A method for generating a ground truth mask for a microscope slide having a tissue specimen placed thereon includes a step of staining the tissue specimen with hematoxylin and eosin (H&E) staining agents. A first magnified image of the H&E stained tissue specimen is obtained, e.g., with a whole slide scanner. The H&E staining agents are then washed from the tissue specimen. A second, different stain is applied to the tissue specimen, e.g., a special stain such as an IHC stain. A second magnified image of the tissue specimen stained with the second, different stain is obtained. The first and second magnified images are then registered to each other. An annotation (e.g., drawing operation) is then performed on either the first or the second magnified images so as to form a ground truth mask, the ground truth mask in the form of closed polygon region enclosing tumor cells present in either the first or second magnified image.