Abstract: The gigapixel scale of whole slide images (WSIs) poses a challenge for histopathology multi-modal chatbots, requiring a global WSI analysis for diagnosis, compounding evidence from different WSI patches. Current visual instruction datasets, generated through large language models, focus on creating question/answer pairs for individual image patches, which may lack diagnostic capacity on their own in histopathology, further complicated by the absence of spatial grounding in histopathology image captions. To bridge this gap, we introduce Quilt-Instruct, a large-scale dataset of $107,131$ histopathology-specific instruction question/answer pairs, that is collected by leveraging educational histopathology videos from YouTube, which provides spatial localization of captions by automatically extracting narrators' cursor movements. In addition, we provide contextual reasoning by extracting diagnosis and supporting facts from the entire video content to guide the extrapolative reasoning of GPT-4. Using Quilt-Instruct, we train Quilt-LLaVA, which can reason beyond the given single image patch, enabling diagnostic reasoning and the capability of spatial awareness. To evaluate Quilt-LLaVA, we propose a comprehensive evaluation dataset created from $985$ images and $1283$ human-generated question-answers. We also thoroughly evaluate Quilt-LLaVA using public histopathology datasets, where Quilt-LLaVA significantly outperforms SOTA by over 10\% on relative GPT-4 score and 4\% and 9\% on open and closed set VQA. Our code, data, and model will be made publicly available.