{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T03:18:52Z","timestamp":1777000732958,"version":"3.51.4"},"reference-count":45,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2023,4,22]],"date-time":"2023-04-22T00:00:00Z","timestamp":1682121600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Upper tract urothelial carcinomas (UTUCs) occur in about 5\u201310% of all urothelial carcinomas and are frequently discovered in high-stage disease. We aimed to evaluate human epidermal growth factor receptor 2 (ERBB2) protein expression immunohistochemically and ERBB2 amplification in UTUCs by fluorescence in situ hybridization, applying a tissue microarray technique. ERBB2 overexpression and ERBB2 amplification were defined according to the recommendations of the American Society of Clinical Oncology\/College of American Pathologists (ASCO\/CAP) for breast cancer and gastric carcinoma (GC), revealing scores of 2+ and 3+ in 10.2% and 41.8% of UTUCs, respectively. The performance parameters showed obviously higher sensitivity of ERBB2 immunoscoring according to the ASCO\/CAP criteria for GC. ERBB2 amplification was detected in 10.5% of UTUCs. ERBB2 overexpression was more likely to be found in high-grade tumors and was associated with tumor progression. Univariable Cox regression analysis revealed a significantly lower progression-free survival (PFS) in cases with ERBB2 immunoscores of 2+ or 3+ according to the ASCO\/CAP guidelines for GC. UTUCs with ERBB2 amplification showed a significantly shorter PFS in the multivariable Cox regression analysis. Irrespective of their ERBB2 status, patients with UTUC treated with platin showed a significantly lower PFS than UTUC patients who had not received any platin-based therapy. In addition, UTUC patients with a normal ERBB2 gene status who had not received platin-based therapy showed significantly longer overall survival. The results suggest that ERBB2 is a biomarker for progression in UTUCs and may define a distinct subgroup of UTUCs. As previously shown, ERBB2 amplification is infrequent. However, the small number of patients diagnosed with ERBB2-amplified UTUC might benefit from ERBB2-targeted cancer therapy. In clinical\u2013pathological routine diagnostics, the determination of ERBB2 amplification is an established method in some defined entities and also successful in small samples. Still, the simultaneous use of ERBB2 immunohistochemistry and ERBB2 in situ hybridization would be important in order to record the low rate of amplified UTUC cases as completely as possible.<\/jats:p>","DOI":"10.3390\/cancers15092414","type":"journal-article","created":{"date-parts":[[2023,4,24]],"date-time":"2023-04-24T02:06:11Z","timestamp":1682301971000},"page":"2414","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["ERBB2 Amplification as a Predictive and Prognostic Biomarker in Upper Tract Urothelial Carcinoma"],"prefix":"10.3390","volume":"15","author":[{"given":"Annette","family":"Zimpfer","sequence":"first","affiliation":[{"name":"Institute of Pathology, University Medical Center Rostock, 18057 Rostock, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Said","family":"Kdimati","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University Medical Center Rostock, 18057 Rostock, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Melanie","family":"Mosig","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University Medical Center Rostock, 18057 Rostock, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henrik","family":"Rudolf","sequence":"additional","affiliation":[{"name":"Institute for Biostatistics and Informatics in Medicine and Ageing Research, University Medical Center Rostock, 18057 Rostock, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heike","family":"Zettl","sequence":"additional","affiliation":[{"name":"Clinical Cancer Registry, University of Rostock, 18055 Rostock, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andreas","family":"Erbersdobler","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University Medical Center Rostock, 18057 Rostock, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oliver W.","family":"Hakenberg","sequence":"additional","affiliation":[{"name":"Department of Urology, University Medical Center Rostock, 18057 Rostock, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthias","family":"Maruschke","sequence":"additional","affiliation":[{"name":"Department of Urology, University Medical Center Rostock, 18057 Rostock, Germany"},{"name":"Department of Urology, HELIOS Hanseklinikum, 18435 Stralsund, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0282-7330","authenticated-orcid":false,"given":"Bj\u00f6rn","family":"Schneider","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University Medical Center Rostock, 18057 Rostock, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,22]]},"reference":[{"key":"ref_1","first-page":"62","article-title":"European Association of Urology Guidelines on Upper Urinary Tract Urothelial Carcinoma: 2020 Update","volume":"79","author":"Babjuk","year":"2020","journal-title":"Eur. Urol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3322\/caac.21551","article-title":"Cancer statistics, 2019","volume":"69","author":"Siegel","year":"2019","journal-title":"CA Cancer J. Clin."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"868","DOI":"10.1016\/j.eururo.2015.06.044","article-title":"European Association of Urology Guidelines on Upper Urinary Tract Urothelial Cell Carcinoma: 2015 Update","volume":"68","author":"Babjuk","year":"2015","journal-title":"Eur. Urol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1545","DOI":"10.1097\/00000478-200412000-00001","article-title":"Urothelial carcinoma of the renal pelvis: A clinicopathologic study of 130 cases","volume":"28","author":"Olgac","year":"2004","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1159\/000457133","article-title":"Upper Urinary Tract Tumors: Which Diagnostic Methods Are Needed?","volume":"98","author":"Maruschke","year":"2017","journal-title":"Urol. Int."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1224","DOI":"10.1002\/cncr.24135","article-title":"Outcomes of Radical Nephroureterectomy: A Series from the Upper Tract Urothelial Carcinoma Collaboration","volume":"115","author":"Margulis","year":"2009","journal-title":"Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1016\/j.urology.2010.04.020","article-title":"Troubling outcomes from population-level analysis of surgery for upper tract urothelial carcinoma","volume":"76","author":"Abouassaly","year":"2010","journal-title":"Urology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/j.urology.2009.10.004","article-title":"A population-based assessment of perioperative mortality after nephroureterectomy for upper-tract urothelial carcinoma","volume":"75","author":"Jeldres","year":"2010","journal-title":"Urology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1268","DOI":"10.1016\/S0140-6736(20)30415-3","article-title":"Adjuvant chemotherapy in upper tract urothelial carcinoma (the POUT trial): A phase 3, open-label, randomised controlled trial","volume":"395","author":"Birtle","year":"2020","journal-title":"Lancet"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"6469","DOI":"10.1038\/sj.onc.1210477","article-title":"The oncogene HER2: Its signaling and transforming functions and its role in human cancer pathogenesis","volume":"26","author":"Moasser","year":"2007","journal-title":"Oncogene"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"6570","DOI":"10.1038\/sj.onc.1206779","article-title":"Biologic and therapeutic role of HER2 in cancer","volume":"22","author":"Pupa","year":"2003","journal-title":"Oncogene"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Torres-Jim\u00e9nez, J., Esteban-Villarrubia, J., and Ferreiro-Monteagudo, R. (2022). Precision Medicine in Metastatic Colorectal Cancer: Targeting ERBB2 (HER-2) Oncogene. Cancers, 14.","DOI":"10.3390\/cancers14153718"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1007\/s10555-015-9552-6","article-title":"HER2 expression status in diverse cancers: Review of results from 37,992 patients","volume":"34","author":"Yan","year":"2015","journal-title":"Cancer Metastasis Rev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1038\/nrc2127","article-title":"Insights from transgenic mouse models of ERBB2-induced breast cancer","volume":"7","author":"Schade","year":"2007","journal-title":"Nat. Rev. Cancer"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1016\/S0140-6736(10)61121-X","article-title":"Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): A phase 3, open-label, randomised controlled trial","volume":"376","author":"Bang","year":"2010","journal-title":"Lancet"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1158\/1078-0432.CCR-18-2039","article-title":"Clonal Relatedness and Mutational Differences between Upper Tract and Bladder Urothelial Carcinoma","volume":"25","author":"Audenet","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1007\/s12253-017-0260-0","article-title":"HER2 and TOP2A Gene Amplification and Protein Expression in Upper Tract Urothelial Carcinomas","volume":"24","author":"Aumayr","year":"2018","journal-title":"Pathol. Oncol. Res."},{"key":"ref_18","first-page":"2544","article-title":"Human epidermal growth factor receptor 2 expression in urothelial carcinoma of the renal pelvis: Correlation with clinicopathologic parameters","volume":"7","author":"Ehsani","year":"2014","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_19","first-page":"653","article-title":"ErbB2, ErbB3 and ErbB4 expression in urothelial tumors of the upper urinary tract and their prognostic significance","volume":"18","author":"Galanakis","year":"2013","journal-title":"J. BUON"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1038\/bjc.1995.14","article-title":"Significance of epidermal growth factor receptor and c-erbB-2 protein expression in transitional cell cancer of the upper urinary tract for tumour recurrence at the urinary bladder","volume":"71","author":"Imai","year":"1995","journal-title":"Br. J. Cancer"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"436","DOI":"10.4132\/jptm.2016.07.12","article-title":"Comparison of the FDA and ASCO\/CAP Criteria for HER2 Immunohistochemistry in Upper Urinary Tract Urothelial Carcinoma","volume":"50","author":"Kim","year":"2016","journal-title":"J. Pathol. Transl. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.urology.2004.08.025","article-title":"HER2 protein overexpression and gene amplification in upper urinary tract transitional cell carcinoma: Systematic analysis applying tissue microarray technique","volume":"65","author":"Langner","year":"2005","journal-title":"Urology"},{"key":"ref_23","first-page":"699","article-title":"HER2 protein overexpression and gene amplification in upper urinary tract urothelial carcinoma-an analysis of 171 patients","volume":"7","author":"Sasaki","year":"2014","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1007\/s00345-016-1871-x","article-title":"HER2 overexpression is associated with worse outcomes in patients with upper tract urothelial carcinoma (UTUC)","volume":"35","author":"Soria","year":"2017","journal-title":"World J. Urol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1016\/j.urology.2005.06.117","article-title":"Frequency and clinicopathologic correlates of ErbB1, ErbB2, and ErbB3 immunoreactivity in urothelial tumors of upper urinary tract","volume":"66","author":"Tsai","year":"2005","journal-title":"Urology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1097\/PAI.0b013e318241cab9","article-title":"Assessment of human epidermal growth factor receptor 2 status in urothelial carcinoma of the upper urinary tract: A study using dual-color in situ hybridization and immunohistochemistry","volume":"20","author":"Colin","year":"2012","journal-title":"Appl. Immunohistochem. Mol. Morphol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e443","DOI":"10.1016\/j.clgc.2019.12.003","article-title":"HER2 Status in Molecular Subtypes of Urothelial Carcinoma of the Renal Pelvis and Ureter","volume":"18","author":"Yorozu","year":"2020","journal-title":"Clin. Genitourin. Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1915","DOI":"10.1007\/s00432-010-0850-7","article-title":"Role of anti-Her-2 therapy in bladder carcinoma","volume":"136","author":"Arranz","year":"2010","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1364","DOI":"10.5858\/arpa.2018-0902-SA","article-title":"Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology\/College of American Pathologists Clinical Practice Guideline Focused Update","volume":"142","author":"Wolff","year":"2018","journal-title":"Arch. Pathol. Lab. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1200\/JCO.2016.69.4836","article-title":"HER2 Testing and Clinical Decision Making in Gastroesophageal Adenocarcinoma: Guideline From the College of American Pathologists, American Society for Clinical Pathology, and the American Society of Clinical Oncology","volume":"35","author":"Bartley","year":"2017","journal-title":"J. Clin. Oncol."},{"key":"ref_31","unstructured":"Amin, M.B. (2022). WHO Classification of Tumours, International Agency for Research on Cancer. [5th ed.]."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Brierley, J.D., Gospodarowicz, M.K., and Wittekind, C. (2017). TNM Classification of Malignant Tumours, John Wiley & Sons, Inc.. [8th ed.].","DOI":"10.1002\/9780471420194.tnmc26.pub3"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1038\/nm0798-844","article-title":"Tissue microarrays for high-throughput molecular profiling of tumor specimens","volume":"4","author":"Kononen","year":"1998","journal-title":"Nat. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"E563","DOI":"10.1016\/j.clgc.2020.03.006","article-title":"Loss of Mismatch-repair Protein Expression and Microsatellite Instability in Upper Tract Urothelial Carcinoma and Clinicopathologic Implications","volume":"18","author":"Schneider","year":"2020","journal-title":"Clin. Genitourin. Cancer"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"R2","DOI":"10.1186\/bcr1843","article-title":"Cytogenetic analysis of HER1\/EGFR, HER2, HER3 and HER4 in 278 breast cancer patients","volume":"10","author":"Sassen","year":"2008","journal-title":"Breast Cancer Res."},{"key":"ref_36","unstructured":"Lenhard, W., and Lenhard, A. (2022, August 23). Berechnung von Testg\u00fctekriterien f\u00fcr Screeningverfahren. Available online: http:\/\/www.psychometrica.de\/testkennwerte.html."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1337","DOI":"10.1093\/annonc\/mdp003","article-title":"Tissue microarray-based study of patients with lymph node-negative breast cancer shows that HER2\/neu overexpression is an important predictive marker of poor prognosis","volume":"20","author":"Choi","year":"2009","journal-title":"Ann. Oncol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1517\/14712598.2013.783007","article-title":"Pertuzumab: Evolving therapeutic strategies in the management of HER2-overexpressing breast cancer","volume":"13","author":"Swain","year":"2013","journal-title":"Expert Opin. Biol. Ther."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1200\/JCO.2006.09.2775","article-title":"American Society of Clinical Oncology\/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer","volume":"25","author":"Wolff","year":"2007","journal-title":"J. Clin. Oncol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3997","DOI":"10.1200\/JCO.2013.50.9984","article-title":"Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology\/College of American Pathologists clinical practice guideline update","volume":"31","author":"Wolff","year":"2013","journal-title":"J. Clin. Oncol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1007\/s11255-014-0866-z","article-title":"Prognostic role of HER2 expression in bladder cancer: A systematic review and meta-analysis","volume":"47","author":"Zhao","year":"2015","journal-title":"Int. Urol. Nephrol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1016\/j.clgc.2016.12.027","article-title":"High Neutrophil-to-lymphocyte Ratio as Prognostic Factor in Patients Affected by Upper Tract Urothelial Cancer: A Systematic Review and Meta-analysis","volume":"15","author":"Marchioni","year":"2017","journal-title":"Clin. Genitourin. Cancer"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1016\/j.eururo.2019.09.006","article-title":"A Consensus Molecular Classification of Muscle-invasive Bladder Cancer","volume":"77","author":"Kamoun","year":"2020","journal-title":"Eur. Urol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1111\/j.1464-410X.2012.11649.x","article-title":"Impact of renal function on eligibility for chemotherapy and survival in patients who have undergone radical nephro-ureterectomy","volume":"112","author":"Xylinas","year":"2013","journal-title":"BJU Int."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.ejca.2014.10.009","article-title":"Multicentre randomised phase II trial of gemcitabine+platinum, with or without trastuzumab, in advanced or metastatic urothelial carcinoma overexpressing Her2","volume":"51","author":"Oudard","year":"2015","journal-title":"Eur. J. Cancer"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/15\/9\/2414\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:21:20Z","timestamp":1760124080000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/15\/9\/2414"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,22]]},"references-count":45,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2023,5]]}},"alternative-id":["cancers15092414"],"URL":"https:\/\/doi.org\/10.3390\/cancers15092414","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,22]]}}}