Development and Validation of Fully Automatic Deep Learning-Based Algorithms for Immunohistochemistry Reporting of Invasive Breast Ductal Carcinoma

Immunohistochemistry (IHC) analysis is a well-accepted and widely used method for molecular subtyping, a procedure for prognosis and targeted therapy of breast carcinoma, the most common type of tumor affecting women. There are four molecular biomarkers namely progesterone receptor (PR), estrogen receptor (ER), antigen Ki67, and human epidermal growth factor receptor 2 (HER2) whose assessment is needed under IHC procedure to decide prognosis as well as predictors of response to therapy. However, IHC scoring is based on subjective microscopic examination of tumor morphology and suffers from poor reproducibility, high subjectivity, and often incorrect scoring in low-score cases. In this paper, we present, a deep learning-based semi-supervised trained, fully automatic, decision support system (DSS) for IHC scoring of invasive ductal carcinoma. Our system automatically detects the tumor region removing artifacts and scores based on Allred standard. The system is developed using 3 million pathologist-annotated image patches from 300 slides, fifty thousand in-house cell annotations, and forty thousand pixels marking of HER2 membrane. We have conducted multicentric trials at four centers with three different types of digital scanners in terms of percentage agreement with doctors. And achieved agreements of 95, 92, 88 and 82 percent for Ki67, HER2, ER, and PR stain categories, respectively. In addition to overall accuracy, we found that there is 5 percent of cases where pathologist have changed their score in favor of algorithm score while reviewing with detailed algorithmic analysis. Our approach could improve the accuracy of IHC scoring and subsequent therapy decisions, particularly where specialist expertise is unavailable. Our system is highly modular. The proposed algorithm modules can be used to develop DSS for other cancer types.

Multi-Stain Multi-Level Convolutional Network for Multi-Tissue Breast Cancer Image Segmentation

Digital pathology and microscopy image analysis are widely employed in the segmentation of digitally scanned IHC slides, primarily to identify cancer and pinpoint regions of interest (ROI) indicative of tumor presence. However, current ROI segmentation models are either stain-specific or suffer from the issues of stain and scanner variance due to different staining protocols or modalities across multiple labs. Also, tissues like Ductal Carcinoma in Situ (DCIS), acini, etc. are often classified as Tumors due to their structural similarities and color compositions. In this paper, we proposed a novel convolutional neural network (CNN) based Multi-class Tissue Segmentation model for histopathology whole-slide Breast slides which classify tumors and segments other tissue regions such as Ducts, acini, DCIS, Squamous epithelium, Blood Vessels, Necrosis, etc. as a separate class. Our unique pixel-aligned non-linear merge across spatial resolutions empowers models with both local and global fields of view for accurate detection of various classes. Our proposed model is also able to separate bad regions such as folds, artifacts, blurry regions, bubbles, etc. from tissue regions using multi-level context from different resolutions of WSI. Multi-phase iterative training with context-aware augmentation and increasing noise was used to efficiently train a multi-stain generic model with partial and noisy annotations from 513 slides. Our training pipeline used 12 million patches generated using context-aware augmentations which made our model stain and scanner invariant across data sources. To extrapolate stain and scanner invariance, our model was evaluated on 23000 patches which were for a completely new stain (Hematoxylin and Eosin) from a completely new scanner (Motic) from a different lab. The mean IOU was 0.72 which is on par with model performance on other data sources and scanners.