William L Harryman ^1* James P Hinton ¹ Rafael Sainz ¹ Jaime MC Gard ¹ John M Ryniawec ¹ Gregory C Rogers ^1,2 Noel A Warfel ^1,2 Beatrice S Knudsen ^3,4 Raymond B Nagle ¹ Juan J Chipollini ⁵ Benjamin R Lee ⁵ Belinda L Sun ⁶ Anne Elizabeth Cress ^1,2*

• ¹ Cancer Center, University of Arizona, Tucson, United States
• ² Department of Cellular and Molecular Medicine, College of Medicine, University of Arizona, Tuczon, Arizona, United States
• ³ Huntsman Cancer Institute, School of Medicine, The University of Utah, Salt Lake City, Utah, United States
• ⁴ Department of Pathology, School of Medicine, The University of Utah, Salt Lake City, Utah, United States
• ⁵ Department of Urology, College of Medicine, University of Arizona, Tucson, Arizona, United States
• ⁶ Department of Pathology, College of Medicine, University of Arizona, Tucson, Arizona, United States

In 2024, prostate cancer (PCa) remains the most common non-skin cancer in males within the United States, with an estimated 299,010 new cases, the highest increase incident trend rate (3.8%) of all cancers, and one of the eight deadliest. PCa cases are projected to double from 1.8 million to 2.9 million per year between 2020 and 2040. According to the National Comprehensive Cancer Network (NCCN) treatment guidelines, most cases (65%) are intermediate risk (Gleason sum score <7 [3+4, 4+3], prostate organ-confined, and PSA ˂ 20) with treatment options limited to active surveillance, external beam radiation, and/or surgery to prevent metastasis in the long term (>10 years). It is increasingly recognized that the two most common subtypes of intermediate risk PCa are cribriform architecture (CA) and intraductal carcinoma of the prostate (IDC-P), which can occur together, and both are associated with increased metastatic risk, biochemical recurrence, and disease-specific mortality. Both subtypes display hypoxia, genomic instability, and are identified as Gleason 4 in pathology reports. However, since false negatives are common (up to 50%) in these subtypes on biopsy, more research is needed to reliably detect these subtypes that have an increased risk for invasive disease. We note that even with mpMRI-guided biopsies, the sensitivity is 54% for cribriform architecture and only 37% for IDC-P. The presence of these PCa subtypes in biopsy or radical prostatectomy (RP) tissue can exclude patients from active surveillance and from designation as intermediate risk disease, further underscoring the need for increased molecular understanding of these subtypes for diagnostic purposes. Understanding the heterogeneity of intermediate risk primary PCa phenotypes, using computational pathology approaches to evaluate the fixed biopsy specimen, or video microscopy of the surgical specimen with AIdriven analysis is now achievable. New research associating the resulting phenotypes with the different therapeutic choices and vulnerabilities will likely prevent extracapsular extension, the definition of high-risk disease, and disease and upstaging of the final pathologic stage.