Automatically detecting and grading cancerous regions on radical prostatectomy (RP) sections facilitates graphical and quantitative pathology reporting, potentially benefitting post-surgery prognosis, recurrence prediction, and treatment planning after RP. Promising results for detecting and grading prostate cancer on digital histopathology images have been reported using machine learning techniques. However, the importance and applicability of those methods have not been fully investigated. We computed three-class tissue component maps (TCMs) from the images, where each pixel was labeled as nuclei, lumina, or other. We applied seven different machine learning approaches: three non-deep learning classifiers with features extracted from TCMs, and four deep learning, using transfer learning with the 1) TCMs, 2) nuclei maps, 3) lumina maps, and 4) raw images for cancer detection and grading on whole-mount RP tissue sections. We performed leave-one-patient-out crossvalidation against expert annotations using 286 whole-slide images from 68 patients. For both cancer detection and grading, transfer learning using TCMs performed best. Transfer learning using nuclei maps yielded slightly inferior overall performance, but the best performance for classifying highergrade cancer. This suggests that 3-class TCMs provide the major cues for cancer detection and grading primarily using nucleus features, which are the most important information for identifying higher-grade cancer. The most used treatment for prostate-cancer (PCa) that is organ-confined is radical prostatectomy (RP), the removal of the prostate gland. Approximately 40% of prostate cancer patients undergo this surgery each year in the United States 1. Serum prostate-specific antigen (PSA) relapse occurs in 17%-29% of patients, reflecting cancer recurrence 2,3. Post-surgery prognosis, recurrence prediction, and selection and guidance for adjuvant therapy are all informed by the surgical pathology report. Typical pathology reports include tumor size, location, spread, and aggressiveness levels. In addition, PCa patients are grouped based on the Gleason score (GS), which is computed as the sum of the primary and secondary Gleason grades 3 at RP, into grade group 1 (GS 6; G3 + 3), grade group 2 (GS 7; G3 + 4), grade group 3 (GS7; G4 + 3), grade group 4 (GS 8; G4 + 4) and grade group 5 (GS 9-10; G4 + 5, G5 + 4, and G5 + 5) disease 4,5 , with treatment determined according to the risk level 6. Thus, although accurate post-RP risk stratification is crucial, currently, clinical pathology reporting is primarily qualitative and subject to intra-and inter-observer variability. This leads to challenges for quantitative and repeatable pathology reporting and interpretation regarding the lesion size, location, spread, and Gleason grade or score 3,7-10 .