HPV cancers are on the rise

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When the human papillomavirus (HPV) vaccine was first introduced in 2006, researchers and clinicians were hopeful that they would finally see a decline in cases of HPV-related cancers. In 2008, more than 11,000 women in the United States were diagnosed with invasive cervical cancer every year, and about 3,800 died from the disease, data show.

And while the vaccine did reduce cancer rates in young people - cases of cervical and other HPV-related cancers are exceedingly rare in vaccinated young adults, studies show - the overall prevalence of HPV-related cancers has remained stubbornly high. That's due in part because the vaccine is offered only to young people and because the HPV virus may remain dormant in the body, resurfacing years later.

More than 80% of sexually active people will be infected with HPV during their lifetime. The body clears 9 out of 10 of these infections, spread through intimate skin-to-skin contact, within two years. But in some people, HPV infections persist and can lead to cancers of the cervix, as well as the throat (oropharynx), penis, anus, vagina, and vulva.

"The problem is in those people where HPV isn't cleared and it stays in the body," says Electra D. Paskett, PhD, director of the Division of Cancer Prevention and Control in the College of Medicine and professor of epidemiology in the College of Public Health at The Ohio State University. "Then when your immune system is weak or compromised, HPV can multiply and run free. It integrates into the DNA of the cells and can turn the cells to become cancerous."

In particular, doctors are witnessing a surge of oropharyngeal cancer, disproportionately affecting men. (Men are diagnosed with head and neck cancers at more than four times the rate diagnosed in women.) Rates of anal, penile, vaginal, and vulval cancers, while rare, are also increasing. And even rates of cervical cancer - the disease people associate most with HPV - have plateaued, despite that medicine holds the means to eliminate this disease.

HPV vaccines are key to that goal. They target the high-risk types of the virus and are nearly 100% effective when administered to preadolescents (ideally, ages 11 to 12), before their bodies have encountered HPV.

Initially approved for girls and young women up to age 26, the HPV vaccine is now approved for males and females up to age 45, though its effectiveness is greater the younger the patient is when receiving it. But uptake has been tepid, due in part to vaccine hesitancy and the stigma associated with sexually transmitted infections.

As part of recent changes to the childhood vaccination schedule, the Centers for Disease Control and Prevention lowered the number of doses of HPV vaccine recommended. Instead of two doses for children and young adolescents, one shot is now recommended. That aligns with positive new data showing that one dose is as effective as two.

"If you're under 15, we can do it with one dose, with very solid evidence that you'll be protected well into your screening years," says Diane M. Harper, MD, professor of family medicine and obstetrics and gynecology at the University of Michigan Medical School and a leading HPV researcher.

But while some experts believe the one-dose strategy will make vaccination easier, the American Academy of Pediatrics and the American College of Obstetrics and Gynecologists continue to recommend two doses until all the available data has been assessed.

And the generations that missed out on the vaccine still face a risk. How great is the threat of HPV-related cancer, and how is it being addressed?

Cervical cancer

Last year 13,360 new cases of cervical cancer were diagnosed and 4,320 women died from the disease, according to the National Cancer Institute. But, unlike other cancers, cervical cancer is almost entirely preventable, experts say, due to the vaccine, effective screening tests (cervical cytology that detects changes in the cells and HPV tests that detect the high-risk types of the virus linked to cancer), and follow-up treatment for precancerous lesions.

The World Health Organization has called for eliminating cervical cancer by prioritizing these three "pillars," says Paskett. And several countries - Sweden, Australia, Denmark, and the United Kingdom - are well on their way to doing just that.

It's another story in the United States, where "there's not been a significant drop in cervical cancer for over 30 years," says Harper.

One problem is that "20% to 40% of women do not get screened for cervical cancer," she says. "Half the women who get the cancer have never been screened."

A lack of preventive health care and fragmented care are factors for some women. An aversion to invasive speculum exams, when cervical cells are collected, particularly among women with a history of sexual trauma, may also play a role, Harper says.

At the same time, women whose screenings reveal precancerous lesions can get lost in the shuffle of the health care system. Numerous uncomfortable visits may be needed to remove the abnormal changes in the cervical cells (plus, these visits do not treat the HPV infection), during which time a patient may have moved, have changed providers, or no longer have insurance coverage.

"In many ways having an HPV infection is like having a chronic disease," says Harper. "You have to keep following up with it. The more persistent the infection, the more dangerous it is."

Alarmingly, the incidence of cervical cancer is rising among some groups of women. A 2022 study found that incidence has grown by 3% every year since 2012 among women ages 30 to 34. Other data show that cases of advanced cervical cancer, which has a five-year survival rate of just 17%, rose 1.3% a year between 2001 and 2018.

There's also been an uptick in cervical cancer diagnoses among women over age 65, who account for 1 in 5 cervical cancer cases, research shows. These late diagnoses reflect the insidious nature of HPV.

"We think that most cervical cancer in older women probably develops from HPV that they were exposed to previously and it has lain dormant," says Sarah Dilley, MD, MPH, assistant professor of gynecologic oncology at Emory University School of Medicine.

Guidelines stipulate that women can stop cervical cancer screening at 65 if they've had three negative Pap tests or two negative HPV tests in the previous 10 years. However, around 30% of women aren't up to date on cervical cancer screenings when they reach 65, and 18% have never been screened at all.

Considering these lapses, Dilley and others have called for changes to the guidelines. Other data support women over 65 receiving a "catch-up" HPV test if they never had the screening. And in December the American Cancer Society advised that women at average risk of cervical cancer who had negative HPV tests or negative results from co-testing with Pap smears and HPV tests at ages 60 and 65 could safely stop screening.

There are other signs of change. Federal guidelines have expanded the options for cervical cancer screenings to include a self-administered HPV test that could improve access. Practices are beginning to make use of the new screening method, Harper says.

"The University of Michigan has completely switched over to self-sampling," she notes. "It's also happening at [many other clinics]. We have to tell women that they have a new option, and if they've never been screened, please give this a try."

Beyond prevention, trials of therapeutic vaccines and alternatives to surgery for abnormal growths are underway. A Phase 3 clinical trial is investigating the malarial drug artesunate in the form of a vaginal insert for women with high-grade dysplastic lesions.

"In Phase 1 trials, the drug had a nearly 70% clearance of HPV types 16 and 18 [the two riskiest HPV types]," says Harper.

"I'm really hopeful that we will have a treatment for HPV that will make having an HPV infection like treating any infection," she adds. "We hope to take an HPV infection from being an ugly cancer into something primary care doctors can treat in their offices."

Oropharyngeal cancer

Each year more than 18,700 men and 3,800 women are diagnosed with oropharyngeal cancer, according to data from the National Cancer Institute. HPV is the culprit in 70% of these cases. The disease primarily affects the tonsils and the base or back of the tongue.

"Oropharynx cancer is now the predominant HPV-related cancer," says Carole Fakhry, MD, MPH, professor of epidemiology, oncology, and otolaryngology head and neck surgery at Johns Hopkins University School of Medicine. "We consider it to be epidemic because the rate of growth is so high."

The typical presentation is a neck mass. "Often the patient says they noticed it when they were shaving, and they might initially get antibiotics until someone figures it out," Fakhry says.

Men in their 60s are typical patients.

"When we first described this, it was really a disease of younger men, and what we've seen is that the median age has been increasing over time," Fakhry adds. "Now we're seeing more and more 80-year-olds with it."

The problem is there are no screening tests for oropharyngeal cancer, Fakhry says. Doctors have tried to use Pap smears, but the anatomy of the throat makes it difficult to access.

"And we don't do HPV testing, because we wouldn't know what to do with it," she says. A positive blood test wouldn't be specific to the head and neck, for instance.

HPV-linked oropharyngeal cancers have a good prognosis, with a five-year survival rate of 90% to 95% in nonsmokers. But the treatment - radiation or surgery alone, in combination with each other, or with chemotherapy - "is a lot for patients to go through," Fakhry points out.

Immunotherapy and personalized treatments based on circulating tumor DNA are now playing a greater role, and there are de-escalation trials that aim to use less of a treatment while tempering side effects, says Fakhry.

Thus the outlook is more favorable than it was 20 years ago. "We're learning more about oropharynx cancer, and we have more nuanced knowledge about how to treat it," she says.

HPV vaccination is the answer for future generations. In the meantime, Fakhry says, "this disease is here with us for the next few decades, so we should remain vigilant." Men should stay alert to masses in the neck, she says, and physicians should waste no time in referring patients for further workup.

Anal and other cancers

Although the absolute number of cases is small, researchers have noted concerning rises in anal cancer as well as penile, vulval, and vaginal malignancies. More than 91% of anal cancers are associated with HPV.

The increase is "pretty dramatic, and this has been happening steadily since the 1970s," says Joel Palefsky, MD, professor of medicine and infectious diseases at the University of California San Francisco School of Medicine. "We hypothesize that that may reflect changes in sexual practices."

In the general population, anal cancer is more than twice as common in women (some 7,700 cases annually) than in men (about 3,570 cases), possibly because there are two routes to infection - anal sexual activity, and spread of the virus from the cervix and the vulva, Palefsky says.

In addition to women with cervical and vulval cancers, men who have sex with men with HIV are at particular risk, says Palefsky.

"In many people's minds, anal cancer has become conflated with that group, when in fact most of the cases do not come from that group," he says. That's led to significant stigma around the cancer.

While vaccination is the key to preventing anal cancer in future generations, secondary prevention is needed for those who didn't receive the vaccine, says Palefsky.

Screening for anal cancer, which is recommended for people in high-risk groups, is adapted from approaches used to screen for cervical cancer. Palefsky's 2022 ANCHOR study showed that "treating the anal precancers just like you would in the cervix actually reduces the incidence of anal cancer," he says.

Anal cancers are mostly caught at Stages 1 and 2, which have good survival rates. But standard treatments can have debilitating side effects.

"Radiation, in particular, since you're aiming it down in the pelvis, leads to a high proportion of people having chronic pain, bleeding, and loss of bowel control," Palefsky says. For that reason, doctors are investigating the use of modulated radiation therapy.

In addition, "there are a number of different studies planned or in progress to see if immunomodulation, such as the use of checkpoint inhibitors, can be used as monotherapy or with various forms of chemoradiation to improve survival," he adds.

Experts hope that such approaches and new screening strategies will make a difference for patients with all HPV-associated cancers over the next few decades, until widespread vaccination makes these cancers diseases of the past.

Says Fakhry, "Hopefully, people are vaccinating and these diseases just go away."