The field of computational pathology has been transformed with recent advances in foundation models that encode histopathology region-of-interests (ROIs) into versatile and transferable feature representations via self-supervised learning (SSL). However, translating these advancements to address complex clinical challenges at the patient and slide level remains constrained by limited clinical data in disease-specific cohorts, especially for rare clinical conditions. We propose TITAN, a multimodal whole slide foundation model pretrained using 335,645 WSIs via visual self-supervised learning and vision-language alignment with corresponding pathology reports and 423,122 synthetic captions generated from a multimodal generative AI copilot for pathology. Without any finetuning or requiring clinical labels, TITAN can extract general-purpose slide representations and generate pathology reports that generalize to resource-limited clinical scenarios such as rare disease retrieval and cancer prognosis. We evaluate TITAN on diverse clinical tasks and find that TITAN outperforms both ROI and slide foundation models across machine learning settings such as linear probing, few-shot and zero-shot classification, rare cancer retrieval and cross-modal retrieval, and pathology report generation.

The expanding adoption of digital pathology has enabled the curation of large repositories of histology whole slide images (WSIs), which contain a wealth of information. Similar pathology image search offers the opportunity to comb through large historical repositories of gigapixel WSIs to identify cases with similar morphological features and can be particularly useful for diagnosing rare diseases, identifying similar cases for predicting prognosis, treatment outcomes and potential clinical trial success. A critical challenge in developing a WSI search and retrieval system is scalability, which is uniquely challenging given the need to search a growing number of slides that each can consist of billions of pixels and are several gigabytes in size. Such systems are typically slow and retrieval speed often scales with the size of the repository they search through, making their clinical adoption tedious and are not feasible for repositories that are constantly growing. Here we present Fast Image Search for Histopathology (FISH), a histology image search pipeline that is infinitely scalable and achieves constant search speed that is independent of the image database size, while being interpretable and without requiring detailed annotations. FISH uses self-supervised deep learning to encode meaningful representations from WSIs and a Van Emde Boas tree for fast search, followed by an uncertainty-based ranking algorithm to retrieve similar WSIs. We evaluated FISH on multiple tasks and datasets with over 22,000 patient cases spanning 56 disease subtypes. We additionally demonstrate that FISH can be used to assist with the diagnosis of rare cancer types where sufficient cases may not be available to train traditional supervised deep models.