The Application and Pitfalls of Immunohistochemical Markers in Challenging Diagnosis of Genitourinary Pathology

center dot Context.-The morphologic features of different entities in genitourinary pathology overlap, presenting a diagnostic challenge, especially when diagnostic materials are limit-ed. Immunohistochemical markers are valuable when morphologic features alone are insufficient for definitive diagnosis. The World Health Organization classification of urinary and male genital tumors has been updated for 2022. An updated review of immunohistochemical mark -ers for newly classified genitourinary neoplasms and their differential diagnosis is needed.Objective.-To review immunohistochemical markers used in the diagnosis of genitourinary lesions in the kidney, bladder, prostate, and testis. We particularly emphasized difficult differential diagnosis and pitfalls in immunohisto-chemistry application and interpretation. New markers and new entities in the 2022 World Health Organization classifications of genitourinary tumors are reviewed. Recommended staining panels for commonly encountered difficult differential diagnoses and potential pitfalls are discussed.Data Sources.-Review of current literature and our own experience.Conclusions.-Immunohistochemistry is a valuable tool in the diagnosis of problematic lesions of the genitourinary tract. However, the immunostains must be carefully interpreted in the context of morphologic findings with a thorough knowledge of pitfalls and limitations.(Arch Pathol Lab Med. 2024;148:13-32; doi: 10.5858/ arpa.2022-0493-RA)