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Arch Ophthalmol. 2002;120:202-204.

Conjunctival papillomas are associated with human papillomavirus (HPV) infection. In children, the lesions are typically manifestations of an infection acquired during delivery.¹ In adults, conjunctival papillomas are most likely venereal and are often associated with anogenital lesions.² Papillomas due to HPV more frequently progress to malignancy in patients with the human immunodeficiency virus (HIV) infection.³ Human papillomavirus types 6, 11, 16, and 18 have been identified in benign and malignant conjunctival lesions using various antigen and DNA detection techniques.² For the first time, to our knowledge, we report the finding of HPV type 33 in conjunctival papillomas excised from an HIV-positive patient.

Report of a Case
A 34-year-old HIV-positive man complained of bilateral conjunctival lesions of 4 years' duration. Ten years earlier, he was diagnosed as having HIV after developing pneumocystis pneumonia, a Mycobacterium avium-intracellulare infection, and perianal HPV condylomata acuminata. While receiving highly active antiretroviral therapy (HAART), including indinavir sulfate, nevirapine, and combivir, he has had no new opportunistic infections and his CD4⁺ cell count has increased above 200/mm³. He sought ophthalmic care because of occasional bleeding from the conjunctival lesions. An initial ocular examination revealed bilateral inferior palpebral conjunctival papillomas that were excised from the right eye. The results of a histopathologic examination showed conjunctival papillomas without atypia. The results of an immunohistochemistry test for HPV types 6, 11, 16, 18, 31, and 33 was negative. The conjunctival lesions recurred, and he was referred to the National Eye Institute, Bethesda, Md. The results of our examination were unremarkable, except for the presence of 1.2- to 1.5-mm nodular lesions on the right upper and lower palpebral conjunctiva and large, confluent, verrucous lesions involving the left upper and lower palpebral conjunctiva (Figure 1). A left palpebral conjunctival excisional biopsy was performed. A histopathologic examination of the biopsy specimen revealed papillary fronds of acanthotic squamous epithelium without atypia and koilocytic changes overlying inflamed fibrovascular cores (Figure 2). Nucleated keratinocytes from the paraffin-embedded specimen were microdissected under direct visualization. After proteinase K digestion, DNA sequences for HPV genotypes 16, 18, and 33 were amplified with a kit (PCR Human Papillomavirus Detection Kit; Pan Vera, Madison, Wis) and transblotted for Southern blot hybridization. Briefly, the common sense primer for HPV types 16, 18, and 33 was 5'-AAGGGCGTAACCGAAATCGGT-3' and the antisense primers of each HPV strain were as follows: 5'-GTTTGCAGCTCTGTGCATA-3' for HPV 16, 5'-GTGTTCAGTTCCGTGCACA-3' for HPV 18, and 5'-GTCTCCAATGCTTGGCACA-3' for HPV 33. The hybridization probes were 5'-CATTTTATGCACCAAAAGAGAACTGCAATG-3' for HPV 16, 5'-TGAGAAACACACCACAATACTATGGCGCGC-3' for HPV 18, and 5'-CATTTTGCAGTAAGGTACTGCACGACTATG-3' for HPV 33. The polymerase chain reaction was performed for each HPV strain under the following conditions: 94° for 30 seconds to denature the primers, 55° for 2 minutes for primer annealing, and 72° for 2 minutes for primer extension. The reaction was repeated for 35 cycles, concluding with a final extension at 72° for 10 minutes. The results demonstrated HPV type 33 DNA sequences in the epithelium of the conjunctival papillomas (Figure 3). Postoperatively, the patient was unavailable for follow-up.

View larger version (46K): [in this window] [in a new window] Figure 1. Diffuse left lower palpebral conjunctival papillomas.

View larger version (74K): [in this window] [in a new window] Figure 2. Photomicrograph showing multiple papillary fronds of acanthotic conjunctival epithelium without atypia or koilocytic changes overlying fibrovascular cores infiltrated by subacute inflammatory cells (arrow) (hematoxylin-eosin, original magnification x400).

View larger version (19K): [in this window] [in a new window] Figure 3. Southern blot detection of amplified DNA polymerase chain reaction products for human papillomavirus (HPV) types 16, 18, and 33 from the epithelia microdissected from the conjunctival papillomas. Lane 1 indicates HPV type 16; lane 2, HPV type 18; and lane 3, HPV type 33.

Comment
Human papillomavirus is an oncogenic double-stranded DNA papovavirus that infects keratinocytes and causes benign and malignant hyperproliferative squamous epithelial tumors. With approximately 100 subtypes identified, HPV is now the most common sexually transmitted disease. Human papillomavirus is the cause of verrucae (skin warts), condylomata acuminata (venereal or genital warts), and mucocutaneous papillomas, which represent 7% to 12% of all conjunctival lesions.^{1, 4} Most commonly associated with benign anogenital lesions and respiratory papillomas, HPV types 6 and 11 are classified as low-risk subtypes because they rarely progress to invasive cancer. Human papillomavirus types 16 and 18 are considered high risk because they are associated with epithelial dysplasia and squamous cell carcinomas, particularly in the uterine cervix and anal canal. Human papillomavirus types 31, 33, 35, 45, 51, 52, and 56 have an intermediate risk of malignancy.⁵

Conjunctival HPV infection may be established during delivery through an infected birth canal, by sexual contact, or by autoinoculation. Human papillomavirus antigens are reported in 5% to 45% of conjunctival papillomas, with HPV types 6 and 11 most commonly found in papillomas from children and HPV types 16 and 18 more frequently associated with dysplasia and carcinoma in older patients. Normal conjunctiva has also been shown to harbor HPV antigens.^{2, 6}

Human papillomavirus type 33 is an uncommon genotype found in benign, dysplastic, and malignant lesions. In a study⁷ defining the distribution of HPV genotypes in male genital lesions, it was detected in only 1 (0.6%) of 175 specimens. Seropositivity to HPV type 33 increased with age in a study⁸ of eastern European women. Primarily found in anogenital lesions, recently HPV type 33 has been associated with breast cancer in Chinese and Japanese patients.⁹

Infection with HIV increases the risk for HPV-associated malignancy and may be a cofactor linking HPV infection and neoplasia.⁵ The immunodeficiency secondary to HIV may facilitate the oncogenic effects of HPV by altering the host susceptibility to HPV infection and impairing immune tumor surveillance. A direct molecular interaction between HIV and HPV could also promote the development of cancer. Recently, it has been shown that the HIV-1 tat protein potentiates the expression of HPV oncoproteins.⁵

The effect of HAART in HIV-infected patients with HPV disease is unclear. Heard and coworkers¹⁰ attributed the reduced prevalence of cervical HPV lesions in HIV-positive women treated with HAART to their increased CD4⁺ cell count. Similarly, anal HPV lesions were more likely to regress in HIV-positive men with higher CD4⁺ cell counts who were receiving HAART. Other studies⁵ involving HIV-positive men with anal HPV lesions who were receiving HAART, however, suggest that anal HPV does not regress and that the improved survival from HAART may paradoxically cause an increased risk of anal cancer.

An increased incidence of conjunctival malignancy in Africa has been attributed to the combination of HIV-induced immunosuppression, HPV infection, and UV light exposure.³ This finding supports the combined effect of HIV and HPV infections on the risk of ocular neoplasia. We report for the first time, to our knowledge, the presence of HPV type 33 in conjunctival papillomas. Although the conjunctival papillomas in our patient were benign, we suspect that the coincidence of the HIV infection and the oncogenic HPV type 33 places the patient at an increased risk for recurrent and persistent conjunctival papillomas and a conjunctival malignancy. Further follow-up is needed to determine if HAART will ameliorate or potentiate the patient's risk of ocular disease.

AUTHOR INFORMATION

Ronald R. Buggage, MD; Janine A. Smith, MD; Defen Shen, PhD; Chi-Chao Chan, MD
Bethesda, Md

Corresponding author and reprints: Dr Buggage, National Eye Institute, National Institutes of Health, 10 Center Dr, Bldg 10, Room 10N112, Bethesda, MD 20892-1857 (e-mail: BuggageR{at}intra.nei.nih.gov).

REFERENCES
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