Does HPV Cause Lung Cancer?

Associations With Non-Smokers, Women, and Geographical Differences

lung cancer cells that contain HPV
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In a 2008 review of 53 studies published in the journal Lung Cancer, the authors stated that HPV may be the second leading cause of lung cancer after cigarette smoking, and additional research on this issue was strongly needed. Since that time a number have studies have found an association between HPV and lung cancer, but this varies significantly with geography, smoking status, gene mutation status, and more. Despite the correlation between HPV and lung cancer (especially in never smokers, women, and Asians), it's not certain whether HPV is a cause of the disease. While few studies have looked at the prognosis of lung cancer that is HPV positive, some suggest that it may be better overall, and predict a better response to treatment.

Understanding HPV (Human Papillomavirus)

HPV (human papillomavirus) is a collection of more than 200 viruses that can infect humans. Of these, roughly 30 are capable of causing cancer, with the most common "cancer-causing" strains being HPV 16 and HPV 18.

HPV is most often spread through skin-to-skin contact, frequently sexually. Most infections with HPV clear spontaneously within 2 years without causing any further problems, but some linger on. Infection with a “cancer-causing” strain of HPV does not mean a person will develop cancer. In fact, most infections with HPV do not develop into cancer.

HPV is known to infect epithelial cells and works to disrupt the normal cellular processes which control cell growth. Even when this occurs, most of these abnormal cells will be detected and removed by our immune systems.

HPV and Cancer

HPV is now well-established as playing a role in most cases of cervical cancer, as well as many cases of vulvar cancer, penile cancer, roughly 95 percent of anal cancers, and 70 percent of oral cancers, especially those occurring in young, non-smoking women. HPV 18 and HPV 16 are the cause of around 70 percent of HPV-induced cervical cancers, and HPV 16 is responsible for over half of HPV induced oral cancers.

Thus, we know that HPV infections can result in cancer and that it causes some cancers near the lung region. We also know that viral infections can contribute to developing lung cancer, for example, those with HIV infections are more likely to develop lung cancer than those not infected with HIV, but can it cause lung cancer?

Lung Cancer Causes and Risk Factors

Looking at the causes of lung cancer is extremely important. Unfortunately, the stigma that lung cancer is a smoker's disease has in some ways slowed progress in evaluating other possible causes. But lung cancer occurs in non-smokers as well. In the United States, 20 percent of women who develop lung cancer have never smoked a single cigarette, and that number rises to 50 percent of women with lung cancer worldwide who are lifelong non-smokers. In fact, lung cancer in never-smokers is the 6th leading cause of cancer-related deaths in the United States.

Increasing Lung Cancer in Young, Never-Smoking Women

Recently in the United States, and increased incidence of lung cancer in young women who have never smoked has been noted, and the potential causes are unknown. This, combined with the number of never smokers worldwide who develop disease, indicates that better research into the causes is greatly needed. Could HPV be one of the culprits?

History and Geography of HPV and Lung Cancer

The possibility that HPV may play a role in the development of lung cancer was first suggested in 1979. Several studies since that time have found evidence of HPV DNA in lung cancers, but this varies significantly depending on geography. In the United States, HPV DNA is found in about 15 percent of lung cancers, depending on the study, with HPV 16 and HPV 18 most commonly found—the strains most implicated in cervical cancer.

In Europe, the presence of HPV DNA in lung cancers is around 17 percent, but this number jumps to 69 percent in Greece and Taiwan and 79 percent in Japan. We do know that lung cancer in non-smokers is more common in Asia. We also know that HPV appears to be more commonly found in lung cancer cells of women and non-smokers than men and people who smoke. In Asian studies, the incidence of HPV in lung cancers was similar between never smokers and ever smokers, whereas the incidence was much higher (by a factor of seven) in never smokers than ever smokers in Europe.

Two 2016 studies illustrate these geographical differences even further. In one study, it was found that Taiwanese women were significantly more likely to develop lung cancer if they had been exposed to HPV. In contrast, a Chinese study found no association between HPV antibodies (a sign of exposure) and the development of lung cancer.

More recently, a 2018 Brazilian study found HPV DNA in nearly half of lung tumors evaluated (HPV 16 in 81 percent and HPV 18 in 19 percent). In this study, however, researchers found not only evidence of HPV, but of E6 and E7 oncoproteins. This can be confusing, but essentially means that the virus was not only present but was active in tumor cells. Their conclusion was that HPV could play a role in causing these lung cancers.

Positive HPV and EGFR Mutations

In East Asia, the incidence of non-small cell lung cancer (particularly lung adenocarcinoma) in never smokers is particularly high. We've known for some time that EGFR mutations (EGFR positive lung cancer) are more common in never smokers, women, individuals of Asian ancestry, and young adults with lung cancer.

In a 2018 study, researchers looked at four studies evaluating lung cancer in Asian countries.

The study found a significantly higher prevalence of EGFR mutations in people with non-small cell lung cancer who were positive for HPV than among those who were negative for the infection.

Overall, the EGFR mutation rate in this group was 38 percent, and the HPV infection rate was 35 percent. The author's conclusion was that HPV was associated with EGFR mutations in lung cancer, at least in an Asian population.

Does HPV Infection Cause Lung Cancer?

Though HPV has been found in lung cancer cells, especially in squamous cell carcinoma of the lungs, the clinical significance of finding HPV in lung cancer cells still isn't known or understood. Let's look at some of the reasons that this question isn't easily answered.

Causation vs. Correlation

Whether the presence of HPV in lung cancer indicates causation (that HPV causes lung cancer) is another question. Just because there is a correlation between 2 things—in this case the presence of HPV and the development of lung cancer—says nothing about causation. The easiest way to describe this is by using an example. There is a strong correlation between eating ice cream and drowning but that does not mean that eating ice cream causes drownings to occur. In this case, there is a correlation between two things that are otherwise unrelated.

In addition, instead of causation or unrelated correlation, the presence of HPV and lung cancer could instead be a "chicken and egg" question. Which came first? Perhaps lung tissue which is damaged by the presence of a cancer is simply more susceptible to becoming infected with HPV. If this were the case, HPV would be considered an "opportunistic infection" much like the infections that people with HIV acquire. With AIDS, it is the damage caused by HIV that renders the body susceptible to infections such as pneumocystis pneumonia, not the other infections causing HIV.

Primary Lung Cancer vs. Metastases

In some studies, lung cancer appears to be more common in those who have had cervical cancer. In one fairly large study (which concluded that HPV is rarely if ever associated with developing lung cancer in Canada and North America), it was found that HPV infection was present in only 1.5 percent of patients, and that all of these patients had experienced previous squamous cell cancers (such as cervical or oral cancer) related to HPV. Even though these lung cancers appeared to be primary lung cancers, the question that was raised is that instead, these infections may represent metastatic cancer to the lungs from the previous cervical and oral cancers.

HPV as a Carcinogen

We're pretty certain that HPV works as a carcinogen —a cancer-causing substance—when it comes to cervical, penile, vaginal, and oral cancers, but what about lung cancer? If HPV is implicated in lung cancer, the current thought seems to be that HPV may be a cofactor in developing lung cancer. In other words, the virus may work together with other risk factors such as radon or tobacco exposures to produce a cancer. It's also thought that, unlike cervical cancer, if HPV is indeed a cause or cofactor in lung cancer, it's likely that this is limited to only some lung cancers.

HPV and Lung Cancer Prognosis

Interestingly, those people who have evidence of HPV in lung cancer cells appear to have a better prognosis than those who do not have evidence of HPV in lung cancer cells. This finding gives some credence to the possible role of HPV in lung cancer when compared to oral cancers. Oral cancers caused by HPV tend to have a better prognosis than those that are related to tobacco use.

In the East Asian study looking at EGFR mutations and HPV above, people with non-small cell lung cancer who tested positive for HPV, had a better prognosis, and were more likely to respond to tyrosine kinase inhibitors (EGFR inhibitors such as Tarceva).

A Word From Verywell

It will likely be some time before we know what, if any, the true relationship between HPV and lung cancer really is. As noted, there are many variables we don't yet understand. Further research will be needed to evaluate the presence of HPV in lung cancer cells, and to explain the great geographical differences that seem to exist. As noted above, even a clear correlation between HPV and lung cancer does not indicate causation. It could be that they are unrelated, or even that lung cancer tissue is more susceptible to infection with HPV and that lung cancer is a "cause" of HPV infection rather than the other way around.

HPV Prevention

So what does this mean for prevention? Minimizing exposure to HPV through safe sex is a good start. For those who are on the fence about the HPV vaccine, this may provide a little further support.

Lowering Lung Cancer Risk

Thankfully we do know of several risk factors for lung cancer over which we have control. Check out these 10 tips for preventing cancer. Make sure you have had your home checked for radon - the leading cause of lung cancer in non-smokers and consider adding some of these foods thought to reduce lung cancer risk to your diet. And don't forget: anyone who has lungs can get lung cancer.

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