Abstract Background The current practice of histopathology review is limited in speed and accuracy. The current diagnostic paradigm does not fully describe the complex and complicated patterns of cancer. To address these needs, we develop an automated and objective system that facilitates a comprehensive and easy information management and decision-making. We also develop a tissue similarity measure scheme to broaden our understanding of tissue characteristics. Results The system includes a database of previously evaluated prostate tissue images, clinical information and a tissue retrieval process. In the system, a tissue is characterized by its morphology. The retrieval process seeks to find the closest matching cases with the tissue of interest. Moreover, we define 9 morphologic criteria by which a pathologist arrives at a histomorphologic diagnosis. Based on the 9 criteria, true tissue similarity is determined and serves as the gold standard of tissue retrieval. Here, we found a minimum of 4 and 3 matching cases, out of 5, for ~80 % and ~60 % of the queries when a match was defined as the tissue similarity score ≥5 and ≥6, respectively. We were also able to examine the relationship between tissues beyond the Gleason grading system due to the tissue similarity scoring system. Conclusions Providing the closest matching cases and their clinical information with pathologists will help to conduct consistent and reliable diagnoses. Thus, we expect the system to facilitate quality maintenance and quality improvement of cancer pathology.