{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T01:51:59Z","timestamp":1792461119547,"version":"4.5.0"},"reference-count":40,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2021,8,4]],"date-time":"2021-08-04T00:00:00Z","timestamp":1628035200000},"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":["2016\u201010781"],"award-info":[{"award-number":["2016\u201010781"]}],"id":[{"id":"10.13039\/501100004622","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Intl Journal of Cancer"],"published-print":{"date-parts":[[2021,11,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Human papillomavirus (HPV)\u2010induced anal intraepithelial neoplasia (AIN, graded 1\u20103) is highly prevalent in HIV\u2010positive (HIV+) men who have sex with men (MSM), but only a minority of lesions progresses to cancer. Our study aimed to characterise comprehensively anal tissue samples from a cross\u2010sectional series (n\u00a0=\u00a0104) of HIV+\u2009MSM and longitudinal series (n\u00a0=\u00a040) of AIN2\/3 progressing to cancer using different biomarkers. The cross\u2010sectional series consisted of 8 normal, 26 AIN1, 45 AIN2, 15 AIN3 and 10 anal squamous cell carcinoma. Tissue sections were immunohistochemically (IHC) stained for p16 (viral transformation marker), Ki\u201067 (cellular proliferation marker) and HPV\u2010E4 (viral production marker). We evaluated the expression of IHC markers and compared it with DNA methylation, a marker for malignant transformation. E4 positivity decreased, whereas p16 and Ki\u201067 scores and methylation marker positivity increased (\n                    <jats:italic>P<\/jats:italic>\n                    \u00a0values\u2009&lt;\u2009.001) with increasing severity of anal lesions. Within AIN2, a heterogeneous biomarker pattern was observed concerning E4, p16 and methylation status, reflecting the biological heterogeneity of these lesions. In the longitudinal series, all AIN2\/3 and carcinomas showed high p16 and Ki\u201067 expression, strong methylation positivity and occasional E4 positivity. We earlier showed that high methylation levels are associated with progression to cancer. The observed E4 expression in some AIN2\/3 during the course of progression to cancer and absence of E4 in a considerable number of AIN1 lesions make the potential clinical significance of E4 expression difficult to interpret. Our data show that IHC biomarkers can help to characterise AIN; however, their prognostic value for cancer risk stratification, next to objective methylation analysis, appears to be limited.\n                  <\/jats:p>","DOI":"10.1002\/ijc.33748","type":"journal-article","created":{"date-parts":[[2021,7,26]],"date-time":"2021-07-26T13:27:25Z","timestamp":1627306045000},"page":"1833-1844","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Characterisation of anal intraepithelial neoplasia and anal cancer in\n                    <scp>HIV<\/scp>\n                    \u2010positive men by immunohistochemical markers p16, Ki\u201067,\n                    <scp>HPV\u2010E4<\/scp>\n                    and\n                    <scp>DNA<\/scp>\n                    methylation markers"],"prefix":"10.1002","volume":"149","author":[{"given":"Ramon P.","family":"van der Zee","sequence":"first","affiliation":[{"name":"Department of Pathology, Cancer Center Amsterdam (CCA) Amsterdam University Medical Centers (Amsterdam UMC), Vrije Universiteit Amsterdam  Amsterdam The Netherlands"},{"name":"Department of Internal Medicine, Division of Infectious Diseases, Amsterdam Institute for Infection and Immunity (AII) Amsterdam UMC, University of Amsterdam  Amsterdam The Netherlands"},{"name":"Department of Dermatology Amsterdam UMC, University of Amsterdam  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris J. L. M.","family":"Meijer","sequence":"additional","affiliation":[{"name":"Department of Pathology, Cancer Center Amsterdam (CCA) Amsterdam University Medical Centers (Amsterdam UMC), Vrije Universiteit Amsterdam  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamzin","family":"Cuming","sequence":"additional","affiliation":[{"name":"Anal Neoplasia Service Homerton University Hospital  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Kreuter","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Venerology and Allergology Helios St. Elisabeth Hospital Oberhausen, University Witten\/Herdecke  Oberhausen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miekel M.","family":"van de Sandt","sequence":"additional","affiliation":[{"name":"DDL Diagnostic Laboratory  Rijswijk The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wim G. V.","family":"Quint","sequence":"additional","affiliation":[{"name":"DDL Diagnostic Laboratory  Rijswijk The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henry J. C.","family":"de Vries","sequence":"additional","affiliation":[{"name":"Department of Dermatology Amsterdam UMC, University of Amsterdam  Amsterdam The Netherlands"},{"name":"Department of Infectious Diseases, STI Outpatient Clinic Public Health Service of Amsterdam (GGD Amsterdam)  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan M.","family":"Prins","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Infectious Diseases, Amsterdam Institute for Infection and Immunity (AII) Amsterdam UMC, University of Amsterdam  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2327-9839","authenticated-orcid":false,"given":"Renske D. M.","family":"Steenbergen","sequence":"additional","affiliation":[{"name":"Department of Pathology, Cancer Center Amsterdam (CCA) Amsterdam University Medical Centers (Amsterdam UMC), Vrije Universiteit Amsterdam  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,8,4]]},"reference":[{"key":"e_1_2_10_2_1","first-page":"924","article-title":"International trends in anal cancer incidence rates","volume":"46","author":"Islami F","year":"2017","journal-title":"Int J Epidemiol"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.33185"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.24215"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.28431"},{"key":"e_1_2_10_6_1","first-page":"343","article-title":"Intraepithelial neoplasia in the anal canal. 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