Human papillomavirus (HPV) has a well-known role in the pathogenesis of squamous cell carcinoma and precursor lesions of the cervix, anogenital region, and head and neck, but its role in the development of squamous neoplasms of the eye, particularly the conjunctiva, remains unclear.
To review recent evidence implicating HPV in the pathophysiology of ocular lesions.
Published articles obtained from a PubMed search of the English literature were the primary sources for this review.
The low-risk HPV types 6 and 11 appear to play a role in the development of at least a subset of conjunctival squamous papillomas. The role of HPV in the pathogenesis of pterygium and ocular surface squamous neoplasia is less well defined. There is evidence to suggest that HPV may be a cofactor in the development of these lesions, acting in concert with ultraviolet radiation and/or human immunodeficiency virus infection in a subgroup of cases.
Human papillomavirus (HPV) infection is one of the most common sexually transmitted diseases. Human papillomavirus is a nonenveloped, double-stranded DNA virus. Its genome contains early genes (E1–E8) required for transcription and replication and late genes (L1, L2) encoding capsid proteins. It is an epitheliotropic virus that infects traumatized epithelial basement membranes and integrates into the host DNA. The E6 and E7 oncoproteins make changes in several cellular pathways, including inactivation of host tumor suppressor genes including p53 and Rb, inhibition of apoptosis, and activation of telomerase, leading to dysregulation of the cell cycle and chromosome instability.1–5 More than 100 different genotypes have been identified and are divided into low-risk and high-risk subtypes according to their potential to induce human malignancy.
Human papillomavirus has a well-known role in the pathogenesis of squamous cell carcinoma of the cervix,6 anogenital region,7 and head and neck including in particular the oropharynx.8 In general, the low-risk HPV types 6 and 11 are associated with benign lesions, whereas the high-risk HPV types 16 and 18 are found in high-grade intraepithelial lesions and invasive cancers.
Ocular squamous neoplasms tend to arise from the limbus, an area of transition from corneal to conjunctival epithelium. Similar to other anatomic regions having a transition zone that is predisposed to dysplasia, such as the uterine cervix, the limbus is thought to contain stem cells where cell proliferation and neoplastic transformation may occur.1,9–11 Human papillomavirus can infect the ocular surface, presumably by autoinoculation from contaminated fingers,12 and has been thought to be involved in the pathogenesis of conjunctival squamous lesions occurring in this region, including pterygium, conjunctival squamous papilloma, and ocular surface squamous neoplasia (conjunctival intraepithelial neoplasia and squamous cell carcinoma). However, the role of HPV in the development of these lesions is controversial, and the World Health Organization International Agency for Research on Cancer has regarded the evidence implicating HPV as an oncogenic agent in ocular surface squamous lesions as weak.3,13 In this review, we summarize the clinicopathologic features of and recent evidence supporting a role for HPV in the pathogenesis of pterygium, conjunctival squamous papilloma, and ocular surface squamous neoplasia.
Pterygium is a common ocular surface lesion characterized by a triangular or wedge-shaped ingrowth of inflamed conjunctiva onto the cornea. Its name is derived from its resemblance clinically to the membranous wing of an insect. The nasal limbus is the most common site of involvement. The patient's primary concern is usually cosmetic, but pterygia can also affect vision if they obscure the visual axis. A pterygium consists of fibrovascular connective tissue covered by conjunctival-type epithelium that merges with that of the cornea with breakdown of the Bowman layer. There is often goblet cell hyperplasia, underlying inflammatory infiltrates, and elastotic degeneration (Figure 1).14 Pterygia are histologically identical to pingueculae, which are degenerative lesions of the conjunctiva that do not involve the cornea. Epithelial hyperplasia or dysplasia may rarely occur, and ocular surface squamous neoplasia (OSSN) or primary conjunctival melanocytic lesions may coexist with pterygia.14,15
The etiology and pathogenesis of pterygium are not clear, and many theories have been proposed to explain its development.16 Long thought to represent a degenerative disease, pterygium has recently been considered to be likely neoplastic in origin.17 Epidemiologic studies suggest that exposure to ultraviolet B light (UVB) is an important risk factor.1,14,18–23 In particular, pterygia are more common in individuals who live near the equator and in those who work outdoors. UVB has been postulated to interact with a variety of cofactors, including HPV and the p53 tumor suppressor gene, to genetically alter nasal limbal epithelial stem cells, leading to the development or recurrence of pterygia.1,14,18,19,24 This “two-hit” hypothesis is supported by the detection of the high-risk HPV strains 16 and 18, encoding E6 and E7 proteins, which interfere with p53 function, in pterygium.14,22,24,25 However, the rates of detection of HPV in pterygia vary considerably (range, 0%–100%) in published reports.1,14,17–19,22,26–33 These discrepancies have been explained by potential ethnic or geographic differences in rates of HPV infection and by varying laboratory techniques used to detect HPV. Alternatively, these results may reflect the heterogeneous nature of pterygium pathogenesis and the possibility that HPV plays a role in the development of only a subset of pterygia.24
Pterygia are typically managed surgically. They may be locally aggressive and have a propensity to recur if inappropriately managed.14 Recurrent lesions tend to behave more aggressively. Adjunctive therapies that have been used include mitomycin C, 5-fluorouracil, and loteprednol etabonate, a topical corticosteroid.34 Because of the possibility of a viral mechanism of development in at least a subset of pterygia, it has been suggested that minimally invasive treatment options including antiviral medications should be considered.24
CONJUNCTIVAL SQUAMOUS PAPILLOMA
Conjunctival squamous papilloma is a relatively common benign epithelial tumor with a peak incidence in men in their third to fourth decade of life. It is an exophytic, sessile or pedunculated conjunctival growth with prominent blood vessels that tends to be located medially and inferiorly within the conjunctiva.4,35 The tumor consists of nonkeratinized, acanthotic squamous epithelium with goblet cells and occasionally koilocytes on the surface of papillary fibrovascular cores (Figure 2). Although dysplastic changes may occur, carcinoma rarely develops in the setting of conjunctival papilloma.36
The etiology of conjunctival papillomas is unknown, but these lesions are strongly associated with HPV infection. Human papillomavirus DNA has been identified by polymerase chain reaction in approximately 50% to 90% of cases.4,36–39 The low-risk HPV types 6 and 11 are the most common types identified in conjunctival papillomas.32,37,39,40 However, other HPV types including types 9, 12, 13, 16, 18, 20, 21, 22, 24, 33, 42, 43, and 45 have also been found.4,36,38,41,42 The mode of transmission of HPV to the conjunctiva is unclear, but it may occur as a result of fetal passage through an infected birth canal, which explains papillomas in children, ocular autoinoculation from contaminated hands, or by activation of a latent HPV infection.43 Tear flow in a superolateral to inferomedial direction with rubbing of eyes, which often involves the nasal aspect, may explain the localization of papillomas to the inferior and medial parts of the conjunctiva.35 Associated underlying conjunctival inflammation is thought to represent the body's immune response to HPV infection.35 Other clinicopathologic features that have been associated with the presence of HPV types 6 and 11 include an extralimbal location, presence of goblet cells, nonkeratinizing squamous epithelium, and absence of elastosis.38
Conjunctival papilloma often regresses spontaneously but may recur in up to 25% of cases.36 Immunomodulatory agents including topical interferon alpha have led to regression of papillomas. It appears that HPV plays a role in a subset of conjunctival papillomas; however, the role of HPV in the etiology of conjunctival squamous papilloma should be examined in light of the host's immune status, including human immunodeficiency virus (HIV) status.34,42 The development of an HPV vaccine, particularly the quadrivalent vaccine against HPV types 6, 11, 16, and 18, is expected to decrease the incidence of those conjunctival papillomas that are the result of HPV infection.4
OCULAR SURFACE SQUAMOUS NEOPLASIA
The term ocular surface squamous neoplasia refers to a spectrum of lesions of the cornea and conjunctiva derived from squamous epithelium, ranging from low-grade dysplasia to invasive squamous carcinoma.10 It is the most common nonmelanocytic neoplastic process of the ocular surface.1,5,44,45 OSSN has historically been considered a disease of aging men, with a mean age in the sixth decade of life.1 However, with the advent of the acquired immunodeficiency syndrome (AIDS) epidemic, the epidemiology of this disease has changed, with OSSN now more frequently being diagnosed in younger women.46
Patients are usually asymptomatic, but they may present with nonspecific irritation, redness, and pain. Symptoms can be confused with those of conjunctivitis.12 OSSN is typically a well-defined, slightly raised, soft, gelatinous lesion located nasally near the limbus in the interpalpebral part of the conjunctiva. It may extend onto the cornea or rarely be isolated to the cornea without conjunctival involvement.9
Numerous pathologic terms have been used in the past to describe these lesions, including Bowen's disease of the conjunctiva, Bowenoid epithelioma, dyskeratosis, dysplasia, epithelial plaque, intraepithelial epithelioma, and precancerous epithelioma.5,10 More recently, terminology similar to that used in gynecologic pathology for intraepithelial neoplasia, conjunctival intraepithelial neoplasia (CIN) or corneal-conjunctival intraepithelial neoplasia, has gained favor.45,47 Grade 1 CIN (mild dysplasia) is characterized by the presence of atypical, occasionally binucleated epithelial cells, sometimes with perinuclear haloes, termed koilocytes. Grade 2 lesions (moderate dysplasia) occupy at least one-half of the epithelial thickness, with greater nuclear irregularity and frequently identified mitoses. Full-thickness epithelial dysplasia with an intact basement membrane is classified as grade 3 CIN (severe dysplasia) or carcinoma in situ. The atypical cells show a high nuclear to cytoplasmic ratio, hyperchromasia, pleomorphism, an irregular nuclear membrane, coarse chromatin, prominent nucleoli, and increased mitoses (Figure 3). Tumors that penetrate the basement membrane are invasive squamous cell carcinomas (SCCs) (Figure 4). There is typically an abrupt transition between the lesion and normal conjunctival epithelium, and the involved epithelium may be thickened or acanthotic. Solar elastosis is present in most OSSN specimens.48 Rare variants of conjunctival SCC include mucoepidermoid carcinoma, spindle cell carcinoma, papillary carcinoma, and adenosquamous carcinoma.5
As in pterygium, the pathogenesis of OSSN is thought to be related mainly to chronic ultraviolet radiation exposure, mainly UVB, which affects the DNA damage repair system.5 This in part explains the higher incidence of these lesions in equatorial regions and in patients having light skin and eye color, older men (assumed to have more intense and longer UVB exposure), and those with a history of actinic lesions. Xeroderma pigmentosum, a rare genetic disorder resulting from defects in DNA repair after UVB damage, is also a risk factor for the development of OSSN.49
OSSN, in particular conjunctival SCC, occurs more frequently in immunosuppressed patients, including organ transplant patients and those with HIV infection/AIDS.50–52 In areas with a high rate of HIV infection, there is a much higher prevalence of OSSN. In the setting of immunosuppression, OSSN occurs in a younger patient population and tends to behave in a more aggressive fashion.46,51,52 It is thought that HIV acts by stimulating the oncogenic action of other viruses such as HPV by enhancing its transmission to target cells and by inducing a state of persistent inflammation.9,36,53
The role of HPV in the pathogenesis of OSSN is somewhat controversial. Numerous studies have been conducted to assess the presence or absence of HPV DNA, RNA, or proteins, including p16 INK4a (p16), a surrogate marker of infection by high-risk HPV subtypes, in OSSN including CIN and SCC. These studies have yielded widely disparate rates of detection of HPV, ranging from 0% to 100%.13,23,40,43,44,48,53–65 These discrepancies have been attributed to variations in specific HPV types examined, method sensitivities, including the nature and condition of specimens evaluated (swab versus biopsy and fresh versus archived formalin-fixed), sample size, and geographic and genetic susceptibilities.13,23 Although HPV type 16 is the most common type identified,13,44 cutaneous HPV types, including HPV types 5 and 8, may be more common than mucosal types, particularly in the setting of HIV infection.50,55,57
Evidence in support of a role for HPV in the development of OSSN includes studies showing that active HPV expression, detected by presence of mRNA, is found only in OSSN and not in normal conjunctiva, similar to what is seen in HPV-associated cervical lesions.63 Also similar to HPV-associated lesions in other anatomic sites, immunohistochemical expression of p16 protein has been identified in conjunctival CIN/SCC (Figure 5).13,23,58 In one recent study, HPV-positive cases of OSSN had a better prognosis that those without evidence of HPV infection.58
An argument against a role for HPV in the pathogenesis of OSSN is the lack of HPV DNA found in a number of reports.19,40,48,62,65 Furthermore, HPV DNA has been found bilaterally in cases of unilateral ocular disease as well as in the normal conjunctiva of patients with genital HPV.36 An additional study54 has also shown that despite the detection of HPV DNA in conjunctival SCC specimens, the specific HPV DNA for the high-risk types 16, 18, 31, and 33 was absent in all of them. Finally, some studies have demonstrated a high prevalence of p16 immunoreactivity in ocular surface lesions that were negative for HPV56,60 or have failed to detect p16 in OSSN.61
Similar to pterygium, infection with HPV alone is not thought to be sufficient for carcinogenesis; HPV in all likelihood acts in concert with other environmental factors, including HIV infection, to produce OSSN in a subset of cases.5,23,50 The use of p16 immunohistochemistry as a surrogate marker is not yet recommended in routine clinical practice.
The prognosis of OSSN is generally good, although local recurrences and metastasis to regional lymph nodes can occur.5 Complete surgical excision of localized lesions is the treatment of choice. Topical chemotherapy with 5-fluorouracil and mitomycin C and topical immunotherapy with interferon have also been used for more extensive or recurrent lesions. Interestingly, the presence or absence of HPV does not appear to affect the response of these lesions to interferon therapy.44
SUMMARY AND CONCLUSIONS
Conjunctival squamous papillomas are strongly associated with HPV infection, particularly the low-risk HPV types 6 and 11, and it is likely that HPV plays a role in the development of at least a subset of these lesions. The potential role of HPV in the pathogenesis of pterygium and OSSN is less clear. Unlike cervical neoplasia, infection with HPV alone is not thought to be sufficient for the development of these lesions. In a subset of pterygia and OSSN, it is possible that HPV acts as a cofactor in conjunction with other environmental agents, including UVB and HIV infection, to produce these lesions. Further studies are warranted to determine the role of cutaneous forms of HPV in the pathogenesis of OSSN.
The authors have no relevant financial interest in the products or companies described in this article.