{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,15]],"date-time":"2026-08-15T05:35:56Z","timestamp":1786772156937,"version":"build-2736575974"},"reference-count":24,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T00:00:00Z","timestamp":1782086400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Urol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Clear cell adenocarcinoma of the urethra (CCAU) is an extremely rare subtype of primary urethral carcinoma. Owing to its low incidence, the optimal treatment strategy for advanced or metastatic disease remains unclear. We report a case of advanced CCAU with lymph node metastases that achieved long-term disease control following multimodal therapy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Case presentation<\/jats:title>\n                    <jats:p>A 60-year-old woman presented with urinary retention and was diagnosed with primary urethral clear cell adenocarcinoma (cT4N2M0) with pelvic lymph node metastases. Neoadjuvant gemcitabine plus cisplatin (GC) chemotherapy achieved a partial response and was followed by robot-assisted radical cystourethrectomy combined with hysterectomy, vaginectomy, and pelvic lymph node dissection. Pathological examination revealed ypT4N2M0 disease with negative surgical margins. Adjuvant nivolumab was initiated but was discontinued because of immune-related hypothyroidism and nodal recurrence. Comprehensive genomic profiling demonstrated microsatellite stability, a low tumor mutational burden (1 mutation\/Mb), and MET and MYC amplifications. As no actionable alterations were identified, GC chemotherapy was reintroduced and again achieved a partial response. The patient remains progression-free 32 months after diagnosis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This case suggests that multimodal treatment combining radical surgery and platinum-based chemotherapy may contribute to durable disease control in selected patients with advanced CCAU and lymph node metastasis. Although genomic profiling did not directly guide therapy in this case, molecular characterization may provide a basis for future individualized treatment strategies for this rare malignancy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fruro.2026.1865730","type":"journal-article","created":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T04:37:49Z","timestamp":1782103069000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Durable disease control after multimodal therapy and platinum-based chemotherapy rechallenge in advanced clear cell adenocarcinoma of the urethra with lymph node metastases: a case report"],"prefix":"10.3389","volume":"6","author":[{"given":"Akihiro","family":"Maeda","sequence":"first","affiliation":[{"name":"Department of Urology, Faculty of Medicine, Saga University","place":["Saga, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shohei","family":"Tobu","sequence":"additional","affiliation":[{"name":"Department of Urology, Faculty of Medicine, Saga University","place":["Saga, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuhei","family":"Kusano","sequence":"additional","affiliation":[{"name":"Department of Urology, Faculty of Medicine, Saga University","place":["Saga, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maki","family":"Kawasaki","sequence":"additional","affiliation":[{"name":"Department of Urology, Faculty of Medicine, Saga University","place":["Saga, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroaki","family":"Kakinoki","sequence":"additional","affiliation":[{"name":"Department of Urology, Faculty of Medicine, Saga University","place":["Saga, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitsuru","family":"Noguchi","sequence":"additional","affiliation":[{"name":"Department of Urology, Faculty of Medicine, Saga University","place":["Saga, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1002\/iju5.12544","article-title":"A rare case of a clear cell carcinoma in a female urethral diverticulum","volume":"6","author":"Gonda","year":"2023","journal-title":"IJU Case Rep"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.4143\/crt.2023.577","article-title":"Clear cell adenocarcinoma of urethra: clinical and pathologic implications and characterization of molecular aberrations","volume":"56","author":"Song","year":"2024","journal-title":"Cancer Res Treat"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2025.1539312","article-title":"Two rare cases of primary clear cell adenocarcinoma of the urethra: clinical experience, case report and literature review","volume":"15","author":"Jiang","year":"2025","journal-title":"Front Oncol"},{"key":"B4","article-title":"EAU guidelines on primary urethral carcinoma","volume-title":"European Association of Urology","author":"Neuzillet","year":"2025"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.urology.2006.08.1057","article-title":"Incidence of primary urethral carcinoma in the United States","volume":"68","author":"Swartz","year":"2006","journal-title":"Urology"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1097\/pas.0000000000001569","article-title":"Primary female urethral carcinoma: proposed staging modifications based on assessment of female urethral histology and analysis of a large series of female urethral carcinomas","volume":"44","author":"Aron","year":"2020","journal-title":"Am J Surg Pathol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijscr.2021.106100","article-title":"Female primary urethral carcinoma: a rare case report","volume":"85","author":"Pratama","year":"2021","journal-title":"Int J Surg Case Rep"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.eucr.2021.101659","article-title":"Urethral clear cell carcinoma: case report and review of literature","volume":"38","author":"Al-Gonaim","year":"2021","journal-title":"Urol Case Rep"},{"key":"B9","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1186\/s12905-022-01835-6","article-title":"Primary clear cell adenocarcinoma of female urinary tract: a case report and literature review","volume":"22","author":"Miao","year":"2022","journal-title":"BMC Womens Health"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.eucr.2024.102882","article-title":"Urethral clear cell adenocarcinoma in an adult female: a rare case report","volume":"58","author":"Seman","year":"2025","journal-title":"Urol Case Rep"},{"key":"B11","article-title":"Clear cell adenocarcinoma of the urethra: a clinicopathologic analysis of 19 cases","volume":"9","author":"Oliva","year":"1996","journal-title":"Mod Pathol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1007\/s00192-025-06244-5","article-title":"Rethinking urethral diverticulum: a narrative review of clinical outcomes and cancer associations","volume":"36","author":"Daniels","year":"2025","journal-title":"Int Urogynecol J"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2022.07.002","article-title":"The 2022 World Health Organization classification of tumors of the urinary system and male genital organs-Part B: prostate and urinary tract tumors","volume":"82","author":"Netto","year":"2022","journal-title":"Eur Urol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.ccr-07-4147","article-title":"Histogenesis of clear cell adenocarcinoma in the urinary tract: evidence of urothelial origin","volume":"14","author":"Sung","year":"2008","journal-title":"Clin Cancer Res"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.modpat.2025.100821","article-title":"Comprehensive molecular, pathological, and clinical characterization of clear cell adenocarcinoma of the urinary tract","volume":"38","author":"Rammal","year":"2025","journal-title":"Mod Pathol"},{"key":"B16","doi-asserted-by":"crossref","DOI":"10.21037\/tlcr.2018.02.08","article-title":"Companion and complementary diagnostics for first-line immune checkpoint inhibitor treatment in non-small cell lung cancer","volume":"7","author":"J\u00f8rgensen","year":"2018","journal-title":"Transl Lung Cancer Res"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa1504627","article-title":"Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer","volume":"373","author":"Brahmer","year":"2015","journal-title":"N Engl J Med"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa2034442","article-title":"Adjuvant nivolumab versus placebo in muscle-invasive urothelial carcinoma","volume":"384","author":"Bajorin","year":"2021","journal-title":"N Engl J Med"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2023.01.016","article-title":"Disease-free survival analysis for patients with high-risk muscle-invasive urothelial carcinoma from the randomized CheckMate 274 trial by PD-L1 combined positive score and tumor cell score","volume":"83","author":"Galsky","year":"2023","journal-title":"Eur Urol"},{"key":"B20","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1007\/s12272-012-0402-6","article-title":"Progress in cancer therapy targeting c-Met signaling pathway","volume":"35","author":"Jung","year":"2012","journal-title":"Arch Pharm Res"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2017.03.005","article-title":"Pulmonary sarcomatoid carcinomas commonly harbor either potentially targetable genomic alterations or high tumor mutational burden as observed by comprehensive genomic profiling","volume":"12","author":"Schrock","year":"2017","journal-title":"J Thorac Oncol"},{"key":"B22","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1634\/theoncologist.2014-0378","article-title":"Prospective comprehensive genomic profiling of advanced gastric carcinoma cases reveals frequent clinically relevant genomic alterations and new routes for targeted therapies","volume":"20","author":"Ali","year":"2015","journal-title":"Oncologist"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2021.02.010","article-title":"Crizotinib in patients with MET-amplified NSCLC","volume":"16","author":"Camidge","year":"2021","journal-title":"J Thorac Oncol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.ccr-19-0994","article-title":"Crizotinib in MET-deregulated or ROS1-rearranged pretreated non-small cell lung cancer (METROS): a phase II, prospective, multicenter, two-arms trial","volume":"25","author":"Landi","year":"2019","journal-title":"Clin Cancer Res"}],"container-title":["Frontiers in Urology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fruro.2026.1865730\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T04:38:02Z","timestamp":1782103082000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fruro.2026.1865730\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,22]]},"references-count":24,"alternative-id":["10.3389\/fruro.2026.1865730"],"URL":"https:\/\/doi.org\/10.3389\/fruro.2026.1865730","relation":{},"ISSN":["2673-9828"],"issn-type":[{"value":"2673-9828","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,22]]},"article-number":"1865730"}}