Multifocal HPV16-positive squamous cell carcinomas in CTLA-4 haploinsufficiency: expanding the spectrum of virus-associated malignancies

Cytotoxic T-lymphocyte associated protein 4 (CTLA-4) haploinsufficiency is an inborn error of immunity characterized by immune dysregulation, autoimmunity, lymphoproliferation, and an increased risk of malignancy. While susceptibility to oncogenic viral infections has been proposed, the relationship between CTLA-4 haploinsufficiency and human papillomavirus (HPV)-driven carcinogenesis remains poorly characterized. We describe a patient with CTLA-4 haploinsufficiency who developed multiple HPV-associated malignancies. Clinical, pathological, virological, and genetic data were reviewed. Germline genetic testing was performed using whole-exome sequencing, and HPV DNA analysis was conducted on available tumor specimens. A man with a history of alopecia totalis and autoimmune thyroiditis developed five distinct malignancies by the age of 50 years, including Epstein-Barr virus (EBV)-associated gastric Hodgkin lymphoma, cutaneous squamous cell carcinoma (SCC), and three independent HPV16-positive SCCs involving the oral cavity, anus, and penis. Germline testing identified CTLA-4 haploinsufficiency caused by a likely pathogenic CTLA4 variant, c.406C > T (p.Pro136Ser). No additional germline variants associated with hereditary cancer predisposition were detected. HPV DNA analysis demonstrated HPV16 positivity in all three mucosal SCCs. This case expands the spectrum of malignancies associated with CTLA-4 haploinsufficiency and suggests that persistent high-risk HPV infection may represent an underrecognized complication of this disorder. The occurrence of three independent HPV16-positive SCCs raises the possibility that CTLA-4 deficiency predisposes to HPV-driven carcinogenesis and supports further investigation of HPV surveillance and cancer prevention strategies in affected individuals.