Human papillomavirus (HPV) infection has well-documented oncogenic potential in anogenital and oropharyngeal tissues 1. However, its contribution to cutaneous carcinogenesis, particularly in the setting of systemic immunosuppression, remains undercharacterized 2. Immunosuppressed patients, including solid-organ transplant recipients and those receiving chronic corticosteroids or immunosuppressive medications, have an elevated risk of nonmelanoma skin cancers (NMSC), but the influence of concurrent HPV infection on this association is less clear 1, 2. Elucidating this relationship may help guide surveillance strategies and prevention efforts in high-risk populations. Using the TriNetX US Collaborative Network, we identified patients with HPV infection (RXNORM:1311095, ICD-10-CM:A63.0, ICD-10-CM:B97.7, ICD-10-CM:C53.9, ICD-10-CM:C54.1, ICD-10-CM:R87.81, ICD-10-CM:R87.82, CPT:87624) and concurrent immunosuppression (defined by transplant status (ICD-10-CM:Z94), long-term systemic steroid use (ICD-10-CM:Z79.52), or immunosuppressant medications (ATC:L04); n = 251,002) and HPV-positive controls without immunosuppression (n = 3,358,885). Propensity score matching yielded 245,027 patients per cohort balanced by age, sex, and race/ethnicity. We acknowledge that differences in healthcare utilization and dermatologic surveillance, particularly among immunosuppressed patients, as well as human immunodeficiency virus (HIV) status and comorbidity burden may contribute to detection or surveillance bias. Outcomes included incident squamous cell carcinoma (SCC), basal cell carcinoma (BCC), melanoma, melanoma in situ, sebaceous carcinoma, Kaposi sarcoma, and other malignant neoplasms of the skin, excluding patients with prior diagnoses (Table 1). Immunosuppressed patients demonstrated higher risks across multiple skin cancer types. SCC occurred in 2405 immunosuppressed versus 1480 control patients (risk ratio RR 1.64, 95% confidence interval CI 1.54–1.75, p < 0.001), BCC in 3098 versus 2533 (RR 1.24, 95% CI 1.17–1.30, p < 0.001), and melanoma in 747 versus 665 (RR 1.13, 95% CI 1.02–1.25, p = 0.023). The most pronounced difference was seen in sebaceous carcinoma of the eyelid (62 vs. 17; RR 3.65, 95% CI 2.13–6.24, p < 0.001). These findings demonstrate that HPV infection in the setting of systemic immunosuppression is associated with increased risk of multiple cutaneous malignancies, suggesting that impaired viral clearance, ultraviolet-induced DNA damage, and chronic local inflammation may act in concert to promote malignant transformation 3-5. The pattern of elevated SCC and sebaceous carcinoma incidence is consistent with the possibility of an interaction involving HPV E6/E7 oncoprotein-mediated p53 and Rb inactivation, leading to unregulated cell cycling, genomic instability, and increased susceptibility to UV-induced mutagenesis 3, 4. In immunocompromised hosts, reduced antigen presentation and altered interferon signaling may further enable viral persistence and immune evasion, contributing to continuous epidermal proliferation and malignant progression 5. These results highlight the importance of early and regular skin cancer screening for immunosuppressed patients. Incorporating HPV vaccination into pre-transplant and long-term immunosuppression management protocols may warrant further investigation as a potential preventative strategy, particularly in younger populations or those with chronic inflammatory diseases requiring systemic therapy. However, whether vaccination modifies the risk of cutaneous malignancy requires further investigation. Dermatologists should emphasize comprehensive sun protection, encourage self-skin examinations, and maintain a low threshold for biopsy of atypical lesions, as malignancies in this cohort may exhibit aggressive or multifocal behavior. Collaborative management among dermatology, infectious disease, oncology, and transplant specialists can optimize preventive care and ensure continuity of surveillance. Limitations include ICD-10-CM coding, which may miss cases and/or the severity of HPV, immunocompromised status, and skin cancer subtypes analyzed. Immunosuppression was defined using ICD-10-CM: Z79.52 and ATC: L04 coding, which does not capture medication dose, duration, or timing, and may introduce heterogeneity in immunosuppressive intensity and potential misclassification. Future research should stratify outcomes by immunosuppressive regimen, including biologic and targeted agents, to determine whether modern therapies confer differential risks. Prospective studies incorporating HPV genotyping, viral load quantification, cytokine profiling, and immune checkpoint markers could clarify causal pathways and identify immunologic biomarkers of susceptibility. Strengthening interdisciplinary approaches and patient education can help translate these findings into durable improvements in skin cancer prevention and survivorship for vulnerable immunosuppressed populations. The authors have nothing to report. Data accessible via TriNetX is presented in aggregate form and only contains anonymized data as per the de-identification standard defined by the US Health Insurance Portability and Accountability Act (HIPAA) in section §164,514(a). Given this study used only de-identified data and did not involve individually identifiable patient data, this study was exempt from Institutional Review Board Approval. The authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request.
Alam et al. (Fri,) studied this question.