Doctors at the National Institutes of Health have discovered a new cause of skin cancer, according to a case report published Wednesday in the New England Journal of Medicine.
The culprit is a type of human papillomavirus (HPV) that’s regularly found on the skin. It’s long been thought to play a role in the development of skin cancer, but wasn’t believed to be a direct cause.
Skin cancer is caused by DNA damage in skin cells. The most common source of that damage is ultraviolet radiation from the sun. HPV can help UV-damaged DNA build up in cells and turn cancerous. However, in the new case report, doctors found that the virus itself could cause cancerous lesions to form.
The discovery was made in a 34-year-old woman with a weakened immune system; experts said it’s highly unlikely that HPV could play the same role in causing skin cancer in a person with a healthy immune system.
“The virus replicated in a somewhat uncontrolled manner and ended up integrating into the skin cells and once they did that, they became cancerous,” said Dr. Andrea Lisco, section chief of the mucosal and cutaneous viral immunopathogenesis unit at the National Institute of Allergy and Infectious Diseases, part of the NIH. Lisco was the woman’s doctor and also the senior author of the case report.
The woman had 43 spots of cutaneous squamous cell carcinoma — the second-most common type of skin cancer, after melanoma — on her face, hands and legs. She had surgery to remove the cancers and immunotherapy, but the cancer returned. When Lisco and his team biopsied several of her new tumors, they found that the woman’s skin cancer was being driven by something they hadn’t seen before: a group of HPVs called beta HPV.
About 90% of people carry a strain of beta HPV. Usually, the virus lives on the skin and doesn’t integrate into the DNA of skin cells.
“We shake hands and we pick up those viruses, but if our immune systems are under control, we are fine,” Lisco said.
It’s a different group of HPV strains — alpha HPVs — that are linked to a range of cancers. Alpha HPVs live on mucus membranes and can integrate into DNA, causing cancers of the cervix, anus, head and neck.
The woman in the case report had a genetic condition that weakened her T-cells (a type of immune cell), leaving her immunocompromised. This allowed the beta HPV living on her skin to behave more like alpha HPV, integrating its DNA into her skin cells and replicating undisturbed, turning the cells cancerous.
“You don’t know how much you can directly apply the information from one patient to the wide variety of patients,” said Dr. Anthony Oro, professor of dermatology at Stanford Medicine, who wasn’t involved in the case.
However, “it suggests that, in the event that the T-cell arm of the immune system is not doing its job, beta-type HPV viruses could contribute to skin cancer, and maybe other kinds of cancers as well,” he said.
The patient needed a stem cell transplant, which replaced her defective T-cells with T-cells that could prevent the HPV from replicating.
“We needed to give this patient a whole new immune system,” Lisco said. It worked. Three years post-transplant, the woman’s skin cancer has not returned.
“It gives us good information about how the interplay of the HPV and the immune system works,” said Dr. Anthony Rossi, a dermatologist and Mohs surgeon at Memorial Sloan Kettering Cancer Center, who also wasn’t involved with the woman’s case.
Doctors have known for a long time that some beta HPVs cause changes on the skin, such as warts on the hands and feet.
“HPV can integrate and cause changes in the cell cycle, especially in people with suppressed immune systems,” Rossi said. “What was novel about this is that they found out it was a beta HPV that integrated into the DNA.”
Other researchers have speculated this was a possibility based on studies in mice, but the new report shows that it can occur in humans. How many people could be at risk is still unknown.
“This is just one patient, and they have this unique situation of an immunological condition that enables the beta HPV to replicate unchecked,” Oro said.
Other biopsies of squamous skin cancers have not detected HPV, meaning not all cases are caused by the viruses. Lisco said that the original notion — that HPV passively contributes to cutaneous squamous cell carcinoma by helping UV radiation damage skin cells, but doesn’t actively help cancer grow — is still the likely explanation for many people.
For them, “protection from UV would be the prevention,” Lisco said — wearing sunscreen and covering up your skin from the sun — adding that immunocompromised people should be monitored more closely. People with weakened immune systems are as much as 100 times more likely to develop squamous cell carcinoma.
The Gardasil HPV vaccine protects against nine strains of alpha HPV and has been shown to lower rates of cervical and head and neck cancers. It’s unclear how much cross-protection, if any, the vaccine provides against other strains of HPV, including beta HPV.
“Even if this strain is not in the vaccine, there is some theory that there is cross-talk between HPV strains,” Rossi said.
Most people will get HPV in their lifetimes. Scientists have so far identified about 200 unique strains of the virus. Alpha-HPV, with its well-established links to cancer, has thus far been the primary subject of research.
“This suggests that this other side of the family might also be important in situations where our immune system is not doing its job,” Oro said.
