Expression of high molecular weight cytokeratin—A novel feature of aggressive and innate hormone‐refractory prostatic adenocarcinoma

Background Castration‐resistance is common in advanced prostatic adenocarcinomas (PACs) treated with androgen deprivation therapy (ADT) and usually occurs after 2 years following treatment. A minority of PACs confer innate ADT resistance without prior hormonal treatment. The expression of HMWCK in PAC cells has not been studied. This study aimed to investigate the clinicopathologic and genomic features of HMWCK‐expressing PACs and the relationship to ADT resistance. Methods A total of 469 PACs were studied for HMWCK expression (39 postradiotherapy, 57 post‐ADT, 373 treatment‐naïve PACs). Clinicopathologic correlations of the HMWCK expression with tumor grade groups, specific tumor morphologies, tumor stages and disease recurrence/persistence/progression were performed. Five HMWCK+ PACs were also sequenced for genetic alterations. Results Thirty one of the 469 cases (6.6%) showed variable HMWCK+ PAC. The HMWCK+ PAC often focally presented in the tumor and vast majority were associated with high Gleason scores and unfavorable growth patterns (cribriform, comedo‐necrosis, and intraductal carcinoma) as well as high tumor stages. A small percentage of the HMWCK+ PCA (2/31, 6.5%) presented with frank squamous histomorphology. Vast majority (22/31, 87%) had no history of prior ADT. The HMWCK+ PAC all displayed diminished to lost expression of AR/NKX3.1. Most of the cases progressed within 12 months of ADT or disease persisted despite ADT. Of the 5 HMWCK+ PACs subjected to gene sequencing, 4 presented with PTEN/PI3K/MAPK pathway alterations. Conclusion The study demonstrated HMWCK+ PAC to be a novel type of innate ADT‐resistant PAC. Overexpression of HMWCK in PAC can be potentially used as a surrogate biomarker for aggressive and innate hormone‐refractory PACs. The genetic alterations imply potential therapeutic implications of PI3K/MAPK inhibitors in the treatment of these deadly diseases.