Evaluation for High-risk HPV in Squamous Cell Carcinomas and Precursor Lesions Arising in the Conjunctiva and Lacrimal Sac

Abstract

High-risk human papilloma virus (HR-HPV) is a well-established causative agent of oropharyngeal squamous cell carcinoma (SCC). In addition, HR-HPV has occasionally been reported to be present in dysplastic and malignant lesions of the conjunctiva and lacrimal sac, although its overall incidence and etiological role in periocular SCC are controversial. Sequential surgical samples of 52 combined cases of invasive SCC (I-SCC) and SCC in situ (SCCIS) from 2 periocular sites (conjunctiva and lacrimal sac) diagnosed over a 14-year period (2000 to 2014) were selected for evaluation, and relevant patient characteristics were documented. p16 immunohistochemistry was performed as a screening test. All p16-positive cases were further evaluated for HR-HPV using DNA in situ hybridization (DNA ISH), and a subset was also analyzed by polymerase chain reaction (PCR). Of 43 ocular surface squamous neoplasias (OSSNs), 30% (n=13; 8 SCCIS and 5 I-SCC cases) were positive for HR-HPV. HPV-positive OSSNs occurred in 8 men and 5 women with a mean age of 60 years (range, 39 to 94 y). HPV type-16 was detected in all conjunctival cases evaluated by PCR. All 5 conjunctival I-SCCs were nonkeratinizing (n=4) or partially keratinizing (n=1) and managed by simple excision. In contrast, HPV-negative conjunctival I-SCCs were predominantly keratinizing (11 keratinizing and 2 nonkeratinizing). Of 9 lacrimal sac I-SCCs (LSSCCs), 66.7% (n=6) were positive for HR-HPV by p16 and DNA ISH; HPV subtypes were HPV-16 (n=5) and HPV-58 (n=1). In addition, 2 p16-positive cases with negative DNA ISH results were HR-HPV positive (HPV-16 and HPV-33) when evaluated by PCR, suggesting that the rate of HR-HPV positivity among the LSSCCs may be as high as 89% (n=8). The combined group of HR-HPV-positive LSSCCs was seen in 4 men and 4 women with a mean age of 60 years (range, 34 to 71 y). Seven of the 8 HPV-positive LSSCCs (87.5%) had a nonkeratinizing or partially keratinizing histomorphology, whereas 1 case (12.5%) was predominantly keratinizing. The presence of HR-HPV in 30% of OSSNs and at least 66.7% of LSSCCs suggests the possibility of an etiologic role for HR-HPV at these sites.

A prospective study of the incidence, associations and outcomes of ocular surface squamous neoplasia in the United Kingdom

“…To date, most published studies of the association between HIV seropositivity and OSSN have taken place in Africa, Asia and North America (USA). Other potential risk factors or associations include human papilloma virus (HPV) infection; [17,24,26] sunlight exposure [23,24,27], which can lead to mutations in the tumour suppressor gene p53; [28] p63, a homologue of p53; [29,30] smoking; [24,31] immunosuppression; [32][33][34] and xeroderma pigmentosa [35,36]. There have also been suggestions of a possible association between OSSN and atopic keratoconjunctivitis [23,32,[37][38][39].…”

Squamous cell carcinoma in the anophthalmic socket: a series of four cases with HPV-16 profiling

“…The association of HPV-16 and carcinomatous transformation was extended to the conjunctiva in 1989 when McDonnell and coworkers identified the virus in all patients investigated with conjunctival SCC 17. There has been a marked variation in detection rates of HPV in periocular SCC and precursors since that time, ranging from 0% to 100% 18. This variation is likely due to differing techniques to identify HPV in biological specimens and differing study designs.…”

“…This variation is likely due to differing techniques to identify HPV in biological specimens and differing study designs. In 2016, Afrogeh and coauthors were the first to examine the incidence of HPV in ocular surface squamous neoplasia using an accepted standardised combination of p16 and in situ hybridisation 18. Using these methods, they found HPV-16 in 30% of conjunctival squamous neoplasia 18…”

Conjunctival Squamous Cell Neoplasia Associated With Ocular Cicatricial Pemphigoid

“…DNA damage, mutations in the tumor suppressor gene, and immunosuppression impairing tumor immune surveillance are also thought to lead to SCC. 2,3,4 There is one prior report in the literature of conjunctival SCC occurring in the setting of OCP. 5 We report two additional cases in which unilateral conjunctival neoplasia occurred in the setting of bilateral OCP.…”

“…1 Squamous cell dysplasia eventuating in invasive carcinoma (SCC) of the conjunctiva is strongly associated with ultraviolet radiation, human immunodeficiency virus (HIV), and human papillomavirus (HPV). 2,3 It most commonly arises in the para-limbal bulbar conjunctiva and is treated with surgical excision and/or topical therapy with interferon alpha-2b or anti-metabolites. 4 Two cases are described in this study who had squamous cell neoplasia (a term embracing both dysplasia and carcinoma) of the inferior palpebral conjunctiva developing in the setting of OCP.…”