Purpose: To identify the frequency of human papilloma virus (HPV) in ocular surface squamous neoplasia (OSSN) and to evaluate differences in clinical features and treatment response of tumors with positive versus negative HPV results. Design: Retrospective case series. Participants: Twenty-seven patients with OSSN. Methods: Ocular surface squamous neoplasia specimens were analyzed for the presence of HPV. Clinical features and response to interferon were determined retrospectively and linked to the presence (versus absence) of HPV. Main Outcome Measures: Clinical characteristics of OSSN by HPV status. Results: Twenty-one of 27 tumors (78%) demonstrated positive HPV results. The HPV genotypes identified included HPV-16 in 10 tumors (48%), HPV-31 in 5 tumors, HPV-33 in 1 tumor, HPV-35 in 2 tumors, HPV-51 in 2tumors, and a novel HPV in 3 tumors (total of 23 tumors because 1 tumor had 3 identified genotypes). Tumors found in the superior limbus were more likely to show positive HPV results (48% vs. 0%; P= 0.06, Fisher exact test). Tumors with positive HPV-16 results were larger (68 vs. 34 mm<sup>2</sup>; P= 0.08, Mann-Whitney U test) and were more likely to have papillomatous morphologic features (50% vs. 12%; P= 0.07, Fisher exact test) compared with tumors showing negative results for HPV-16. Human papilloma virus status was not found to be associated with response to interferon therapy (P= 1.0, Fisher exact test). Metrics found to be associated with anonfavorable response to interferon were male gender and tumors located in the superior conjunctivae. Conclusions: The presence of HPV in OSSN seems to be more common in lesions located in the nonexposed, superior limbus. Human papilloma virus presence does not seem to be required for a favorable response to interferon therapy.
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