Squamous cell papillomas of the conjunctiva are common benign lesions, and HPV is strongly associated with their occurrence.10
Investigations of conjunctival papilloma biopsies for the presence of HPV using PCR analysis have identified HPV DNA in 44%–92% of the lesions.10
The HPV types found in conjunctival papillomas are most commonly HPV 6 and HPV 11 ().
HPV DNA in conjunctival papillomas; comparison of published data
Sjö et al investigated 20 normal conjunctiva biopsy specimens for the presence of HPV and found that all were HPV negative. They concluded that conjunctiva is not an HPV reservoir.10
In contrast, Karcioglu and Issa investigated 19 normal conjunctiva biopsy specimens for the presence of HPV and found HPV 16 and HPV 18 in six patients (32%).16
Conjunctival papillomas typically show an exophytic growth pattern that can be sessile or pedunculated and repeating fibrovascular cores with a geometrically arranged set of red dots are typical findings in the slit lamp examination. Papillomas may also have a mixed or, rarely, an inverted growth pattern.17
Most papillomas are located medially and inferiorly in the conjunctiva. The localization of conjunctival papillomas according to the study of Sjö et al was on the palpebrae 38%, fornices 11%, bulbus 24%, limbus 0%, and caruncle 27%.17
Dysplasia may be present in the lesions, but carcinoma rarely develops in conjunctival papillomas.17
The differential diagnosis of conjunctival papillomas includes a variety of tumors: (1) benign tumors of surface epithelium as keratoacanthoma, epithelial inclusion cyst, benign hyperplasia of epithelium, and actinic keratosis, (2) malignant lesions of surface epithelium as conjunctival intraepithelial neoplasia and squamous cell carcinoma, (3) vascular tumors as pyogenic granuloma, lymphangioma and capillary hemangioma, (4) conjunctival lymphomas, (5) nonpigmented conjunctival melanomas, and (6) secondary tumors. The medical history, slit-lamp examination, and the specific clinical and histopathological features of each tumor are used for accurate diagnosis.
Sjö et al reviewed the files of 219 patients with 245 conjunctival papillomas. They found that conjunctival papillomas are more frequent in men 60.3% (95% confidence interval [CI]: 53.7%–66.9%). The highest incidence of conjunctival papillomas was found among patients aged 20–29 years.17
This is in accordance with the study of Dunne et al who found the highest prevalence of cervicovaginal HPV infection among women aged 20–24 years18
and in accordance also with the study of Insinga et al who found the highest prevalence of genital warts in women aged 20–24 years and in men aged 25–29 years.19
The mode of transmission of HPV infection of the conjunctiva in adults is considered to be autoinoculation from contaminated fingers to the conjunctiva. Sonnex et al have documented hand carriage of HPV types in patients with genital warts.20
Conjunctival papillomas have also been reported in infants. The transmission is considered to happen during birth from the affected genital tract of women to the conjunctiva of the newborn.21
Koilocytosis (nuclear pyknosis and cytoplasmic clearing) is a morphological hallmark of HPV infection. Koilocytosis was present in both of our cases.
Most commonly, LR HPV 6 and HPV 11 are found in most conjunctival papillomas. The same types are responsible for more than 90% of condyloma acuminata (genital warts). HR HPV 16 and HPV 18 have also been found in conjunctival papillomas. These types are strongly associated with the occurrence of high-grade uterine cervical intra-epithelial neoplasia and cervical cancer. HPV 16 and HPV 18 are responsible for more than 70% of cervical cancers followed by other HR HPV types. Other types found in conjunctival papillomas in case reports are HPV 33, HPV 45, and HPV 13.15
Conjunctival papillomas often show spontaneous regression and cure. It must also be kept in mind that recurrences are frequent (6%–27%).14
There is a variety of treatment choices for treating large and symptomatic conjunctival papillomas that may cause also cosmetic defects. Surgical excision of the lesion and cryotherapy to the adjacent conjunctiva is considered to be the treatment of choice.25
The amniotic membrane can be used to cover large epithelial defects after the excision of the affected conjunctiva. In addition, topical MMC and topical interferon alpha 2b have been used to prevent recurrences and also to treat recurrent papillomas.26
Another agent that has been used for the treatment of conjunctival papillomas is oral cimetidine.28
In our two patients, the treatment of the conjunctival papillomas included surgical excision of the lesion and cryotherapy to the adjacent conjunctiva. Topical MMC was used to prevent recurrences. In the patient with the diffuse papillomatous lesion in bulbar conjunctiva, after the excision, the extended epithelial defect was covered with amniotic membrane with an excellent outcome (). Recurrences were not observed in either patient during the long follow-up period.
(A) Patient 1: 4th postoperative day with the amniotic membrane (arrows) covering the defect of the excised pathological conjunctiva and (B) 6 months after surgery; excellent ocular surface without signs of tumor recurrence.
The oncogenic properties of HPVs are attributed mainly to two viral oncoproteins, E6 and E7. These oncoproteins are necessary for the induction and maintenance of the transformed phenotype. The E6 oncoprotein of the HR HPV types alters numerous cellular pathways, including inactivating p53, blocking apoptosis, activating telomerase, disrupting cell adhesion, polarity, and epithelial differentiation, altering transcription, and reducing immune recognition.29
The E7 oncoprotein of the HR HPV types also alters numerous cellular pathways, including activation of E2F-dependent DNA transcription through degradation of the retinoblastoma oncosuppressor protein (pRB), dysregulation of the G1/S checkpoint of the cell cycle, dysregulation of the epigenetic reprogramming, causing subversion of p53 function, blocking apoptosis, modulating the cytostatic signaling (TGF-β resistance, TNF-α resistance, compromission of IFN signaling, interference with IGF signaling), altering the cellular metabolism, and inducing chromosomal instability.30
In contrast, the E6 and E7 oncoproteins of the LR HPV types have greatly decreased transforming and immortalizing activities in comparison to HR E6 and E7 oncoproteins.30
HR HPV types can cause cervical, anal, and other genital cancers. The association between HPV and squamous cell carcinoma of the conjunctiva has been examined. Squamous cell carcinoma of the conjunctiva (SCCC) is a rare tumor that has been strongly associated with UV radiation and immunosuppression (particularly in HIV patients).32
The role of HPV infection in the etiology of SCCC remains unclear. HPV16 or HPV 18 DNA and mRNA corresponding to the E6 region have been detected in conjunctival intraepithelial neoplasia.34
Conjunctival intraepithelial neoplasia is a precursor of SCCC. A few other studies have identified the presence of HPV 16 and HPV 18 in severe dysplastic lesions and carcinomas of the conjunctiva.35
HPV 6 and HPV 11 have also been found in severe dysplasias and carcinomas of the conjunctiva.36
In addition, cutaneous HPV types, most commonly HPV 5 and HPV 8, have been found in SCCC, especially in HIV positive patients.37
In contrast, multiple other studies have failed to find a strong association of HPV with SCCC.12
According to the 2007 International Agency for Research on Cancer on the carcinogenicity of HPV in humans, limited evidence was available for the carcinogenicity of HPV in the conjunctiva.39
The development of an HPV vaccine and immunization against HPV is expected to have a strong impact on the incidence of HPV-related diseases. There are two presently available prophylactic vaccines (quadrivalent and bivalent). They were based on the production of L1 recombinant proteins of HPV, produced in the form of pentamers, that form virus-like particles, which are “empty shells” that do not contain infectious HPV DNA.40
The quadrivalent vaccine includes virus-like particles of the HPV types 16, 18, 6, and 11. The bivalent vaccine includes virus-like particles of the HPV types 16 and 18. The two vaccines are most efficient if used at preadolescent age, before the beginning of sexual activity. HR HPV types 16 and 18 are responsible for more than 70% of the cases of cervical cancer. LR HPV types 6 and 11 are responsible for more than 90% of genital warts. The HPV types 6 and 11 are found in the majority of conjunctival papillomas. Muñoz et al investigated the impact of the quadrivalent prophylactic vaccine against HPV types 6, 11, 16, and 18 on all HPV-associated genital disease in a population of sexually naïve women (HPV-unexposed). They concluded that prophylactic vaccination was 95%–100% effective in reducing HPV 16/18-related high-grade cervical, vulvar, and vaginal lesions and 97% effective in reducing HPV 6/11 related genital warts.42
Thus, for ophthalmology, the quadrivalent vaccine is expected to decrease the incidence of conjunctival papillomas due to HPV infection. In contrast, the HPV vaccination is not expected to prevent SCCC because HPV is not the main oncogenic agent in SCCC. Ultraviolet radiation and immunosuppression (particularly in HIV patients) appear to play a much greater role in the etiology of SCCC. Finally, it should be mentioned that the HPV vaccine can offer a certain degree of cross-protection against other HPV types that are genetically and antigenically closely related to vaccine types. For instance, HPV 31 and HPV 35 are strongly related to HPV 16 and HPV 45 is strongly related to HPV 18.
In conclusion, HPV infection is considered the most common sexually transmitted disease and can also infect the ocular surface. Squamous cell papillomas of the conjunctiva are common benign epithelial tumors, and HPV is strongly associated with their occurrence. Based on the clinical picture, the ophthalmologist, in cooperation with the pathologist, can recommend the appropriate laboratory examinations to confirm the diagnosis and treat the conjunctival papillomas to achieve the best outcome and prevent recurrences.