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. 2022 Oct;100 Suppl 272(Suppl 272):3-33.
doi: 10.1111/aos.15244.

Human papillomavirus-related neoplasia of the ocular adnexa

Ingvild Margrethe Sellaeg Ramberg  1
Affiliations

Human papillomavirus-related neoplasia of the ocular adnexa

Ingvild Margrethe Sellaeg Ramberg. Acta Ophthalmol. 2022 Oct.

Abstract
in English, French

Human papillomaviruses (HPV) are involved in approximately 5% of solid cancers worldwide. The mucosotropic genotypes infect the stratified epithelium of various locations, where persistent infection may lead to invasive carcinomas. 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. 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-situ hybridization, and p16 immunohistochemistry. The genomic profile was investigated by high-throughput DNA sequencing targeting 523 cancer-relevant genes. The literature to date on carcinomas of the lacrimal drainage system and the conjunctiva was summarized. In the Danish cohort, 67% of all carcinomas of the lacrimal drainage system and 21% of all conjunctival carcinomas were HPV-positive. HPV16 was the most frequently implicated genotype. A full-thickness expression of the viral oncogenes E6 and E7 was evident in almost all HPV DNA-positive cases. The HPV-positive carcinomas of the conjunctiva and the lacrimal drainage system shared histopathological and genomic features distinct from their HPV-negative counterparts. The HPV-positive carcinomas were characterized by a non-keratinizing morphology, p16 overexpression, high transcriptional activity of HPV E6/E7, and frequent pathogenic variants in the PI3K-AKT signaling cascade. In contrast, the HPV-negative carcinomas were characterized by a keratinizing morphology, lack of p16 and E6/E7 expression, and frequent somatic pathogenic variants in TP53, CDKN2A, and RB1. Among the patients with conjunctival tumors, HPV positivity was associated with a younger age at diagnosis and a higher risk of recurrence. 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-positive carcinomas of the ocular adnexa share genomic and phenotypic characteristics with HPV-positive 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-positive carcinomas of other locations. Future research will further elucidate the diagnostic, prognostic, and predictive role of HPV in these carcinomas.

Human papillomavirus (HPV) forårsager ca. 5% af alle non-haematologiske cancertilfaelde på verdensplan. De slimhindeafficerende genotyper inficerer flerlagede pladeepitheler i forskellige anatomiske lokalisationer, og en persisterende infektion kan medføre cancerudvikling. Den kausale rolle for HPV i udviklingen af visse anogenitale og for hoved-hals cancer er veletableret, men rollen i udviklingen af carcinomer i det okulaere adnexa (conjunctiva og tårevejene) er stadig behaeftet med usikkerhed. Vi udførte derfor en serie af studier for at undersøge sammenhaengen mellem HPV og udviklingen af carcinom i conjunctiva og tårevejene og karakterisere den kliniske, histologiske og genetiske profil af tumorerne baseret på HPV-status i en landsdaekkende, dansk kohorte. Ved brug af landsdaekkende patientregistre, indsamlede vi kliniske og histopatologiske data samt tumormateriale fra patienter diagnosticeret med carcinom i conjunctiva eller tårevejene og deres potentielle forstadier. Undersøgelser for HPV i tumormaterialet blev foretaget ved p16 immunhistokemi, HPV DNA polymerase chain reaction (PCR) og ved HPV E6/E7 mRNA in-situ hybridisering. Den genetiske profil blev undersøgt ved high-throughput DNA-sekventering målrettet 523 cancer-relevante gener. Litteraturen omhandlende associationen mellem HPV og conjunctival intraepithelial neoplasi og carcinom blev gennemgået. I det danske materiale var 67% af tårevejscarcinomerne og 21% af alle conjunctivale carcinomer HPV-positive. I begge lokalisationer var HPV16 den hyppigste genotype. Alle HPV-positive tumorer, fraset én, udtrykte ekspression af de virale onkogener E6 og E7. Histopatologiske og genetiske undersøgelser viste at de HPV-positive carcinomer udgået fra conjunctiva og tårevejene delte genotypiske og faenotypiske traek der adskilte dem fra de HPV-negative carcinomer. De HPV-positive carcinomer var karakterisereret af en ikke-keratiniserende morfologi, p16-ekspression, udtalt ekspression af HPV E6/E7 og hyppige patogene varianter i PI3K-AKT signalleringskaskaden. Derimod var de HPV-negative carcinomer karakteriseret af en keratiniserende morfologi og hyppige patogene varianter i TP53, CDKN2A, og RB1. For at konkludere, støtter vores resultater op om at HPV spiller en kausal rolle i subgrupper af carcinomer og deres forstadier der udgår fra conjunctiva og tårevejene. Vores undersøgelser har vist, at de HPV-positive carcinomer deler genetiske og faenotypiske karakteristika med HPV-positive carcinomer i andre anatomiske lokalisationer. Det er derfor muligt, at disse patienter kan indgå i fremtidige basket-trials og kan drage nytte af de behandlingsmetoder der udvikles til hyppigere forekomne HPV-positive carcinomer. Fremtidig forskning vil videre afgøre den diagnostiske, prognostiske, og praediktive vaerdi af HPV i carcinomer i det okulaere adnexa.

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Figures

FIGURE 1
FIGURE 1
A timeline illustrating important aspects in the history of human papillomavirus (HPV) and their implication in cancer. Events regarding HPV in ocular adnexal tissue is marked in red. IARC: International Agency for Reseach on Cancer. The figure is created with Biorender.com.
FIGURE 2
FIGURE 2
The phylogenetic tree of the human papillomaviruses shows the evolutionary relationship between human papillomaviruses as of 2015. More genotypes have now officially been established, and by 1 September 2021 the total number of HPVs is 228. Genotypes that are considered carcinogenic in cervical cancer (“high‐risk genotypes”) by the International Agency for Research on Cancer are written in red. The figure is from Egawa et al., Human Papillomaviruses; Epithelial Tropisms, and the Development of Neoplasia. Viruses (2015):7:3863–3890 and is published under the CC‐BY 4.0 license (Egawa et al., 2015).
FIGURE 3
FIGURE 3
Inactivation of pRb, by phosphorylation or inactivation by HPV E7, activates the transcription factor family E2F at the G1/S checkpoint of mitosis. The progression of the cell cycle leads to a compensatory expression of the tumor suppressor p16. The figure is created with BioRender.com.
FIGURE 4
FIGURE 4
The epithelia of the conjunctiva and the lacrimal drainage system from Ramberg I, Heegaard S. Human Papillomavirus Related Neoplasia of the Ocular Adnexa. Viruses. 2021. 13:1522. Published under the CC‐BY license.
FIGURE 5
FIGURE 5
An overview of the patient material included in the present thesis.
FIGURE 6
FIGURE 6
Morphology and p16 expression in conjunctival squamous cell carcinoma (SCC). (a) A moderately differentiated, basaloid conjunctival SCC with scant cytoplasm without evidence of keratinization and intercellular bridges on an inflammatory stroma (Hematoxylin–Eosin, scale bar = 150 μm). (b) The tumor exhibit block‐positive p16‐expression and was HPV16 positive (p16 immunohistochemistry, scale bar = 200 μm). (c) A well‐differentiated conjunctival SCC with irregular‐sized nests and the presence of large keratin pearls (Hematoxylin–Eosin, scale bar = 300 μm). The tumor was HPV negative by polymerase chain reaction (not shown) and (d) did not express p16 (p16 immunohistochemistry, scale bar = 300 μm).
FIGURE 7
FIGURE 7
The most frequently altered genes in conjunctival intraepithelial neoplasia and carcinoma, stratified by human papillomavirus (HPV) status. From Ramberg I, Vieira FG, Toft PB, von Buchwald C, Funding M, Nielsen FC, Heegaard S. Genomic Alterations in Human Papillomavirus‐Positive and ‐Negative Conjunctival Squamous Cell Carcinomas. Invest Ophthalmol Vis Sci. 2021 Nov 1;62(14):11.
FIGURE 8
FIGURE 8
The most frequently altered genes in lacrimal sac squamous cell carcinoma, stratified by human papillomavirus (HPV) status. From Ramberg I, Vieira FG, Toft PB, von Buchwald C, Heegaard S. Viral and Genomic Drivers of Squamous Cell Neoplasms Arising in the Lacrimal Drainage System. Cancers 2022, 14, 2558.
FIGURE 9
FIGURE 9
The PI3K‐AKT signaling pathway (simplified). The figure is created with Biorender.com.
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