Fine-grained classification of whole slide images (WSIs) is essential in precision oncology, enabling precise cancer diagnosis and personalized treatment strategies. The core of this task involves distinguishing subtle morphological variations within the same broad category of gigapixel-resolution images, which presents a significant challenge. While the multi-instance learning (MIL) paradigm alleviates the computational burden of WSIs, existing MIL methods often overlook hierarchical label correlations, treating fine-grained classification as a flat multi-class classification task. To overcome these limitations, we introduce a novel hierarchical multi-instance learning (HMIL) framework. By facilitating on the hierarchical alignment of inherent relationships between different hierarchy of labels at instance and bag level, our approach provides a more structured and informative learning process. Specifically, HMIL incorporates a class-wise attention mechanism that aligns hierarchical information at both the instance and bag levels. Furthermore, we introduce supervised contrastive learning to enhance the discriminative capability for fine-grained classification and a curriculum-based dynamic weighting module to adaptively balance the hierarchical feature during training. Extensive experiments on our large-scale cytology cervical cancer (CCC) dataset and two public histology datasets, BRACS and PANDA, demonstrate the state-of-the-art class-wise and overall performance of our HMIL framework. Our source code is available at https://github.com/ChengJin-git/HMIL.

Convolutional neural networks (CNNs) have shown remarkable progress in medical image segmentation. However, the lesion segmentation remains a challenge to state-of-the-art CNN-based algorithms due to the variance in scales and shapes. On the one hand, tiny lesions are hard to delineate precisely from the medical images which are often of low resolutions. On the other hand, segmenting large-size lesions requires large receptive fields, which exacerbates the first challenge. In this article, we present a scale-aware super-resolution (SR) network to adaptively segment lesions of various sizes from low-resolution (LR) medical images. Our proposed network contains dual branches to simultaneously conduct lesion mask SR (LMSR) and lesion image SR (LISR). Meanwhile, we introduce scale-aware dilated convolution (SDC) blocks into the multitask decoders to adaptively adjust the receptive fields of the convolutional kernels according to the lesion sizes. To guide the segmentation branch to learn from richer high-resolution (HR) features, we propose a feature affinity (FA) module and a scale affinity (SA) module to enhance the multitask learning of the dual branches. On multiple challenging lesion segmentation datasets, our proposed network achieved consistent improvements compared with other state-of-the-art methods. Code will be available at: https://github.com/poiuohke/SASR_Net.

Cytology screening from Papanicolaou (Pap) smears is a common and effective tool for the preventive clinical management of cervical cancer, where abnormal cell detection from whole slide images serves as the foundation for reporting cervical cytology. However, cervical cell detection remains challenging due to 1) hazily-defined cell types (e.g., ASC-US) with subtle morphological discrepancies caused by the dynamic cancerization process, i.e., cell class ambiguity, and 2) imbalanced class distributions of clinical data may cause missed detection, especially for minor categories, i.e., cell class imbalance. To this end, we propose a holistic and historical instance comparison approach for cervical cell detection. Specifically, we first develop a holistic instance comparison scheme enforcing both RoI-level and class-level cell discrimination. This coarse-to-fine cell comparison encourages the model to learn foreground-distinguishable and class-wise representations. To emphatically improve the distinguishability of minor classes, we then introduce a historical instance comparison scheme with a confident sample selection-based memory bank, which involves comparing current embeddings with historical embeddings for better cell instance discrimination. Extensive experiments and analysis on two large-scale cytology datasets including 42,592 and 114,513 cervical cells demonstrate the effectiveness of our method. The code is available at https://github.com/hjiangaz/HERO.

Instance segmentation plays a vital role in the morphological quantification of biomedical entities such as tissues and cells, enabling precise identification and delineation of different structures. Current methods often address the challenges of touching, overlapping or crossing instances through individual modeling, while neglecting the intrinsic interrelation between these conditions. In this work, we propose a Gradient Anomaly-aware Biomedical Instance Segmentation approach (GAInS), which leverages instance gradient information to perceive local gradient anomaly regions, thus modeling the spatial relationship between instances and refining local region segmentation. Specifically, GAInS is firstly built on a Gradient Anomaly Mapping Module (GAMM), which encodes the radial fields of instances through window sliding to obtain instance gradient anomaly maps. To efficiently refine boundaries and regions with gradient anomaly attention, we propose an Adaptive Local Refinement Module (ALRM) with a gradient anomaly-aware loss function. Extensive comparisons and ablation experiments in three biomedical scenarios demonstrate that our proposed GAInS outperforms other state-of-the-art (SOTA) instance segmentation methods. The code is available at https://github.com/DeepGAInS/GAInS.

Deep learning (DL)-based rib fracture detection has shown promise of playing an important role in preventing mortality and improving patient outcome. Normally, developing DL-based object detection models requires a huge amount of bounding box annotation. However, annotating medical data is time-consuming and expertise-demanding, making obtaining a large amount of fine-grained annotations extremely infeasible. This poses a pressing need for developing label-efficient detection models to alleviate radiologists' labeling burden. To tackle this challenge, the literature on object detection has witnessed an increase of weakly-supervised and semi-supervised approaches, yet still lacks a unified framework that leverages various forms of fully-labeled, weakly-labeled, and unlabeled data. In this paper, we present a novel omni-supervised object detection network, ORF-Netv2, to leverage as much available supervision as possible. Specifically, a multi-branch omni-supervised detection head is introduced with each branch trained with a specific type of supervision. A co-training-based dynamic label assignment strategy is then proposed to enable flexible and robust learning from the weakly-labeled and unlabeled data. Extensive evaluation was conducted for the proposed framework with three rib fracture datasets on both chest CT and X-ray. By leveraging all forms of supervision, ORF-Netv2 achieves mAPs of 34.7, 44.7, and 19.4 on the three datasets, respectively, surpassing the baseline detector which uses only box annotations by mAP gains of 3.8, 4.8, and 5.0, respectively. Furthermore, ORF-Netv2 consistently outperforms other competitive label-efficient methods over various scenarios, showing a promising framework for label-efficient fracture detection. The code is available at: https://github.com/zhizhongchai/ORF-Net.

Histopathology image analysis serves as the gold standard for cancer diagnosis. Efficient and precise diagnosis is quite critical for the subsequent therapeutic treatment of patients. So far, computer-aided diagnosis has not been widely applied in pathological field yet as currently well-addressed tasks are only the tip of the iceberg. Whole slide image (WSI) classification is a quite challenging problem. First, the scarcity of annotations heavily impedes the pace of developing effective approaches. Pixelwise delineated annotations on WSIs are time consuming and tedious, which poses difficulties in building a large-scale training dataset. In addition, a variety of heterogeneous patterns of tumor existing in high magnification field are actually the major obstacle. Furthermore, a gigapixel scale WSI cannot be directly analyzed due to the immeasurable computational cost. How to design the weakly supervised learning methods to maximize the use of available WSI-level labels that can be readily obtained in clinical practice is quite appealing. To overcome these challenges, we present a weakly supervised approach in this article for fast and effective classification on the whole slide lung cancer images. Our method first takes advantage of a patch-based fully convolutional network (FCN) to retrieve discriminative blocks and provides representative deep features with high efficiency. Then, different context-aware block selection and feature aggregation strategies are explored to generate globally holistic WSI descriptor which is ultimately fed into a random forest (RF) classifier for the image-level prediction. To the best of our knowledge, this is the first study to exploit the potential of image-level labels along with some coarse annotations for weakly supervised learning. A large-scale lung cancer WSI dataset is constructed in this article for evaluation, which validates the effectiveness and feasibility of the proposed method. Extensive experiments demonstrate the superior performance of our method that surpasses the state-of-the-art approaches by a significant margin with an accuracy of 97.3%. In addition, our method also achieves the best performance on the public lung cancer WSIs dataset from The Cancer Genome Atlas (TCGA). We highlight that a small number of coarse annotations can contribute to further accuracy improvement. We believe that weakly supervised learning methods have great potential to assist pathologists in histology image diagnosis in the near future.

Automated detection of cancer metastases in lymph nodes has the potential to improve the assessment of prognosis for patients. To enable fair comparison between the algorithms for this purpose, we set up the CAMELYON17 challenge in conjunction with the IEEE International Symposium on Biomedical Imaging 2017 Conference in Melbourne. Over 300 participants registered on the challenge website, of which 23 teams submitted a total of 37 algorithms before the initial deadline. Participants were provided with 899 whole-slide images (WSIs) for developing their algorithms. The developed algorithms were evaluated based on the test set encompassing 100 patients and 500 WSIs. The evaluation metric used was a quadratic weighted Cohen's kappa. We discuss the algorithmic details of the 10 best pre-conference and two post-conference submissions. All these participants used convolutional neural networks in combination with pre- and postprocessing steps. Algorithms differed mostly in neural network architecture, training strategy, and pre- and postprocessing methodology. Overall, the kappa metric ranged from 0.89 to -0.13 across all submissions. The best results were obtained with pre-trained architectures such as ResNet. Confusion matrix analysis revealed that all participants struggled with reliably identifying isolated tumor cells, the smallest type of metastasis, with detection rates below 40%. Qualitative inspection of the results of the top participants showed categories of false positives, such as nerves or contamination, which could be targeted for further optimization. Last, we show that simple combinations of the top algorithms result in higher kappa metric values than any algorithm individually, with 0.93 for the best combination.

Lymph node metastasis is one of the most important indicators in breast cancer diagnosis, that is traditionally observed under the microscope by pathologists. In recent years, with the dramatic advance of high-throughput scanning and deep learning technology, automatic analysis of histology from whole-slide images has received a wealth of interest in the field of medical image computing, which aims to alleviate pathologists' workload and simultaneously reduce misdiagnosis rate. However, the automatic detection of lymph node metastases from whole-slide images remains a key challenge because such images are typically very large, where they can often be multiple gigabytes in size. Also, the presence of hard mimics may result in a large number of false positives. In this paper, we propose a novel method with anchor layers for model conversion, which not only leverages the efficiency of fully convolutional architectures to meet the speed requirement in clinical practice but also densely scans the whole-slide image to achieve accurate predictions on both micro- and macro-metastases. Incorporating the strategies of asynchronous sample prefetching and hard negative mining, the network can be effectively trained. The efficacy of our method is corroborated on the benchmark dataset of 2016 Camelyon Grand Challenge. Our method achieved significant improvements in comparison with the state-of-the-art methods on tumor localization accuracy with a much faster speed and even surpassed human performance on both challenge tasks.

Lymph node metastasis is one of the most significant diagnostic indicators in breast cancer, which is traditionally observed under the microscope by pathologists. In recent years, computerized histology diagnosis has become one of the most rapidly expanding directions in the field of medical image computing, which aims to alleviate pathologists' workload and simultaneously reduce misdiagnosis rate. However, automatic detection of lymph node metastases from whole slide images remains a challenging problem, due to the large-scale data with enormous resolutions and existence of hard mimics resulting in a large number of false positives. In this paper, we propose a novel framework by leveraging fully convolutional networks for efficient inference to meet the speed requirement for clinical practice, while reconstructing dense predictions under different offsets for ensuring accurate detection on both microand macro-metastases. Incorporating with the strategies of asynchronous sample prefetching and hard negative mining, the network can be effectively trained. Extensive experiments on the benchmark dataset of 2016 Camelyon Grand Challenge corroborated the efficacy of our method. Compared with the state-of-the-art methods, our method achieved superior performance with a faster speed on the tumor localization task and even surpassed human performance on the WSI classification task.