The present techniques provide systems and methods for registering images of tissue spots on a tissue microarray (TMA). In studies involving multiple biomarkers being studied on the same TMA, the TMA slide is removed from the microscope, stained, and then imaged, often multiple times. The present techniques relate to validation of the registration of the acquired images of the same TMA. An automatic approach to register the images and detect registration failures as provided herein may enhance the rapid analysis of the tissues. Artifacts such as tissue folding and tissue loss are also determined automatically.