{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T16:07:37Z","timestamp":1791389257072,"version":"4.3.3"},"reference-count":55,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2023,9,19]],"date-time":"2023-09-19T00:00:00Z","timestamp":1695081600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004622","name":"KWF Kankerbestrijding","doi-asserted-by":"publisher","award":["KWF 2016\u201010382"],"award-info":[{"award-number":["KWF 2016\u201010382"]}],"id":[{"id":"10.13039\/501100004622","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Histopathology"],"published-print":{"date-parts":[[2024,1]]},"abstract":"<jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>Adequate diagnosis of human papillomavirus (HPV)\u2010associated high\u2010grade squamous intraepithelial lesion (HSIL) and HPV\u2010independent vulvar intraepithelial neoplasia (VIN) is essential but can be challenging. We comprehensively characterized a large population\u2010based series of vulvar lesions, originally reported as high\u2010grade VIN, and assessed the cancer risk.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>\n                      Baseline high\u2010grade VIN of 751 patients were categorized by histopathological reassessment, integrating the results of immunohistochemistry (p16\n                      <jats:sup>INK4a<\/jats:sup>\n                      , p53, Ki\u201067) and HPV DNA testing. Integrated analyses resulted in 88.4% HPV\u2010associated lesions (77.0% HSIL, 10.9% low\u2010grade SIL [LSIL], and 0.4% vulvar squamous cell carcinoma [VSCC]), 10.9% HPV\u2010independent lesions (6.1% HPV\u2010independent VIN, 4.7% nondysplastic lesions, and 0.1% VSCC) and 1.1% inconclusive lesions. HSIL demonstrated p16\n                      <jats:sup>INK4a<\/jats:sup>\n                      block\u2010positivity in 99.0%, increased Ki\u201067 in \u22652\/3rd of the epithelium in 93.6%, and HPV positivity in 99.6%. In HSIL, a p53 wildtype mid\u2010epithelial staining pattern was common (51.6%) while this was not observed in HPV\u2010independent lesions. HPV\u2010independent VIN harboured mutant p53 patterns in 65.2% and showed a wide morphological spectrum, ranging from differentiated to nondifferentiated (\u2018HPV\u2010associated\u2010like\u2019, in 41.3%). Kaplan\u2013Meier analyses showed a 10\u2010year cancer risk of 8.0% in HPV\u2010associated HSIL, 67.4% in HPV\u2010independent VIN\/p53mutant, and 27.8% in HPV\u2010independent VIN\/p53wildtype. Strikingly, the 10\u2010year cancer risk was 73.3% in HPV\u2010independent VIN with nondifferentiated (\u2018HPV\u2010associated\u2010like\u2019) morphology.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Immunohistochemistry by p16\n                      <jats:sup>INK4a<\/jats:sup>\n                      and p53 is highly recommended for optimal categorization into HPV\u2010associated and HPV\u2010independent VIN, which is of utmost importance given the different cancer risk. The high cancer risk of HPV\u2010independent VIN underscores the need for surgical treatment and close follow\u2010up, especially in case of a p53 mutant pattern and\/or nondifferentiated morphology.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/his.15050","type":"journal-article","created":{"date-parts":[[2023,9,19]],"date-time":"2023-09-19T21:20:18Z","timestamp":1695158418000},"page":"301-314","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["High\u2010grade vulvar intraepithelial neoplasia: comprehensive characterization and long\u2010term vulvar carcinoma risk"],"prefix":"10.1111","volume":"84","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9159-5609","authenticated-orcid":false,"given":"Nikki B","family":"Thuijs","sequence":"first","affiliation":[{"name":"Amsterdam UMC Location Vrije Universiteit Amsterdam, Pathology  Amsterdam the Netherlands"},{"name":"Cancer Center Amsterdam, Imaging and Biomarkers  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"van Beurden","sequence":"additional","affiliation":[{"name":"Netherlands Cancer Institute\/Antoni Van Leeuwenhoek Hospital, CGOA, Gynecology  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvia","family":"Duin","sequence":"additional","affiliation":[{"name":"Amsterdam UMC Location Vrije Universiteit Amsterdam, Pathology  Amsterdam the Netherlands"},{"name":"Cancer Center Amsterdam, Imaging and Biomarkers  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dani\u00eblle A M","family":"Heideman","sequence":"additional","affiliation":[{"name":"Amsterdam UMC Location Vrije Universiteit Amsterdam, Pathology  Amsterdam the Netherlands"},{"name":"Cancer Center Amsterdam, Imaging and Biomarkers  Amsterdam the Netherlands"},{"name":"Department of Pathology and Medical Biology University Medical Center Groningen, University of Groningen  Groningen the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Berkhof","sequence":"additional","affiliation":[{"name":"Amsterdam UMC Location Vrije Universiteit Amsterdam, Epidemiology and Data Science  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renske D M","family":"Steenbergen","sequence":"additional","affiliation":[{"name":"Amsterdam UMC Location Vrije Universiteit Amsterdam, Pathology  Amsterdam the Netherlands"},{"name":"Cancer Center Amsterdam, Imaging and Biomarkers  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9610-8064","authenticated-orcid":false,"given":"Maaike C G","family":"Bleeker","sequence":"additional","affiliation":[{"name":"Amsterdam UMC Location Vrije Universiteit Amsterdam, Pathology  Amsterdam the Netherlands"},{"name":"Cancer Center Amsterdam, Imaging and Biomarkers  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,9,19]]},"reference":[{"key":"e_1_2_11_2_1","volume-title":"Female genital tumours: WHO classification of tumors","author":"Herrington CS","year":"2020"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1097\/LGT.0000000000000559"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(22)00469-X"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1136\/ijgc-2021-003262"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2008.11.037"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.33198"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/modpathol.2012.235"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00428-021-03070-0"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1097\/LGT.0000000000000572"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.5858\/arpa.LGT200570"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/his.14238"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2559.2005.02321.x"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1097\/PAS.0000000000001540"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1097\/PAS.0b013e3181b40081"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1136\/jclinpath-2018-205271"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/his.14109"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41379-020-0524-1"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.03195-13"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa021641"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1128\/jcm.35.3.791-795.1997"},{"key":"e_1_2_11_22_1","unstructured":"Central Office for Statistics (CBS).Bevolking; kerncijfers. [updated 2022 Date of access: 07\u201006\u20102019]. Available at:https:\/\/opendata.cbs.nl\/statline\/#\/CBS\/nl\/dataset\/37296ned\/table?ts=1530179088973."},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(23)00066-9"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.pas.0000213291.96401.48"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.MP.0000081051.55284.2A"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1097\/PGP.0000000000000364"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1097\/00128360-200504000-00007"},{"key":"e_1_2_11_28_1","first-page":"1209","article-title":"Relationship of human papillomavirus with seborrheic keratosis of the female genital tract \u2013 a case\u2010series and literature review","volume":"36","author":"Dasgupta S","year":"2021","journal-title":"Histol. Histopathol."},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.prp.2017.11.009"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1097\/PGP.0000000000000509"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.modpat.2023.100145"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41379-020-0527-y"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(90)90409-8"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.2157286"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.1711690407"},{"key":"e_1_2_11_36_1","first-page":"201","article-title":"Beyond p16 immunostaining: an overview of biomarkers in anal squamous intraepithelial lesions","volume":"34","author":"Albuquerque A","year":"2019","journal-title":"Histol. Histopathol."},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.15179"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.3390\/v10010045"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.modpat.2022.100010"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1111\/his.14860"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ygyno.2019.05.010"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21218091"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-17-1302"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.humpath.2009.11.015"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ygyno.2020.09.024"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.1097\/LGT.0000000000000678"},{"key":"e_1_2_11_47_1","doi-asserted-by":"publisher","DOI":"10.1111\/his.14442"},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41379-022-01079-7"},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.33459"},{"key":"e_1_2_11_50_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.34537"},{"key":"e_1_2_11_51_1","doi-asserted-by":"publisher","DOI":"10.3390\/ph14040324"},{"key":"e_1_2_11_52_1","doi-asserted-by":"publisher","DOI":"10.1097\/PGP.0000000000000317"},{"key":"e_1_2_11_53_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.pgp.0000177646.38266.6a"},{"key":"e_1_2_11_54_1","first-page":"21","article-title":"Lichen sclerosus and squamous cell carcinoma","volume":"103","author":"Gutierrez\u2010Pascual M","year":"2012","journal-title":"Actas Dermosifiliogr."},{"key":"e_1_2_11_55_1","doi-asserted-by":"publisher","DOI":"10.1097\/LGT.0000000000000169"},{"key":"e_1_2_11_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ygyno.2017.05.018"}],"container-title":["Histopathology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/his.15050","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,2]],"date-time":"2024-01-02T23:23:00Z","timestamp":1704237780000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/his.15050"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,19]]},"references-count":55,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2024,1]]}},"alternative-id":["10.1111\/his.15050"],"URL":"https:\/\/doi.org\/10.1111\/his.15050","archive":["Portico"],"relation":{},"ISSN":["0309-0167","1365-2559"],"issn-type":[{"value":"0309-0167","type":"print"},{"value":"1365-2559","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,9,19]]},"assertion":[{"value":"2023-06-15","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-08-31","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-09-19","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}