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While the causative role of HPV in certain anogenital and head and neck carcinomas is well established, the role of HPV in carcinomas arising in the mucosal membranes of the ocular adnexal tissue (the lacrimal drainage system and the conjunctiva) has been a topic of great uncertainty. Therefore, we conducted a series of studies to assess the correlation between HPV and carcinomas arising in the mucosa of the ocular adnexal tissue and characterize the clinical, histopathological, and genomic features of the tumors in the context of HPV status in a Danish nationwide cohort.<\/jats:p><jats:p>We collected clinical and histopathological data and tumor specimens from patients with carcinomas of the conjunctiva and the lacrimal drainage system, and their potential precursors, identified in Danish nationwide registries. The HPV status of the tumors was determined by the combined use of HPV DNA polymerase chain reaction (PCR), HPV E6\/E7 mRNA in\u2010situ hybridization, and p16 immunohistochemistry. The genomic profile was investigated by high\u2010throughput DNA sequencing targeting 523 cancer\u2010relevant genes. The literature to date on carcinomas of the lacrimal drainage system and the conjunctiva was summarized.<\/jats:p><jats:p>In the Danish cohort, 67% of all carcinomas of the lacrimal drainage system and 21% of all conjunctival carcinomas were HPV\u2010positive. HPV16 was the most frequently implicated genotype. A full\u2010thickness expression of the viral oncogenes E6 and E7 was evident in almost all HPV DNA\u2010positive cases. The HPV\u2010positive carcinomas of the conjunctiva and the lacrimal drainage system shared histopathological and genomic features distinct from their HPV\u2010negative counterparts. The HPV\u2010positive carcinomas were characterized by a non\u2010keratinizing morphology, p16 overexpression, high transcriptional activity of HPV E6\/E7, and frequent pathogenic variants in the PI3K\u2010AKT signaling cascade. In contrast, the HPV\u2010negative carcinomas were characterized by a keratinizing morphology, lack of p16 and E6\/E7 expression, and frequent somatic pathogenic variants in <jats:italic>TP53<\/jats:italic>, <jats:italic>CDKN2A<\/jats:italic>, and <jats:italic>RB1<\/jats:italic>. Among the patients with conjunctival tumors, HPV positivity was associated with a younger age at diagnosis and a higher risk of recurrence.<\/jats:p><jats:p>In conclusion, the results support an etiological role of HPV in a subset of conjunctival and LDS carcinomas and their precursor lesions. Our investigations have shown that the HPV\u2010positive carcinomas of the ocular adnexa share genomic and phenotypic characteristics with HPV\u2010positive carcinomas of other anatomical locations. Therefore, these patients may be eligible for inclusion in future basket trials and future treatment regimens tailored to the more frequently occurring HPV\u2010positive carcinomas of other locations. Future research will further elucidate the diagnostic, prognostic, and predictive role of HPV in these carcinomas.<\/jats:p>","DOI":"10.1111\/aos.15244","type":"journal-article","created":{"date-parts":[[2022,10,7]],"date-time":"2022-10-07T03:30:56Z","timestamp":1665113456000},"page":"3-33","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Human papillomavirus\u2010related neoplasia of the ocular adnexa"],"prefix":"10.1111","volume":"100","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4980-5905","authenticated-orcid":false,"given":"Ingvild Margrethe Sell\u00e6g","family":"Ramberg","sequence":"first","affiliation":[{"name":"Faculty of Health and Medical Sciences University of Copenhagen  Copenhagen Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,10,6]]},"reference":[{"key":"e_1_2_12_2_1","unstructured":"Advanced Cell Diagnostics. 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