CLINICOPATHOLOGIC REPORTS, CASE REPORTS, AND SMALL CASE SERIES SECTION EDITOR: W. RICHARD GREEN, MD lomata acuminata. While receiving flamed fibrovascular cores Conjunctival Papillomas highly active antiretroviral therapy (Figure 2). Nucleated keratino- Caused by Human (HAART), including indinavir sul- cytes from the paraffin-embedded Papillomavirus Type 33 fate, nevirapine, and combivir, he has specimen were microdissected un- had no new opportunistic infections der direct visualization. After protein- Conjunctival papillomas are associ- and his CD4+ cell count has in- ase K digestion, DNA sequences for ated with human papillomavirus creased above 200/mm3. He sought HPV genotypes 16, 18, and 33 were (HPV) infection. In children, the le- ophthalmic care because of occa- amplified with a kit (PCR Human sions are typically manifestations of sional bleeding from the conjuncti- Papillomavirus Detection Kit; Pan an infection acquired during deliv- val lesions. An initial ocular exami- Vera, Madison, Wis) and transblot- ery.1 In adults, conjunctival papillo- nation revealed bilateral inferior ted for Southern blot hybridization. mas are most likely venereal and are palpebral conjunctival papillomas that Briefly, the common sense primer for often associated with anogenital le- were excised from the right eye. The HPV types 16, 18, and 33 was 5Ј- sions.2 Papillomas due to HPV more results of a histopathologic examina- AAGGGCGTAACCGAAATC- frequently progress to malignancy in tion showed conjunctival papillo- GGT-3Ј and the antisense primers of patients with the human immuno- mas without atypia. The results of an each HPV strain were as follows: 5Ј- deficiency virus (HIV) infection.3 Hu- immunohistochemistry test for HPV GTTTGCAGCTCTGTGCATA-3Ј for man papillomavirus types 6, 11, 16, types 6, 11, 16, 18, 31, and 33 was HPV 16, 5Ј-GTGTTCAGTTCCGT- and 18 have been identified in be- negative. The conjunctival lesions re- GCACA-3Ј for HPV 18, and 5Ј- nign and malignant conjunctival le- curred, and he was referred to the Na- GTCTCCAATGCTTGGCACA-3Ј for sions using various antigen and DNA tional Eye Institute, Bethesda, Md. HPV 33. The hybridization probes detection techniques.2 For the first The results of our examination were were 5Ј-CATTTTATGCAC- time, to our knowledge, we report the unremarkable, except for the pres- CAAAAGAGAACTGCAATG-3Ј for finding of HPV type 33 in conjunc- ence of 1.2- to 1.5-mm nodular le- HPV 16, 5Ј-TGAGAAACACACCA- tival papillomas excised from an HIV- sions on the right upper and lower CAATACTATGGCGCGC-3Ј for positive patient. palpebral conjunctiva and large, con- HPV 18, and 5Ј-CATTTTGCAG- fluent, verrucous lesions involving the TAAGGTACTGCACGACTATG-3Ј Report of a Case. A 34-year-old HIV- left upper and lower palpebral con- for HPV 33. The polymerase chain re- positive man complained of bilateral junctiva (Figure 1). A left palpe- action was performed for each HPV conjunctival lesions of 4 years’ dura- bral conjunctival excisional biopsy strain under the following condi- tion. Ten years earlier, he was diag- was performed. A histopathologic ex- tions: 94° for 30 seconds to denature nosed as having HIV after develop- amination of the biopsy specimen re- the primers, 55° for 2 minutes for ing pneumocystis pneumonia, a vealed papillary fronds of acanthotic primer annealing, and 72° for 2 min- Mycobacterium avium-intracellulare squamous epithelium without atypia utes for primer extension. The reac- infection, and perianal HPV condy- and koilocytic changes overlying in- tion was repeated for 35 cycles, con- Figure 1. Diffuse left lower palpebral conjunctival papillomas. 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 ϫ400). (REPRINTED) ARCH OPHTHALMOL / VOL 120, FEB 2002 WWW.ARCHOPHTHALMOL.COM 202 ©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/03/2021 cluding with a final extension at 72° for 10 minutes. The results demon- strated HPV type 33 DNA sequences in the epithelium of the conjunctival Case papillomas (Figure 3). Postopera- tively, the patient was unavailable for follow-up. Comment. Human papillomavirus is Positive an oncogenic double-stranded DNA Control papovavirus that infects keratino- cytes and causes benign and malig- nant hyperproliferative squamous 12 3 epithelial tumors. With approxi- mately 100 subtypes identified, HPV Figure 3. Southern blot detection of amplified DNA polymerase chain reaction products for human is now the most common sexually 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. transmitted disease. Human papillo- mavirus is the cause of verrucae (skin warts), condylomata acuminata (ve- cently HPV type 33 has been asso- fections on the risk of ocular neo- nereal or genital warts), and muco- ciated with breast cancer in Chi- plasia. We report for the first time, cutaneous papillomas, which repre- nese and Japanese patients.9 to our knowledge, the presence of sent 7% to 12% of all conjunctival Infection with HIV increases the HPV type 33 in conjunctival papil- lesions.1,4 Most commonly associ- risk for HPV-associated malignancy lomas. Although the conjunctival ated with benign anogenital lesions and may be a cofactor linking HPV papillomas in our patient were be- and respiratory papillomas, HPV infection and neoplasia.5 The immu- nign, we suspect that the coinci- types 6 and 11 are classified as low- nodeficiency secondary to HIV may dence of the HIV infection and the risk subtypes because they rarely facilitate the oncogenic effects of oncogenic HPV type 33 places the progress to invasive cancer. Human HPV by altering the host susceptibil- patient at an increased risk for re- papillomavirus types 16 and 18 are ity to HPV infection and impairing current and persistent conjunctival considered high risk because they are immune tumor surveillance. A di- papillomas and a conjunctival ma- associated with epithelial dysplasia rect molecular interaction between lignancy. Further follow-up is and squamous cell carcinomas, par- HIV and HPV could also promote needed to determine if HAART will ticularly in the uterine cervix and anal the development of cancer. Re- ameliorate or potentiate the pa- canal. Human papillomavirus types cently, it has been shown that the tient’s risk of ocular disease. 31, 33, 35, 45, 51, 52, and 56 have HIV-1 tat protein potentiates the ex- an intermediate risk of malig- pression of HPV oncoproteins.5 Ronald R. Buggage, MD nancy.5 The effect of HAART in HIV- Janine A. Smith, MD Conjunctival HPV infection infected patients with HPV disease Defen Shen, PhD may be established during delivery is unclear. Heard and coworkers10 at- Chi-Chao Chan, MD through an infected birth canal, by tributed the reduced prevalence of Bethesda, Md sexual contact, or by autoinocula- cervical HPV lesions in HIV- tion. Human papillomavirus anti- positive women treated with HAART + Corresponding author and reprints: Dr gens are reported in 5% to 45% of to their increased CD4 cell count. Buggage, National Eye Institute, Na- conjunctival papillomas, with HPV Similarly, anal HPV lesions were tional Institutes of Health, 10 Center Dr, types 6 and 11 most commonly more likely to regress in HIV- + Bldg 10, Room 10N112, Bethesda, MD found in papillomas from children positive men with higher CD4 cell 20892-1857 (e-mail: BuggageR@intra and HPV types 16 and 18 more fre- counts who were receiving HAART. .nei.nih.gov). quently associated with dysplasia Other studies5 involving HIV- and carcinoma in older patients. positive men with anal HPV lesions 1. McDonnell PJ, McDonnell JM, Kessis T, et al. Detection of human papillomavirus type 6/11 Normal conjunctiva has also been who were receiving HAART, how- DNA in conjunctival papillomas by in situ hy- 2,6 shown to harbor HPV antigens. ever, suggest that anal HPV does not bridization with radioactive probes. Hum Pathol. Human papillomavirus type 33 regress and that the improved sur- 1987;18:1115-1119. 2. Miller DM, Brodell RT, Levine MR. The conjunc- is an uncommon genotype found in vival from HAART may paradoxi- tival wart: report of a case and review of treat- benign, dysplastic, and malignant le- cally cause an increased risk of anal mentoptions.OphthalmicSurg.1994;25:545-548. sions. In a study7 defining the dis- cancer. 3. Waddell KM, Lewallen S, Lucas SB, et al. Car- cinoma of the conjunctiva and HIV infection tribution of HPV genotypes in male An increased incidence of con- in Uganda and Malawi. Br J Ophthalmol. 1996; genital lesions, it was detected in junctival malignancy in Africa has 80:503-508. 4. Cotran RS, Kumar N, Collins T. Neoplasia: Rob- only 1 (0.6%) of 175 specimens. Se- been attributed to the combination bins Pathologic Basis of Disease. Philadelphia, Pa: ropositivity to HPV type 33 in- of HIV-induced immunosuppres- WB Saunders Co; 1999:311-312, 1048-1051. creased with age in a study8 of east- sion, HPV infection, and UV light ex- 5. Palefsyk JM. Anal squamous intraepithelial le- 3 sions in human immunodeficiency virus– ern European women. Primarily posure. This finding supports the positive men and women. Semin Oncol. 2000; found in anogenital lesions, re- combined effect of HIV and HPV in- 27:471-479. (REPRINTED) ARCH OPHTHALMOL / VOL 120, FEB 2002 WWW.ARCHOPHTHALMOL.COM 203 ©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/03/2021 6. Naghasfar Z, McDonnell PJ, McDonnell JM, et al. Genital tract papillomavirus type 6 in re- current conjunctival papilloma. Arch Ophthal- mol. 1986;104:1814-1815. 7. Grce M, Husnjak K, Skerlev M, Lipozencic J, Pavelic K. Detection and typing of human pap- illomaviruses by means of polymerase chain re- action and fragment length polymorphism in male genital lesions.