objective standard. In this thesis, we focus on developing automated methods for quantitative assessment of histology WSIs with the aim of improving the precision and reproducibility of cancer diagnosis. More specifically, the designed automated computational pathology algorithms are based on deep learning models in conjunction with algebraic topology and visual attention mechanisms. To the best of our knowledge, the applicability of attention and topology based methods have not been explored in the domain of computational pathology. In this regard, we propose an algorithm for computing persistent homology profiles (topological features) and propose two variants for effective and reliable tumour segmentation of colorectal cancer WSIs. We show that incorporation of deep features along with topological features improves the overall performance for tumour segmentation. We then present the first-ever systematic study (contest) for scoring the human epidermal growth factor receptor 2 (HER2) biomarker on breast cancer histology WSIs. Further, we devise a reinforcement learning based attention mechanism for HER2 scoring that sequentially identifies and analyses the diagnostically relevant regions within a given image, mimicking the histopathologist who would not usually analyse every part of the slide at the highest magnification. We demonstrate the proposed model outperforms other methods participated in our systematic study, most of them were using state-of-the-art deep convolutional networks. Finally, we propose a multi-task learning framework for simultaneous cell detection and classifi- cation, which we named as Hydra-Net. We then compute an image based biomarker which we refer as digital proximity signature (DPS), to predict overall survival in diffuse large B-cell lymphoma (DLBCL) patients. Our results suggest that patients with high collagen-tumour proximity are likely to experience better overall survival

Learning where to see : a novel attention model for automated immunohistochemical scoring

Estimatingover-amplification of human epidermal growth factor receptor2 (HER2) on invasive breast cancer (BC) is regarded as a significant predictive and prognostic marker. We propose a novel deep reinforcement learning (DRL) based model that treats immunohistochemical (IHC) scoring of HER2 as a sequential learning task. For a given image tile sampled from multi-resolution giga-pixel whole slide image (WSI), the model learns to sequentially identify some of the diagnostically relevant regions of interest (ROIs) by following a parameterized policy. The selected ROIs are processed by recurrent and residual convolution networks to learn the discriminative features for different HER2 scores and predict the next location, without requiring to process all the subimage patches of a given tile for predicting the HER2 score, mimicking the histopathologist who would not usually analyse every part of the slide at the highest magnification. The proposed model incorporates a task-specific regularization term and inhibition of return mechanism to prevent the model from revisiting the previously attended locations. We evaluated our model on two IHC datasets: a publicly available dataset from the HER2 scoring challenge contest and another dataset consisting of WSIs of gastroenteropancreatic neuroendocrine tumor sections stained with Glo1 marker. We demonstrate that the proposed model out performs other methods based on state-of-the-art deep convolutional networks. To the best of our knowledge, this is the first study using DRL for IHC scoring and could potentially lead to wider use of DRL in the domain of computational pathology reducing the computational burden of the analysis of large multi-gigapixel histology images

Persistent homology for fast tumor segmentation in whole slide histology images

Automated tumor segmentation in Hematoxylin & Eosin stained histology images is an essential step towards a computer-aided diagnosis system. In this work we propose a novel tumor segmentation approach for a histology whole-slide image (WSI) by exploring the degree of connectivity among nuclei using the novel idea of persistent homology profiles. Our approach is based on 3 steps: 1) selection of exemplar patches from the training dataset using convolutional neural networks (CNNs); 2) construction of persistent homology profiles based on topological features; 3) classification using variant of k-nearest neighbors (k-NN). Extensive experimental results favor our algorithm over a conventional CNN

Fast and accurate tumor segmentation of histology images using persistent homology and deep convolutional features

Tumor segmentation in whole-slide images of histology slides is an important step towards computer-assisted diagnosis. In this work, we propose a tumor segmentation framework based on the novel concept of persistent homology profiles (PHPs). For a given image patch, the homology profiles are derived by efficient computation of persistent homology, which is an algebraic tool from homology theory. We propose an efficient way of computing topological persistence of an image, alternative to simplicial homology. The PHPs are devised to distinguish tumor regions from their normal counterparts by modeling the atypical characteristics of tumor nuclei. We propose two variants of our method for tumor segmentation: one that targets speed without compromising accuracy and the other that targets higher accuracy. The fast version is based on the selection of exemplar image patches from a convolution neural network (CNN) and patch classification by quantifying the divergence between the PHPs of exemplars and the input image patch. Detailed comparative evaluation shows that the proposed algorithm is significantly faster than competing algorithms while achieving comparable results. The accurate version combines the PHPs and high-level CNN features and employs a multi-stage ensemble strategy for image patch labeling. Experimental results demonstrate that the combination of PHPs and CNN features outperforms competing algorithms. This study is performed on two independently collected colorectal datasets containing adenoma, adenocarcinoma, signet and healthy cases. Collectively, the accurate tumor segmentation produces the highest average patch-level F1-score, as compared with competing algorithms, on malignant and healthy cases from both the datasets. Overall the proposed framework highlights the utility of persistent homology for histopathology image analysis

Classification of lung cancer histology images using patch-level summary statistics

There are two main types of lung cancer: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), which are grouped accordingly due to similarity in behaviour and response to treatment. The main types of NSCLC are lung adenocarcinoma (LUAD), which accounts for about 40% of all lung cancers and lung squamous cell carcinoma (LUSC), which accounts for about 25-30% of all lung cancers. Due to their differences, automated classification of these two main subtypes of NSCLC is a critical step in developing a computer aided diagnostic system. We present an automated method for NSCLC classification, that consists of a two-part approach. Firstly, we implement a deep learning framework to classify input patches as LUAD, LUSC or non-diagnostic (ND). Next, we extract a collection of statistical and morphological measurements from the labeled whole-slide image (WSI) and use a random forest regression model to classify each WSI as lung adenocarcinoma or lung squamous cell carcinoma. This task is part of the Computational Precision Medicine challenge at the MICCAI 2017 conference, where we achieved the greatest classification accuracy with a score of 0.81

Glyoxalase 1 copy number variation in patients with well differentiated gastroentero-pancreatic neuroendocrine tumours (GEP-NET)

Background: The glyoxalase-1 gene (GLO1) is a hotspot for copy-number variation (CNV) in human genomes. Increased GLO1 copy-number is associated with multidrug resistance in tumour chemotherapy, but prevalence of GLO1 CNV in gastro-entero-pancreatic neuroendocrine tumours (GEP-NET) is unknown. Methods: GLO1 copy-number variation was measured in 39 patients with GEP-NET (midgut NET, n = 25; pancreatic NET, n = 14) after curative or debulking surgical treatment. Primary tumour tissue, surrounding healthy tissue and, where applicable, additional metastatic tumour tissue were analysed, using real time qPCR. Progression and survival following surgical treatment were monitored over 4.2 ± 0.5 years. Results: In the pooled GEP-NET cohort, GLO1 copy-number in healthy tissue was 2.0 in all samples but significantly increased in primary tumour tissue in 43% of patients with pancreatic NET and in 72% of patients with midgut NET, mainly driven by significantly higher GLO1 copy-number in midgut NET. In tissue from additional metastases resection (18 midgut NET and one pancreatic NET), GLO1 copy number was also increased, compared with healthy tissue; but was not significantly different compared with primary tumour tissue. During mean 3 - 5 years follow-up, 8 patients died and 16 patients showed radiological progression. In midgut NET, a high GLO1 copy-number was associated with earlier progression. In NETs with increased GLO1 copy number, there was increased Glo1 protein expression compared to non-malignant tissue. Conclusions: GLO1 copy-number was increased in a large percentage of patients with GEP-NET and correlated positively with increased Glo1 protein in tumour tissue. Analysis of GLO1 copy-number variation particularly in patients with midgut NET could be a novel prognostic marker for tumour progression

Her2 challenge contest: a detailed assessment of automated her2 scoring algorithms in whole slide images of breast cancer tissues

Aims Evaluating expression of the Human epidermal growth factor receptor 2 (Her2) by visual examination of immunohistochemistry (IHC) on invasive breast cancer (BCa) is a key part of the diagnostic assessment of BCa due to its recognised importance as a predictive and prognostic marker in clinical practice. However, visual scoring of Her2 is subjective and consequently prone to inter-observer variability. Given the prognostic and therapeutic implications of Her2 scoring, a more objective method is required. In this paper, we report on a recent automated Her2 scoring contest, held in conjunction with the annual PathSoc meeting held in Nottingham in June 2016, aimed at systematically comparing and advancing the state-of-the-art Artificial Intelligence (AI) based automated methods for Her2 scoring. Methods and Results The contest dataset comprised of digitised whole slide images (WSI) of sections from 86 cases of invasive breast carcinoma stained with both Haematoxylin & Eosin (H&E) and IHC for Her2. The contesting algorithms automatically predicted scores of the IHC slides for an unseen subset of the dataset and the predicted scores were compared with the “ground truth” (a consensus score from at least two experts). We also report on a simple Man vs Machine contest for the scoring of Her2 and show that the automated methods could beat the pathology experts on this contest dataset. Conclusions This paper presents a benchmark for comparing the performance of automated algorithms for scoring of Her2. It also demonstrates the enormous potential of automated algorithms in assisting the pathologist with objective IHC scoring