{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T01:26:05Z","timestamp":1778635565694,"version":"3.51.4"},"reference-count":47,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2022,7,23]],"date-time":"2022-07-23T00:00:00Z","timestamp":1658534400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"DFG","award":["40947457"],"award-info":[{"award-number":["40947457"]}]},{"name":"Institutional Funds of the University of Tuebingen Hospital","award":["40947457"],"award-info":[{"award-number":["40947457"]}]},{"name":"Medical Faculty at the University of Tuebingen","award":["40947457"],"award-info":[{"award-number":["40947457"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Diagnosis and grading of non-invasive papillary urothelial tumors according to the current WHO classification poses some challenges for pathologists. The diagnostic reproducibility of separating low-grade and high-grade lesions is low, which impacts their clinical management. Whereas papillary urothelial neoplasms with low malignant potential (PUN-LMP) and low-grade papillary non-invasive carcinoma (LG-PUC) are comparable and show frequent local recurrence but rarely metastasize, high-grade papillary non-invasive carcinoma (HG-PUC) has a poor prognosis. The main objective of this work is to develop a multiparametric classification to unambiguously distinguish low-grade and high-grade tumors, considering immunohistochemical stains for p53, FGFR3, CK20, MIB-1, p16, p21 and p-HH3, and pathogenic mutations in TP53, FGFR3, TP53, ERCC2, PIK3CA, PTEN and STAG2. We reviewed and analyzed the clinical and histological data of 45 patients with a consensus diagnosis of PUN-LMP (n = 8), non-invasive LG-PUC (n = 23), and HG-PUC (n = 14). The proliferation index and mitotic count assessed with MIB-1 and P-HH3 staining, respectively correlated with grading and clinical behavior. Targeted sequencing confirmed frequent FGFR3 mutations in non-invasive papillary tumors and identified mutations in TP53 as high-risk. Cluster analysis of the different immunohistochemical and molecular parameters allowed a clear separation in two different clusters: cluster 1 corresponding to PUN-LMP and LG-PUC (low MIB-1 and mitotic count\/FGFR3 and STAG2 mutations) and cluster 2, HG-PUC (high MIB-1 and mitosis count\/CK20 +++ expression, FGFR3 WT and TP53 mutation). Further analysis is required to validate and analyze the reproducibility of these clusters and their biological and clinical implication.<\/jats:p>","DOI":"10.3390\/ijms23158133","type":"journal-article","created":{"date-parts":[[2022,7,24]],"date-time":"2022-07-24T22:49:02Z","timestamp":1658702942000},"page":"8133","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Multiparametric Classification of Non-Muscle Invasive Papillary Urothelial Neoplasms: Combining Morphological, Phenotypical, and Molecular Features for Improved Risk Stratification"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0636-7623","authenticated-orcid":false,"given":"Ivonne A.","family":"Montes-Mojarro","sequence":"first","affiliation":[{"name":"Institute of Pathology and Neuropathology and Comprehensive Cancer Center Tuebingen, Eberhard-Karls-University, 72076 Tuebingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Saki","family":"Hassas","sequence":"additional","affiliation":[{"name":"Institute of Pathology and Neuropathology and Comprehensive Cancer Center Tuebingen, Eberhard-Karls-University, 72076 Tuebingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sina","family":"Staehle","sequence":"additional","affiliation":[{"name":"Institute of Pathology and Neuropathology and Comprehensive Cancer Center Tuebingen, Eberhard-Karls-University, 72076 Tuebingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Philip","family":"Sander","sequence":"additional","affiliation":[{"name":"Institute of Pathology and Neuropathology and Comprehensive Cancer Center Tuebingen, Eberhard-Karls-University, 72076 Tuebingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5532-4868","authenticated-orcid":false,"given":"Niklas","family":"Harland","sequence":"additional","affiliation":[{"name":"Department of Urology, Eberhard-Karls-University, 72076 Tuebingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5182-8295","authenticated-orcid":false,"given":"Lina Maria","family":"Serna-Higuita","sequence":"additional","affiliation":[{"name":"Department of Clinical Epidemiology and Applied Biostatistics, Eberhard Karls University, 72076 Tuebingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7732-0788","authenticated-orcid":false,"given":"Irina","family":"Bonzheim","sequence":"additional","affiliation":[{"name":"Institute of Pathology and Neuropathology and Comprehensive Cancer Center Tuebingen, Eberhard-Karls-University, 72076 Tuebingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hans","family":"B\u00f6sm\u00fcller","sequence":"additional","affiliation":[{"name":"Institute of Pathology and Neuropathology and Comprehensive Cancer Center Tuebingen, Eberhard-Karls-University, 72076 Tuebingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4207-9928","authenticated-orcid":false,"given":"Arnulf","family":"Stenzl","sequence":"additional","affiliation":[{"name":"Department of Urology, Eberhard-Karls-University, 72076 Tuebingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5496-293X","authenticated-orcid":false,"given":"Falko","family":"Fend","sequence":"additional","affiliation":[{"name":"Institute of Pathology and Neuropathology and Comprehensive Cancer Center Tuebingen, Eberhard-Karls-University, 72076 Tuebingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1895","DOI":"10.1007\/s00345-019-02984-4","article-title":"The global burden of urinary bladder cancer: An update","volume":"38","author":"Richters","year":"2020","journal-title":"World J. 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