Flat Intraurothelial Neoplasia Exhibiting Diffuse Immunoreactivity for CD44 and Cytokeratin 5 (Urothelial Stem Cell/Basal Cell Markers): A Variant of Intraurothelial Neoplasia Commonly Associated With Muscle-invasive Urothelial Carcinoma

摘要

Background: Immunoreactivity for CD44 and cytokeratin (CK)5 (urothelial stem/basal cell markers) are decreased/negative in the common type of intraurothelial neoplasia including urothelial carcinomas (UC) in situ. Recent studies also reveal that a majority of muscle-invasive UC are basal-like UC with large areas of positive CD44/CK5 immunoreactivity. In addition, approximately 80% of muscle-invasive UC develop de novo as nonpapillary invasive UC. In this study, we investigate the CD44/CK5 immunoreactivity of the flat intraurothelial neoplasia (FIUN) associated with nonpapillary invasive UC. Materials and Methods: Consecutive cases of nonpapillary UC were submitted for immunostaining. Immunostaining for CK5/ CD44 was scored as high for staining of >25% thickness of urothelium and low for lesser immunoreactivity. Results: In total, 109 consecutive cases were grouped into: in situ UC [carcinoma in situ (CIS)] (n = 11), pT1 (n = 14), and pT2-4 (n = 84) with surface urothelium available for study. Forty-four cases including CIS (n = 9), pT1 (n = 12), and pT2-4 (n = 23) showed FIUN with low/negative CD44/CK5 reactivity; 40 cases showed strong CK20 reactivity. Sixty-two cases including CIS (n = 2), pT1 (n = 2), and pT2-4 (n = 58) showed extensive FIUN exhibiting high CD44/CK5 reactivity; 30 cases showed reactive CK20. FIUN lesions with high CD44/CK5 reactivity scores were associated with mild (urothelial dysplasia) to moderate atypia (CIS) and were rarely preceded by papillary UC. Most invasive UC associated with FIUN with high CD44/CK5 reactivity also exhibited extensive CD44/CK5 reactivity. The remaining 3 cases showed only reactive urothelium. Of interest, 4 cases with FIUN showed negative CD44/CK5/CK20 reactivity. Conclusions: Existence of CD44/CK5-immunoreactive (or basal-like) FIUN is consistent with the recent distinction of basal and luminal subtypes of UC. This type of FIUN is often associated with UC with progression to high-stage disease not preceded by recurrent papillary UC.