Primary urethral adenocarcinoma harbors recurrent KRAS and EGFR alterations.

Primary urethral adenocarcinoma is an extremely rare malignancy with an unclear pathogenesis. Previously, we reported 4 brachytherapy-associated (BA) urethral mucinous adenocarcinomas that developed following treatment for prostate cancer. In the present study, we report one additional BA and 3 radiation-independent (RI) urethral adenocarcinomas. The aim of this study is to explore the molecular alterations and to compare the clinicopathologic features. RNA sequencing was performed on 5 tumors, and a next-generation sequencing (NGS)-based fusion assay was used to identify gene fusions in 6 tumors. Additionally, NGS-based targeted genomic DNA sequencing was employed to analyze one metastatic BA tumor and one metastatic RI tumor. The 8 patients had a mean age of 67 (range: 37-87) years, with one being female in the RI cohort. Cystoscopy revealed the following urethral findings: a papillary lesion (4/7), mass causing obstruction (1/7) and irregular friable tissue (2/7). Seven patients underwent urethrectomy with cystectomy/prostatectomy/hysterectomy. The mean tumor size was 3.4 cm (range: 1.5-6.5). Adenocarcinoma in situ was noted in 5 tumors. All 5 BA tumors originated from the prostatic urethra, with 4 showing mucinous morphology and one enteric morphology, and showed moderate to poor differentiation and tumor stages of pT2 (2/4), pT3 (1/3) and pT4 (1/4). Two patients developed metastasis, one at 3.3 and one at 4.2 years after diagnosis, and all patients were alive at a median follow-up of 4.5 (range: 2-14) years. In contrast, 3 RI tumors arose from bulbar, prostatic, or female mid/distal urethra, presenting as enteric, mucinous, and not otherwise specified (NOS) subtypes, with well to moderate differentiation and a tumor stage of pT4 (2/2). Two died of the disease, while one was alive without disease at a median follow-up of 4 (range: 2.2-14.5) years. All tumors were diffusely positive for CK20, CDX2 (7/7), and AMACR (3/3), and lacked nuclear β-catenin expression (5/5). Most expressed CK7 (5/7). KRAS mutations (p.Gly12Val and p.Gly13Asp) were observed in one BA mucinous tumor and one RI NOS tumor with the p.Gly13Asp mutation also detected in the metastatic RI tumor. The EGFR p.Ser784Phe mutation was detected in one RI enteric tumor. TP53 p.Val172Phe, CDKN2A p.Leu32_Leu37del, and amplifications of EGFR and MDM2, were identified in a metastatic BA enteric tumor. No fusion transcripts were identified. In conclusion, urethral adenocarcinoma harbors recurrent KRAS and EGFR alterations, independent of prior radiotherapy. RI tumors appear to be associated with a worse prognosis compared to BA tumors.