{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T14:46:30Z","timestamp":1793112390486,"version":"4.5.0"},"reference-count":24,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2024,10,25]],"date-time":"2024-10-25T00:00:00Z","timestamp":1729814400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Introduction<\/jats:title>\n<jats:p>The prognostic significance of nodal micrometastasis and isolated tumor cells (ITC) in urinary bladder cancer (UBC) is unknown. We aimed to evaluate the prevalence, clinical impact, and clinicopathological characteristics of nodal micrometastasis and ITC in UBC.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Materials and methods<\/jats:title>\n<jats:p>A total of 124 patients with UBC undergoing surgery were investigated. Detection of micrometastasis and ITC was performed using pancytokeratin immunohistochemistry (IHC). Histopathologic and clinical findings were correlated with patients\u2019 outcome.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Result<\/jats:title>\n<jats:p>IHC detected nodal micrometastasis and ITC (pNmi group) in 12.9% (13\/101) of originally node-negative patients and in 26.1% (6\/23) of originally node-positive patients (pN+ group). The remaining 88 were truly node-negative patients (pN0 group). After IHC, all 13 patients in the pNmi group were upstaged from pN0 to pN1-2 and one patient in the pN+ group was changed from pN1 to pN2. Nodal micrometastasis and ITC were significantly associated with mixed urothelial carcinoma (UC) (<jats:italic>p<\/jats:italic> = 0.002), UC with discohesive pattern (<jats:italic>p<\/jats:italic> = 0.006), glandular differentiation (<jats:italic>p<\/jats:italic> = 0.043), lymphovascular invasion (<jats:italic>p<\/jats:italic> = 0.009), and budding-like tumor cell clusters (<jats:italic>p<\/jats:italic> = 0.002). The pNmi group had significantly worse cancer-specific survival than the pN0 group in univariate (<jats:italic>p<\/jats:italic> = 0.004) and multivariate (<jats:italic>p<\/jats:italic> = 0.040) analysis.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusion<\/jats:title>\n<jats:p>IHC frequently identified nodal micrometastasis and ITC in originally node-negative UBC patients on routine pathological examination. Nodal micrometastasis and ITC were independently associated with cancer-related mortality in UBC. IHC might be selectively used to detect micrometastasis and ITC in UBC having specific pathological features.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0302445","type":"journal-article","created":{"date-parts":[[2024,10,25]],"date-time":"2024-10-25T17:30:01Z","timestamp":1729877401000},"page":"e0302445","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["Prognostic value of isolated tumor cells and micrometastasis of lymph nodes in invasive urinary bladder cancer"],"prefix":"10.1371","volume":"19","author":[{"given":"Harin","family":"Cheong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youngeun","family":"Yoo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sun Hee","family":"Sung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanghui","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong Hyeon","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyoung Ae","family":"Kong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1849-5120","authenticated-orcid":true,"given":"Heae Surng","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min-Sun","family":"Cho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,10,25]]},"reference":[{"key":"pone.0302445.ref001","volume-title":"AJCC Cancer Staging Manual","author":"Mahul B. Amin SBE","year":"2017","edition":"8"},{"issue":"1","key":"pone.0302445.ref002","first-page":"15","article-title":"Epidemiology of Bladder Cancer.","volume":"8","author":"K Saginala","year":"2020","journal-title":"Med Sci"},{"issue":"9","key":"pone.0302445.ref003","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.6004\/jnccn.2018.0072","article-title":"NCCN guidelines insights: bladder cancer, version 5.2018.","volume":"16","author":"TW Flaig","year":"2018","journal-title":"Journal of the National Comprehensive Cancer Network."},{"issue":"10","key":"pone.0302445.ref004","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.6004\/jnccn.2016.0131","article-title":"NCCN guidelines insights: bladder cancer, version 2.2016.","volume":"14","author":"PE Clark","year":"2016","journal-title":"Journal of the National Comprehensive Cancer Network."},{"issue":"5","key":"pone.0302445.ref005","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1093\/ajcp\/112.5.649","article-title":"Can immunohistochemistry enhance the detection of micrometastases in pelvic lymph nodes from patients with high-grade urothelial carcinoma of the bladder?","volume":"112","author":"XJ Yang","year":"1999","journal-title":"Am J Clin Pathol"},{"issue":"6","key":"pone.0302445.ref006","doi-asserted-by":"crossref","first-page":"419","DOI":"10.3109\/00365599.2011.599336","article-title":"Incidence of occult lymph-node metastasis missed by standard pathological examination in patients with bladder cancer undergoing radical cystectomy","volume":"45","author":"JB Jensen","year":"2011","journal-title":"Scandinavian journal of urology and nephrology"},{"issue":"9","key":"pone.0302445.ref007","doi-asserted-by":"crossref","first-page":"874","DOI":"10.1093\/jjco\/hyv091","article-title":"Prospective mapping of lymph node metastasis in Japanese patients undergoing radical cystectomy for bladder cancer: characteristics of micrometastasis","volume":"45","author":"R Matsumoto","year":"2015","journal-title":"Japanese journal of clinical oncology"},{"issue":"1","key":"pone.0302445.ref008","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s41241-016-0005-5","article-title":"Diagnosis of micrometastasis in muscle invasive bladder cancer through immunohistochemistry analysis: is there indication for routine evaluation?","volume":"36","author":"G Cuck","year":"2016","journal-title":"Applied Cancer Research"},{"issue":"1","key":"pone.0302445.ref009","doi-asserted-by":"crossref","first-page":"28","DOI":"10.4103\/2278-330X.149946","article-title":"Immunohistochemical detection of axillary lymph node micrometastases in node negative breast cancer patients using cytokeratin and epithelial membrane antigen","volume":"4","author":"M Choudhury","year":"2015","journal-title":"South Asian J Cancer"},{"key":"pone.0302445.ref010","unstructured":"Ed. Molch H. WHO Classification of Tumours of the Urinary System and Male Genital Organs 4th Edition. 4th ed2016."},{"issue":"1","key":"pone.0302445.ref011","first-page":"60","article-title":"Prospective evaluation of the prognostic relevance of molecular staging for urothelial carcinoma. Cancer","volume":"107","author":"HL Copp","year":"2006","journal-title":"Interdisciplinary International Journal of the American Cancer Society"},{"issue":"10","key":"pone.0302445.ref012","doi-asserted-by":"crossref","first-page":"3773","DOI":"10.1158\/1078-0432.CCR-04-2297","article-title":"Detection of micrometastases in pelvic lymph nodes in patients undergoing radical cystectomy for focally invasive bladder cancer by real-time reverse transcriptase-PCR for cytokeratin 19 and uroplakin II","volume":"11","author":"T Kurahashi","year":"2005","journal-title":"Clinical cancer research"},{"issue":"6","key":"pone.0302445.ref013","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1016\/j.eururo.2008.04.059","article-title":"Molecular lymph node staging in bladder urothelial carcinoma: impact on survival.","volume":"54","author":"M Mar\u00edn-Aguilera","year":"2008","journal-title":"European urology"},{"issue":"9","key":"pone.0302445.ref014","doi-asserted-by":"crossref","first-page":"1310","DOI":"10.1111\/j.1464-410X.2012.11025.x","article-title":"Biomarkers vs conventional histological analysis to detect lymph node micrometastases in bladder cancer: a real improvement?","volume":"110","author":"C Gazquez","year":"2012","journal-title":"BJU international."},{"issue":"5","key":"pone.0302445.ref015","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1016\/j.ejso.2005.01.001","article-title":"The prognostic significance of axillary lymph-node micrometastases in breast cancer patients","volume":"31","author":"GP Kuijt","year":"2005","journal-title":"Eur J Surg Oncol"},{"issue":"3","key":"pone.0302445.ref016","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1111\/j.1075-122X.2004.21328.x","article-title":"Occult metastases in axillary lymph nodes as a predictor of survival in node\u2010negative breast carcinoma with long\u2010term follow\u2010up","volume":"10","author":"W Reed","year":"2004","journal-title":"The breast journal"},{"issue":"4","key":"pone.0302445.ref017","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1111\/j.1075-122X.2006.00267.x","article-title":"Biological significance of occult micrometastases in histologically negative axillary lymph nodes in breast cancer patients using the recent American Joint Committee on Cancer breast cancer staging system","volume":"12","author":"HJ Kahn","year":"2006","journal-title":"The breast journal"},{"issue":"3","key":"pone.0302445.ref018","first-page":"171","article-title":"Immunohistochemical detection and significance of axillary lymph node micrometastases in breast carcinoma. A study of 97 cases.","volume":"15","author":"C Elson","year":"1993","journal-title":"Analytical and quantitative cytology and histology."},{"issue":"10","key":"pone.0302445.ref019","doi-asserted-by":"crossref","first-page":"1315","DOI":"10.1038\/modpathol.2012.94","article-title":"Tumor budding in colorectal carcinoma: time to take notice.","volume":"25","author":"B Mitrovic","year":"2012","journal-title":"Modern Pathology"},{"issue":"4","key":"pone.0302445.ref020","doi-asserted-by":"crossref","first-page":"273","DOI":"10.5152\/tud.2018.58269","article-title":"Prognostic significance of tumor budding in muscle invasive urothelial carcinomas of the bladder","volume":"45","author":"\u00dc K\u00fc\u00e7\u00fck","year":"2019","journal-title":"Turkish journal of urology"},{"issue":"9","key":"pone.0302445.ref021","doi-asserted-by":"crossref","first-page":"1338","DOI":"10.1111\/cas.12990","article-title":"Tumor budding, a novel prognostic indicator for predicting stage progression in T1 bladder cancers","volume":"107","author":"K Fukumoto","year":"2016","journal-title":"Cancer science"},{"key":"pone.0302445.ref022","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.urology.2019.04.006","article-title":"Tumor budding: prognostic value in muscle-invasive bladder cancer","volume":"130","author":"LL Soriano","year":"2019","journal-title":"Urology"},{"issue":"6","key":"pone.0302445.ref023","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1007\/s00428-014-1580-z","article-title":"Poorly differentiated clusters (PDCs) as a novel histological predictor of nodal metastases in pT1 colorectal cancer.","volume":"464","author":"V Barresi","year":"2014","journal-title":"Virchows Archiv"},{"issue":"2","key":"pone.0302445.ref024","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1097\/PAS.0b013e318235edee","article-title":"New criteria for histologic grading of colorectal cancer.","volume":"36","author":"H Ueno","year":"2012","journal-title":"The American journal of surgical pathology"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0302445","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,25]],"date-time":"2024-10-25T17:30:10Z","timestamp":1729877410000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0302445"}},"subtitle":[],"editor":[{"given":"Lorenzo","family":"Faggioni","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2024,10,25]]},"references-count":24,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2024,10,25]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0302445","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10,25]]}}}