Marked attenuation of P63 expression in plasmacytoid urothelial carcinoma with expanded immunohistochemical framework including E-cadherin, P120, HER2 and TRPS1

Abstract

Aims Plasmacytoid urothelial carcinoma (PUC) is an aggressive morphological subtype characterized by discohesive single-cell infiltration and frequent loss of epithelial adhesion. Although p63 is widely regarded as a reliable urothelial lineage marker in conventional urothelial carcinoma, its expression may be reduced or absent in plasmacytoid tumours, creating an important diagnostic pitfall. This multi-institutional study aimed to characterize the clinicopathological and immunohistochemical profile of PUC, with particular emphasis on p63 immunoreactivity and its relationship to adhesion-related markers and other diagnostically relevant immunophenotypes.Methods and results A total of 93 cases initially diagnosed as PUC were retrospectively reviewed across multiple centres. After histopathological re-evaluation, 70 confirmed cases were included. Immunohistochemical analysis was performed for p63, e-cadherin, p120 catenin, TRPS1, HER2/Neu. The cohort comprised 70 patients with a median age of 66.5 years (IQR, 59.8-72.0) and a strong male predominance of 85.7% (60/70). Most specimens were obtained from transurethral resections (64.3%, 45/70) and radical cystectomy specimens (34.3%, 24/70). The median tumour size was 3.0 cm (IQR, 1.0-5.0), and the median proportion of plasmacytoid differentiation was 80% (IQR, 20-100). Morphologically, tumours were classified as classic plasmacytoid in 65.7% (46/70), pleomorphic in 22.9% (16/70) and desmoplastic in 11.4% (8/70). Concurrent variant histology was identified in 21.4% (15/70), most commonly micropapillary (12.9%, 9/70) and sarcomatoid (7.1%, 5/70) components. Lymphovascular invasion was present in 51.4% (36/70), and concomitant carcinoma in situ was detected in 35.7% (25/70). Immunohistochemically, p63 expression was retained in only 10.0% of tumours (7/70). HER2 membranous overexpression was observed in 58.6% (41/70), while loss of E-cadherin expression was highly prevalent (84.3%, 59/70). Aberrant p120 catenin expression was common, with cytoplasmic localization in 72.9% (51/70) and complete loss in 17.1% (12/70). TRPS1 immunostaining was available in 54 tumours and was negative in 92.6% of evaluable cases (50/54).Conclusion PUC demonstrates a distinctive immunophenotype characterized by frequent loss of p63 and disruption of the e-cadherin/p120 adhesion complex. Recognition of p63 attenuation, together with adhesion-related markers and HER2 status, provides a useful diagnostic framework for distinguishing this aggressive subtype from conventional urothelial carcinoma and its mimickers.