BI15 Immunosuppression increases the risk for human papillomavirus 8-associated keratinocyte carcinoma

Abstract Immunosuppression increases the risk of keratinocyte carcinomas (KCs), which include squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). The risk is increased notably among organ transplant recipients on immunosuppressant therapies. Recently, we determined that actinic keratoses (AKs), a treatable precursor for KC, are more frequently present around KC in immunosuppressed patients [Tuckwell W, Omenyo R, Malladi N, Patel G. Nonmelanoma skin cancers and immunosuppression: identifying keratinous red flags. Br J Dermatol 2024; 191 (Suppl. 1): i142]. Whether AKs in immunosuppressed individuals are attributable to human papillomavirus (HPV)8, as in immunocompetent people, remains to be determined (Morgan HJ, Olivero C, Shorning BY et al. HPV8-induced STAT3 activation led keratinocyte stem cell expansion in human actinic keratoses. JCI Insight 2024; 9: e177898). Our null hypothesis was that the frequency of HPV8 within AKs should be similar between immunocompetent and immunosuppressed individuals with a similar risk for KC. Following ethical (19/NS/0012) and National Health Service research and development approvals, patients with histologically diagnosed AK were recruited. Histology samples were retrieved and analysed for the presence of koilocytes. Medical records were examined to identify immunosuppressed individuals using the terms ‘immunosuppression’, ‘transplant’, ‘lymphoma’ and ‘chemotherapy’. A review of current medication was also carried out. Statistical analyses using Fisher’s exact test, odds ratios and hazard ratios were used to test the null hypothesis. In total, 104 of the 274 patients recruited had no antecedent history of KC, a suitable baseline for comparison as a prior KC increases the likelihood of subsequent KC. In the ensuing 10 years, 33 patients developed invasive KC (40 BCCs and 37 SCCs). In this cohort, the patients who developed skin cancer showed no difference in age, sex, immunocompetence or body site. In both groups, the majority of AKs were located on the head. The development of subsequent KC was also unrelated to the histological subtype (classical, bowenoid, acantholytic or lichenoid) of the removed AK. Although AKs are a risk factor for KC, none of the other features examined predicted those at increased risk of subsequent KC. Patients with HPV8-associated AK with koilocytes (n = 68) were of similar age but were more likely to be immunosuppressed (29% vs. 11%, P = 0.05) and male (56% vs. 28%, P = 0.01) than those without, and they had mainly head lesions (66%, P = 0.67). In the subsequent 10 years, patients with HPV8 AKs developed more KCs than those without (63 vs. 14, P = 0.02), notably SCC (odds ratio 3.1, P = 0.02), and there was a significant accrual of KC (hazard ratio 5.5, 95% confidence interval 2.3–12.9, P < 0.001). HPV8 AKs were more prevalent in immunosuppressed patients (odds ratio 3.33, P = 0.05); however, immunosuppression did not add to the risk of subsequent SCC. Immunosuppression greatly increases the risk of HPV8-associated AKs and therefore KC.