An Attention Based Pipeline for Identifying Pre-Cancer Lesions in Head and Neck Clinical Images

Early detection of cancer can help improve patient prognosis by early intervention. Head and neck cancer is diagnosed in specialist centres after a surgical biopsy, however, there is a potential for these to be missed leading to delayed diagnosis. To overcome these challenges, we present an attention based pipeline that identifies suspected lesions, segments, and classifies them as non-dysplastic, dysplastic and cancerous lesions. We propose (a) a vision transformer based Mask R-CNN network for lesion detection and segmentation of clinical images, and (b) Multiple Instance Learning (MIL) based scheme for classification. Current results show that the segmentation model produces segmentation masks and bounding boxes with up to 82% overlap accuracy score on unseen external test data and surpassing reviewed segmentation benchmarks. Next, a classification F1-score of 85% on the internal cohort test set. An app has been developed to perform lesion segmentation taken via a smart device. Future work involves employing endoscopic video data for precise early detection and prognosis.

Nuclei-Location Based Point Set Registration of Multi-Stained Whole Slide Images

Whole Slide Images (WSIs) provide exceptional detail for studying tissue architecture at the cell level. To study tumour microenvironment (TME) with the context of various protein biomarkers and cell sub-types, analysis and registration of features using multi-stained WSIs is often required. Multi-stained WSI pairs normally suffer from rigid and non-rigid deformities in addition to slide artefacts and control tissue which present challenges at precise registration. Traditional registration methods mainly focus on global rigid/non-rigid registration but struggle with aligning slides with complex tissue deformations at the nuclei level. However, nuclei level non-rigid registration is essential for downstream tasks such as cell sub-type analysis in the context of protein biomarker signatures. This paper focuses on local level non-rigid registration using a nuclei-location based point set registration approach for aligning multi-stained WSIs. We exploit the spatial distribution of nuclei that is prominent and consistent (to a large level) across different stains to establish a spatial correspondence. We evaluate our approach using the HYRECO dataset consisting of 54 re-stained images of H\&E and PHH3 image pairs. The approach can be extended to other IHC and IF stained WSIs considering a good nuclei detection algorithm is accessible. The performance of the model is tested against established registration algorithms and is shown to outperform the model for nuclei level registration.

An AI based Digital Score of Tumour-Immune Microenvironment Predicts Benefit to Maintenance Immunotherapy in Advanced Oesophagogastric Adenocarcinoma

Gastric and oesophageal (OG) cancers are the leading causes of cancer mortality worldwide. In OG cancers, recent studies have showed that PDL1 immune checkpoint inhibitors (ICI) in combination with chemotherapy improves patient survival. However, our understanding of the tumour immune microenvironment in OG cancers remains limited. In this study, we interrogate multiplex immunofluorescence (mIF) images taken from patients with advanced Oesophagogastric Adenocarcinoma (OGA) who received first-line fluoropyrimidine and platinum-based chemotherapy in the PLATFORM trial (NCT02678182) to predict the efficacy of the treatment and to explore the biological basis of patients responding to maintenance durvalumab (PDL1 inhibitor). Our proposed Artificial Intelligence (AI) based marker successfully identified responder from non-responder (p < 0.05) as well as those who could potentially benefit from ICI with statistical significance (p < 0.05) for both progression free and overall survival. Our findings suggest that T cells that express FOXP3 seem to heavily influence the patient treatment response and survival outcome. We also observed that higher levels of CD8+PD1+ cells are consistently linked to poor prognosis for both OS and PFS, regardless of ICI.

Cell Maps Representation For Lung Adenocarcinoma Growth Patterns Classification In Whole Slide Images

Lung adenocarcinoma is a morphologically heterogeneous disease, characterized by five primary histologic growth patterns. The quantity of these patterns can be related to tumor behavior and has a significant impact on patient prognosis. In this work, we propose a novel machine learning pipeline capable of classifying tissue tiles into one of the five patterns or as non-tumor, with an Area Under the Receiver Operating Characteristic Curve (AUCROC) score of 0.97. Our model's strength lies in its comprehensive consideration of cellular spatial patterns, where it first generates cell maps from Hematoxylin and Eosin (H&E) whole slide images (WSIs), which are then fed into a convolutional neural network classification model. Exploiting these cell maps provides the model with robust generalizability to new data, achieving approximately 30% higher accuracy on unseen test-sets compared to current state of the art approaches. The insights derived from our model can be used to predict prognosis, enhancing patient outcomes.

An Automated Pipeline for Tumour-Infiltrating Lymphocyte Scoring in Breast Cancer

Tumour-infiltrating lymphocytes (TILs) are considered as a valuable prognostic markers in both triple-negative and human epidermal growth factor receptor 2 (HER2) positive breast cancer. In this study, we introduce an innovative deep learning pipeline based on the Efficient-UNet architecture to predict the TILs score for breast cancer whole-slide images (WSIs). We first segment tumour and stromal regions in order to compute a tumour bulk mask. We then detect TILs within the tumour-associated stroma, generating a TILs score by closely mirroring the pathologist's workflow. Our method exhibits state-of-the-art performance in segmenting tumour/stroma areas and TILs detection, as demonstrated by internal cross-validation on the TiGER Challenge training dataset and evaluation on the final leaderboards. Additionally, our TILs score proves competitive in predicting survival outcomes within the same challenge, underscoring the clinical relevance and potential of our automated TILs scoring pipeline as a breast cancer prognostic tool.

Transformer-based Model for Oral Epithelial Dysplasia Segmentation

Oral epithelial dysplasia (OED) is a premalignant histopathological diagnosis given to lesions of the oral cavity. OED grading is subject to large inter/intra-rater variability, resulting in the under/over-treatment of patients. We developed a new Transformer-based pipeline to improve detection and segmentation of OED in haematoxylin and eosin (H&E) stained whole slide images (WSIs). Our model was trained on OED cases (n = 260) and controls (n = 105) collected using three different scanners, and validated on test data from three external centres in the United Kingdom and Brazil (n = 78). Our internal experiments yield a mean F1-score of 0.81 for OED segmentation, which reduced slightly to 0.71 on external testing, showing good generalisability, and gaining state-of-the-art results. This is the first externally validated study to use Transformers for segmentation in precancerous histology images. Our publicly available model shows great promise to be the first step of a fully-integrated pipeline, allowing earlier and more efficient OED diagnosis, ultimately benefiting patient outcomes.

Domain Generalization in Computational Pathology: Survey and Guidelines

Deep learning models have exhibited exceptional effectiveness in Computational Pathology (CPath) by tackling intricate tasks across an array of histology image analysis applications. Nevertheless, the presence of out-of-distribution data (stemming from a multitude of sources such as disparate imaging devices and diverse tissue preparation methods) can cause \emph{domain shift} (DS). DS decreases the generalization of trained models to unseen datasets with slightly different data distributions, prompting the need for innovative \emph{domain generalization} (DG) solutions. Recognizing the potential of DG methods to significantly influence diagnostic and prognostic models in cancer studies and clinical practice, we present this survey along with guidelines on achieving DG in CPath. We rigorously define various DS types, systematically review and categorize existing DG approaches and resources in CPath, and provide insights into their advantages, limitations, and applicability. We also conduct thorough benchmarking experiments with 28 cutting-edge DG algorithms to address a complex DG problem. Our findings suggest that careful experiment design and CPath-specific Stain Augmentation technique can be very effective. However, there is no one-size-fits-all solution for DG in CPath. Therefore, we establish clear guidelines for detecting and managing DS depending on different scenarios. While most of the concepts, guidelines, and recommendations are given for applications in CPath, we believe that they are applicable to most medical image analysis tasks as well.

A Fully Automated and Explainable Algorithm for the Prediction of Malignant Transformation in Oral Epithelial Dysplasia

Oral epithelial dysplasia (OED) is a premalignant histopathological diagnosis given to lesions of the oral cavity. Its grading suffers from significant inter-/intra- observer variability, and does not reliably predict malignancy progression, potentially leading to suboptimal treatment decisions. To address this, we developed a novel artificial intelligence algorithm that can assign an Oral Malignant Transformation (OMT) risk score, based on histological patterns in the in Haematoxylin and Eosin stained whole slide images, to quantify the risk of OED progression. The algorithm is based on the detection and segmentation of nuclei within (and around) the epithelium using an in-house segmentation model. We then employed a shallow neural network fed with interpretable morphological/spatial features, emulating histological markers. We conducted internal cross-validation on our development cohort (Sheffield; n = 193 cases) followed by independent validation on two external cohorts (Birmingham and Belfast; n = 92 cases). The proposed OMTscore yields an AUROC = 0.74 in predicting whether an OED progresses to malignancy or not. Survival analyses showed the prognostic value of our OMTscore for predicting malignancy transformation, when compared to the manually-assigned WHO and binary grades. Analysis of the correctly predicted cases elucidated the presence of peri-epithelial and epithelium-infiltrating lymphocytes in the most predictive patches of cases that transformed (p < 0.0001). This is the first study to propose a completely automated algorithm for predicting OED transformation based on interpretable nuclear features, whilst being validated on external datasets. The algorithm shows better-than-human-level performance for prediction of OED malignant transformation and offers a promising solution to the challenges of grading OED in routine clinical practice.

CoNIC Challenge: Pushing the Frontiers of Nuclear Detection, Segmentation, Classification and Counting

Nuclear detection, segmentation and morphometric profiling are essential in helping us further understand the relationship between histology and patient outcome. To drive innovation in this area, we setup a community-wide challenge using the largest available dataset of its kind to assess nuclear segmentation and cellular composition. Our challenge, named CoNIC, stimulated the development of reproducible algorithms for cellular recognition with real-time result inspection on public leaderboards. We conducted an extensive post-challenge analysis based on the top-performing models using 1,658 whole-slide images of colon tissue. With around 700 million detected nuclei per model, associated features were used for dysplasia grading and survival analysis, where we demonstrated that the challenge's improvement over the previous state-of-the-art led to significant boosts in downstream performance. Our findings also suggest that eosinophils and neutrophils play an important role in the tumour microevironment. We release challenge models and WSI-level results to foster the development of further methods for biomarker discovery.

Consistency Regularisation in Varying Contexts and Feature Perturbations for Semi-Supervised Semantic Segmentation of Histology Images

Semantic segmentation of various tissue and nuclei types in histology images is fundamental to many downstream tasks in the area of computational pathology (CPath). In recent years, Deep Learning (DL) methods have been shown to perform well on segmentation tasks but DL methods generally require a large amount of pixel-wise annotated data. Pixel-wise annotation sometimes requires expert's knowledge and time which is laborious and costly to obtain. In this paper, we present a consistency based semi-supervised learning (SSL) approach that can help mitigate this challenge by exploiting a large amount of unlabelled data for model training thus alleviating the need for a large annotated dataset. However, SSL models might also be susceptible to changing context and features perturbations exhibiting poor generalisation due to the limited training data. We propose an SSL method that learns robust features from both labelled and unlabelled images by enforcing consistency against varying contexts and feature perturbations. The proposed method incorporates context-aware consistency by contrasting pairs of overlapping images in a pixel-wise manner from changing contexts resulting in robust and context invariant features. We show that cross-consistency training makes the encoder features invariant to different perturbations and improves the prediction confidence. Finally, entropy minimisation is employed to further boost the confidence of the final prediction maps from unlabelled data. We conduct an extensive set of experiments on two publicly available large datasets (BCSS and MoNuSeg) and show superior performance compared to the state-of-the-art methods.