No, we’re not talking about COVID-19 here. But emerging evidence shows a link between the human papillomavirus (HPV) and squamous cell carcinomas of the skin. Viruses may play a role in other skin cancers, too. Here’s what we know so far.
By Meghan Rabbitt
The spot on the patient’s finger looked like a run-of-the-mill wart, but Désirée Ratner, MD, knew better and did a biopsy. When the New York City-based dermatologist sent it to the lab, she ordered human papillomavirus (HPV) testing. Why? Because of the emerging field of research on the link between this virus and squamous cell carcinoma (SCC) of the skin, also called cutaneous squamous cell carcinoma (cSCC).
“Oftentimes I’ll look at a lesion and know it’s a cSCC, but because of where it is, you wouldn’t think sun exposure caused it,” says Dr. Ratner, who is editor-in-chief of Carcinomas & Keratoses, the SCF’s digital publication for medical professionals on nonmelanoma skin cancers. “You have to wonder why it’s there, and sure enough when you test it, it’s positive for HPV.”
When you hear the word “virus,” you likely first think about the coronavirus that caused a global pandemic and so many tragic deaths. Before that changed our lives, you probably just associated a virus with catching a cold. But certain viruses can also lead to cancer. For example, the hepatitis B virus leads to an estimated 360,000 cases of liver cancer globally each year, according to a 2020 study in The Lancet.
When you hear “HPV,” you may think about the sexually transmitted diseases that can cause genital warts and cancerous cells in the cervix, anus or oral cavity. You may also know about the HPV vaccine, which was developed to prevent the growing number of cases of HPV-related cancer. That same study estimates that nearly 700,000 cancers a year worldwide are attributable to the HPV virus, not including skin cancers. Now, emerging research shows that many cSCCs test positive for high-risk strains of HPV — and scientists are eager to learn more.
“There’s been a lot of evidence associating the presence of HPV infection with cSCC, but we don’t yet know if HPV directly causes cSCC,” says Adela Rambi G. Cardones, MD, associate professor of dermatology at Duke University Medical Center, who has studied the connection between HPV and cSCC. “However, we do have a few theories about how that might happen.”
How Can a Virus Cause Cancer?
For starters, we know that viruses enter cells and can cause damage or create changes in these cells that set them up for cancer. “Viruses can cause cells to proliferate abnormally,” says Dr. Cardones. “They can also deploy mechanisms that circumvent or manipulate the immune system to allow abnormal cells to escape destruction.”
In a healthy person, the immune system’s surveillance system seeks out abnormal cells and kills them before they become cancerous. For example, a good immune system can clear HPV so that you don’t have any symptoms, says Dr. Ratner. “But if you don’t clear it, the virus will live in your epithelial cells, which line the surfaces of your body, and you may or may not know it’s there,” she says. “We think that over time, viruses act as co-carcinogens and generate lesions — clusters of cancerous cells in the cervix, in the mouth and even on the skin.”
It’s important to keep in mind that while HPV is transmitted sexually, it doesn’t just spread during sex, says Dr. Ratner. “HPV is transmitted through breaks in the skin,” she says. “The reason it can lead to genital warts is because the rubbing that happens during sexual intercourse causes breaks in the skin there.” And because HPV lives in the top layers of skin, it can also be transferred outside the bedroom. “The reason you might have a lesion on your hand is because you have a little cut there, and the virus is able to seed there,” adds Dr. Ratner.
What You Need to Know
So, what does this mean for patients, especially those at risk for cSCC? We know a very important line of defense against all cancers, not just skin cancers, is a robust immune system. “There’s an entire field of oncology that focuses on immunotherapy,” says Dr. Cardones. “It’s a testament to how important the immune system is in fighting cancer.” If you are immunosuppressed due to a medical condition or medications that you are taking, this is something your dermatologist needs to know.
If you know you’ve been exposed to HPV — whether you’ve had genital warts, an abnormal Pap smear or a biopsy or blood test that’s been positive for one or more strains of the virus — bring it up with your dermatologist, says Dr. Cardones. “There’s no clear guidance yet about how a positive HPV test might change our surveillance of skin cancers, but it certainly can’t hurt to talk about it with your doctor.” That discussion should also include how often you should be screened for skin cancers, as well as what to watch out for, such as spots that look like harmless warts. It’s important to remember the other well-established risk factors for cSCC — such as excessive UV exposure — that your dermatologist will consider.
If you have been exposed to HPV and are concerned that this connection between HPV and cSCC dooms you to an eventual skin cancer diagnosis, take a deep breath: While some studies have shown that HPV is associated with skin cancer, other research has indicated no connection. However, a recent article in the journal Nature found that immunity to some of those HPV strains may actually protect against skin cancer. The authors wrote that creating a vaccine could boost antiviral immunity in the skin and might help prevent skin cancers. Both Dr. Ratner and Dr. Cardones say this points to a need to know more about the specific strains of HPV that matter when it comes to a connection with skin cancers. Further research in the skin “virome” (the community of viruses living on our skin) could lead the way.
“There are more than 200 strains of HPV, and the only ones we currently test for are the most common high-risk types,” says Dr. Ratner. There’s a lot more we need to learn about the HPV types that matter most when it comes to skin cancer, adds Dr. Cardones. “We still need to figure out what is clinically important,” she says. “What HPV strain should we be looking for? What part of the skin should we test? When should this testing happen, and who should be tested? It’s a very complicated issue, but the good news is that technologies are getting more accurate, and scientists are working hard to find answers.
Can the HPV Vaccine Treat Skin Cancer?
When Anna Nichols, MD, and her colleagues at the University of Miami published a paper showing that one of the HPV vaccines (Gardasil 9) helped prevent the growth of new cSCCs, dermatologists everywhere took notice. Could injecting the vaccine directly into existing tumors (as the scientists at the University of Miami first did with the help of a 2018 Skin Cancer Foundation research grant) clear cSCCs by prompting an immune response? It worked for one 97-year-old patient with multiple tumors, and Dr. Nichols’ paper on that was cited as one of the top 10 Most Talked About Articles of 2018 for JAMA Dermatology. More recently, her team’s April 2020 case report in JAAD showed it worked for an 87-year-old patient with a large, painful cSCC lesion on his palm. While this research is still in its infancy, Dr. Nichols and others are hoping for more funding to explore this promising treatment further.
“While there is certainly a lot of excitement about the possible use of the HPV vaccine to treat and prevent skin cancer, we don’t have enough data yet to support this use of the vaccine,” says Dr. Cardones. “These vaccines are designed to protect against specific strains of HPV that are typically associated with mucosal lesions — in the mouth or throat, the genitalia and the cervix, for example. We know that for cSCCs, the involved HPV virus strains may be different.”
Dr. Nichols says, “We can’t promise spectacular results in other patients, because we don’t understand the mechanism yet. But I hope that in the future many patients will benefit from this innovative line of research.”
Are Other Viruses Linked to Skin Cancer?
Merkel Cell Carcinoma
Merkel cell carcinoma (MCC) is a rare and very dangerous type of skin cancer. About 80 percent of the 3,000 cases of MCC diagnosed in the U.S. each year are caused by a polyomavirus. This common virus lives in the skin of most people, without signs and symptoms, and without ever developing into MCC. Since MCC is an extremely rare disease, scientists are not certain how or why the virus causes the disease in some people. Other factors, such as exposure to ultraviolet (UV) radiation from the sun and having a suppressed immune system, also play a role. While MCC is about three to five times more likely to be deadly than melanoma, with early detection, MCC can be treated successfully.
According to a 2020 study in The Lancet, about 42,000 cases a year globally of Kaposi’s sarcoma, which can develop on the skin, are attributable to the human herpesvirus type 8. Most people infected with this type of herpesvirus don’t get Kaposi’s sarcoma. It is more common in people with a compromised immune system from HIV/AIDS or from medicines required after an organ transplant.
Meghan Rabbitt is a freelance writer and editor based in Boulder, Colorado, whose work is published in Women’s Health, O, The Oprah Magazine, Prevention, Health and many more print and digital media outlets.