Beyond Sun Damage: A Rare Case Of HPV Causing Skin Cancer Unravelled By Genomics
Although the majority of HPV-related cancers develop in mucosal tissues like the throat or cervix, the rare case of a 34-year-old woman with recurrent cutaneous squamous-cell carcinoma implies that some skin-based HPV types may also directly cause cancer in people with weakened immune systems
Skin cancer is one of the most common cancer types in the world, affecting millions of people each year. For years, we have known that skin cancer is mainly caused by UV light. But a recent case study raises an interesting question: could certain viruses also cause some skin cancers, moving beyond their long-assumed role as a minor helper in sun-damaged cells? A report published in the New England Journal of Medicine describes an unusual case that challenges long-held assumptions about how skin cancers develop and highlights the important role of the immune system in keeping viral infections under control.
What we know about skin cancer, HPV
There are two major types of non-melanoma skin cancers, basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC). Both types are mainly caused by long-term exposure to UV light, which damages skin cells. Most cSCCs are treatable, however, in a small proportion of cases, the tumour may become invasive or recurrent even after surgery.
Human papillomaviruses (HPVs) are a large family of viruses that infect the skin and mucous membranes. There are over 200 known types, and most of them cause no symptoms at all. Certain HPV subtypes, referred to as “high-risk” HPVs, have the potential to cause cervical, anal or throat cancers. Others cause harmless warts by infecting the skin. Until recently, the HPV types that infect the skin were thought to be at most minor causes of skin cancer because they might aid in the normal repair of DNA after sun damage, but they did not further promote the growth of cancer once tumours were formed. However, that presumption is called into question by the new case.
When a common virus behaves unusually
The focus of the study was a complex case involving a 34-year-old woman suffering from an unusual medical history. The patient had been living with multiple skin problems for years. She had over 40 recurrent instances of cutaneous squamous cell carcinoma along with numerous wart-like lesions on her skin and inside her mouth, which were linked to an HPV infection. Normally, HPV infections are harmless and clear up on their own. But the HPV type detected in this woman, HPV19, is usually considered a low-risk skin strain not associated with cancer. Additionally, despite multiple surgeries and treatments, one of her forehead tumours kept coming back. This prompted her doctors to look deeper into what was causing the persistent growth.
When researchers at the U.S. National Institutes of Health (NIH) analysed the tumour tissue from the patient using next-generation sequencing, they discovered that the aggressive tumour did not have the classic genetic fingerprint suggestive of sun-damage or UV-related mutations. Instead, they found that the tumour contained genetic material from the HPV19 virus, a virus that infects the skin but has not been linked to cancer before. Even more remarkably, the HPV19 DNA had incorporated itself into the genome of the tumour, indicating that the virus was actively promoting the growth of the cancer. This startling finding instantly caused the investigation’s focus to change from outside variables, such as sun exposure, to the patient’s internal defences.
Uncovering an immune defect
To understand why this patient’s HPV infection had become so aggressive, doctors examined her immune system. Sequencing the patient’s germline DNA revealed that the patient carried mutations in the ZAP70 gene linked to a group of disorders known as primary immunodeficiency.
ZAP70 is essential for the proper activation of T-cells, a type of white blood cell that recognises and destroys infected or abnormal cells. When this gene is defective, the body’s ability to mount an effective immune response is reduced. Severe forms of ZAP70 deficiency are known to cause a condition called severe combined immunodeficiency (SCID), which is usually diagnosed in infancy. In this woman’s case, the mutations only partially disrupted ZAP70 function. This allowed her immune system to develop, but left her with weakened T-cell activity, enough to let HPV-infected cells persist and multiply unchecked.
Since conventional treatment options were failing, the doctors decided to treat the underlying immune defect in the patient through an allogenic hematopoietic cell transplant, a procedure that replaces defective immune cells with healthy ones from a donor. Post-transplant, her T-cell function returned to normal, and her immune system was able to detect and eliminate the HPV-infected cells effectively. In the months following the transplant, all HPV-related lesions, including the recurrent skin cancer, resolved completely. The patient has remained cancer-free for more than three years since the procedure.
Lessons from a rare case
Although a very rare presentation, this case provides valuable insights into how the immune system, viruses, and cancer interact. The immune system is essential in preventing cancer because T-cells can identify and destroy early abnormal cells before they have a chance to proliferate out of control. When this defence mechanism is weakened, either by genetic defects or other causes, viruses or mutated cells can gain an advantage and lead to disease. Although the majority of HPV-related cancers develop in mucosal tissues like the throat or cervix, this case implies that some skin-based HPV types may also directly cause cancer in people with weakened immune systems. It also emphasizes how effective NGS technologies are at revealing otherwise unnoticed links between immune dysfunction and cancer.
The case is a unique instance and not proof that HPV frequently causes skin cancer. UV radiation continues to be the main risk factor for the majority of people, and shielding the skin from the sun is still the best method of preventing cutaneous squamous cell carcinoma. The case does, however, imply that tests that assess both immune function and HPV activity may be helpful for patients with multiple, recurrent, or treatment-resistant skin cancers. Boosting the immune system with vaccines or immune-based treatments may be a crucial component of treatment in these situations. It also highlights how advances in genomic medicine are transforming the way doctors understand disease. By revealing hidden links between infection, immunity, and cancer, genomics allows clinicians to move beyond treating visible symptoms to uncovering root causes. Studying such rare cases not only helps individual patients but also deepens our overall understanding of how cancers develop, showing how genomic insights are reshaping modern medicine.
