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The Most Frequently Asked Questions About HPV (And A Few Infrequent Ones Too)
1) What is the human papilloma virus (HPV)?Open or CloseThe term HPV is used to describe a family of viruses that has more than 200 members. According the HPV Research Group at the University of Washington, “These viruses are classified biologically (and phylogenetically) into cutaneous or mucosal types depending on whether they generally infect keratinizing or non-keratinizing epithelium. (Formal classification of individual genotypes is based on the sequence homology in the L1 region of the genome.)” Some members of this family cause warts (papillomas). These are transmitted by skin to skin contact. Other members of this family can cause cancer. At least 40 members of this virus family are thought to contribute to the development of cancer via infection from the skin or mucous membranes of an infected person. These are known as high risk types. Most HPV-caused cancers arise from an infection with types 16 or 18.
Though there are many different types of HPV, they are not equally common. Types 6 and 11 cause 90 percent of genital warts (also called condylomata acuminata or venereal warts). Types 30, 42, 43, 45, 51, 54, 55, 70 make up the other 10 percent of genital wart cases. Types 6 and 11 also cause something called laryngeal papillomatosis, also known as respiratory papillomatosis, which is a rare disease where benign cancers form in the throat. These are NOT the strains that are generally associated with causing HPV cancers. Genital warts do NOT turn into cancer. They are, however, more contagious than the common warts one gets on the hands and feet. There are between 0.5 to 1 million new cases of HPV caused genital warts diagnosed in the US each year.
Some strains of papilloma viruses are associated with common warts on your hands (strains 2, 7, 22) as well as plantar warts on your feet (strains 1, 2, 4, 63). A more complete table showing HPV types and disease associations can be found in Eileen Burd’s review Human Papillomavirus and Cervical Cancer (Clinical. Microbiol Rev. 2002, 16(1), 1-17. doi 10.1128/CMR.16.1.1-17.2003)
That a virus is actually responsible for the development of skin warts was not figured out until 1907. That the HPV virus is responsible for causing a number of human cancers was not determined until 1983 by Dr. Harald zur Hauzen, a German virologist. The work arose out of studies on genital warts, which were shown to harbor papilloma viruses. Eventually it was figured out that a high percentage of cervical cancers were found to harbor specific strains of papilloma viruses. This led to a worldwide effort to examine a large number of cervical cancers for the presence of papilloma virus. in 1995 the International Biological Study on Cervical Cancer group looked at cervical cancer samples from 22 countries. HPV was found in more than nine out of every ten cervical cancer samples (93 percent), and this figure was consistent across the globe. This 93 percent figure actually turned out to be an underestimate. In 1999, a group of scientists carefully retested the samples and found that virtually all cervical cancer samples (99.7 per cent) contained the virus. This indicated that HPV infection is an important trigger for cervical cancer. This was, and remains to this day, the strongest link between HPV and the cancers it causes. More details can be found in Harald zur Hauzen’s Nobel Prize biography. He shared the Nobel Prize in Physiology or Medicine with two other scientists (who discovered the HIV virus) in 2008.
2) How common is infection with this virus?Open or CloseHPV infections are the most common sexually transmitted infection. More than 79 million Americans are currently infected with this virus. To put this in context, the total population of the US in 2018 was about 328 million people, so about 25 percent of the population is currently infected. In addition, about 14 million more people in the US are infected with HPV every year. That’s a huge number compared to new cases of other sexually transmitted diseases such as chlamydia (1.7 million), gonorrhea (556,000), or primary or secondary syphilis (about 30,000). For additional context, the number of new cases of HIV (which is not just spread via sex) is estimated to be about 38,000 per year in the U.S. About 80 percent of the US population will be infected with HPV sometime in their lifetimes.
The probability of a woman in the US acquiring an HPV infection sometime in her life is about 85 percent; for men the likelihood is 91 percent. These numbers go up with an increase in the number of sexual partners. Immunization with the HPV vaccine prevents infection with the virus.
The Centers for Disease Control and Prevention (CDC) estimates that more than 90 percent of HPV infections are "cleared" by the body within two years, and this usually happens within six months. However, it is not known for certain whether the body actually gets rid of the virus altogether, or – as appears to happen in at least some women – the virus is merely suppressed to a low, undetectable level. It's possible that either scenario can occur, depending on the woman.
It’s believed that these suppressed HPV infections can "re-activate" years later, most likely due to changes in your immune system. In addition, if you have sexual contact with a new partner, you could get a new HPV infection with a different strain of the virus.
Molano M. et al Determinants of clearance of human papillomavirus infections in Colombian women with normal cytology: a population-based, 5-year follow-up study. Am J Epidemiol 2003;158(5):486–94. doi: 10.1093/aje/kwg171.
Franco EL et al Epidemiology of acquisition and clearance of cervical human papillomavirus infection in women from a high-risk area for cervical cancer. J Infect Dis 1999;180(5):1415–23. doi: 10.1086/315086.
Ho GY et al. Persistent genital human papillomavirus infection as a risk factor for persistent cervical dysplasia. J Natl Cancer Inst 1995;87(18):1365–71. doi: 10.1093/jnci/87.18.1365.
3) What types of cancer does this virus cause?Open or CloseHPV infection is associated with six different types of cancer. Both men and women can get cancer of the oropharynx (the back of the throat as well as the tonsils and base of the tongue) as well as the anus/rectum following HPV infections. Men can also get penile cancer from HPV, and women can develop cervical, vaginal, and vulvar cancers from the virus.
A new report suggests that cancers of the vocal cords are also caused by HPV in both men and women, but I am awaiting confirmation of this initial observation. The research found that 10 out of 10 patients with vocal cord tumors were all positive for cancer-causing strains of HPV, and these patients were all under the age of 30, and 3 were 10 to 19! Bayan et al Glottic Carcinoma in Young Patients. Annals of Otology, Rhinology & Laryngology, 2019; 128 (3_suppl): 25S DOI: 10.1177/0003489418818852
According to the National Cancer Institute, the HPV virus is believed to be responsible for about 70% of cervical cancers, 65 percent of vaginal cancers, 50 percent of vulvar cancers, 35 percent of penile cancers, 95 percent of anal cancers, and 70 percent of oropharyngeal (back of the throat, tonsil, and base of the tongue) cancers. The cellular types of these cancers include carcinomas of the cervix and squamous cell carcinomas of the vagina, vulva, penis, anus, rectum, and oropharynx.
Data from the CDC indicates that in 2015, oropharyngeal cancers made up only 14% of all HPV-cancers in women. The most prevalent HPV-cancer in women is cervical cancer (48%), followed by anal cancers (18%), vulval cancers (16%), and vaginal cancers (3%). Contrast this with men, where oropharyngeal cancers made up 82% of all HPV-cancers in men, followed by anal cancers (12%) and penile cancers (6%).
Worldwide, high risk HPV strains (6/11/16/18/31/33/45/52/58) are thought to cause about 90 percent of cancers of the tissues mentioned above. HPV-caused cancers account for about 5 percent of all cancers worldwide. Broken down by gender, that’s about 8.6% of women and 0.8% of men. The reason for the disparity is the large number of cervical cancer cases in women in less developed countries.
de Martel et al Worldwide burden of cancer attributable to HPV by site, country and HPV type
Int J Cancer. 2017 Aug 15; 141(4): 664–670, doi: 10.1002/ijc.30716
4) How do you catch the strains of HPV that cause cancer?Open or CloseHPV is primarily spread by intimate skin to skin contact. You can be exposed to the virus by having oral, vaginal, or anal sexual contact with someone who is already infected. The virus can be transmitted by penetrative as well as non-penetrative sexual contact (genital-genital, oral-genital, anal-genital, oral-anal). Since many people have no symptoms of infection, it’s pretty common to become infected and to not even realize that has happened.
Most people will never develop symptoms of the infection as their immune systems will successfully eliminate the virus. However, some infected individuals will go on to develop either genital or anal warts, or to develop oral, anal, vaginal, vulval, penile, or cervical cancers. It can take years or even decades for these cancers to develop, making it very difficult to identify when a person actually became infected. Risk factors for catching HPV infections include an early age of first sexual intercourse, an increasing number of sexual partners, smoking, and having a compromised immune system (see details below).
Source: CDC Genital HPV Infection - Fact Sheet
It had been thought that the hands can also transmit a genital, oral, or anal HPV infection. However, a new report in 2019 showed that the hands are actually a very unlikely source of viral transmission.
Malagon et al Hand-to-genital and genital-to-genital transmission of human papillomaviruses between male and female sexual partners (HITCH): a prospective cohort study. The Lancet Infectious Diseases Feb. 2019
5) HPV-caused cancers account for what percentage of all human cancers?Open or CloseWorldwide, about 16 percent of all cancers are caused by infectious diseases (primarily the bacteria Helicobacter pylori as well as HPV and hepatitis B and C viruses). Since HPV causes about 28 percent of all infection-related cancers globally, this means that about 5 percent of all cancers worldwide. Broken down by gender, that’s about 8.6% of women and 0.8% of men. The reason for the disparity is the large number of cervical cancer cases developed by women in poorer nations.
de Martel et al Worldwide burden of cancer attributable to HPV by site, country and HPV type
Int J Cancer. 2017 Aug 15; 141(4): 664–670, doi: 10.1002/ijc.30716
A higher proportion of cancer cases are due to infection in lower income countries, particularly in Asia and Sub-Saharan Africa. Women in these areas often do not get Pap tests that would show the possible development of cervical pre-cancers at an early stage, and these women are also much less likely to get the HPV vaccine that prevents infection with this cancer-causing virus.
6) How many people in the US get these cancers every year?Open or CloseLet’s start by looking at the previous numbers from the US in from 1999 to 2015, courtesy of the CDC:
There were a total of 43,371 HPV-associated cancers per year in 2015 in the US (not all of these are caused by HPV, as explained below). Let’s break that down by gender:
There were 24,432 cases of HPV-associated cancers in women, including 11,788 cases of cervical cancer, 3,890 cases of vulvar cancer, 809 cases of vaginal cancer, 4,507 cases of anal cancer, and 3,438 cases of oropharyngeal cancer.
There were 18,939 cases of HPV-associated cancers in men, including 1,224 cases of penile cancer, 2,236 cases of anal cancer, and 15,479 cases of oropharyngeal cancer.
The American Cancer Society projects 53,000 cases of head and neck cancers (about 70% of which are caused by HPV) will be diagnosed in the United States this year, and an estimated 10,860 people will die of these cancers.
The most common HPV cancer in women is cervical cancer, but in men, it’s oropharyngeal cancer. Note that of the two HPV associated cancers that both men and women can get, the ratios are highly skewed. Anal cancers in women outnumber those in men by 2 to 1. Oropharyngeal cancers in men outnumber those in women by 4.5 to 1.
Now not all of these HPV-associated cancers are actually caused by HPV. That’s because not every cancer case for these tissues is tested to look for the presence of HPV. However, studies have been done to estimate the percentage of these cancers that are believed to be caused by the virus. These percentages are 99% for cervical cancer, 90% for anal cancer, 75% for vaginal cancer, 70% for vulvar cancer, 60% for penile cancer, and 70% oropharyngeal cancer.
So let’s redo the math to find out how many cancer cases can really be attributed to HPV:
Cervical: 11,788 cases x 0.99 = 11,670
Anal: [4,507 cases (women) + 2,236 cases (men)] x 0.90 = 6,069
Vaginal: 809 cases x 0.75 = 607
Vulvar: 3,890 x 0.70 = 2723
Penile: 1,224 x 0.60 = 734
Oropharyngeal: [3,438 cases (women) + 15,479 cases (men)] x 0.70 = 13,242
Total number: 35,045 cases would actually be caused by HPV. That represents about 81% of the cases across all tissue types.
Now let’s look at the latest numbers published by the CDC in 2019. As you can see below, the numbers have hardly changed at all from 1999-2015. Still about 35,000 cases per year of HPV-caused cancers in the US. The numbers here are broken out into three groups:
Those caused by HPV strains targeted by the current HPV vaccine Gardasil 9 (9vHPV-targeted)
Those caused by other HPV strains that are NOT targeted by the current HPV vaccine Gardasil 9 (Other HPV)
Those that have causes other than HPV (HPV-negative)
7) What are the risk factors for catching HPV?Open or CloseThe risk factors for catching HPV infections include:
Number of sexual partners. The more sexual partners you have, the more likely you are to contract a genital HPV infection. Having sex with a partner who has had multiple sex partners also increases your risk.
Age. Common warts occur mostly in children. Genital warts occur most often in adolescents and young adults.
Weakened immune systems. People who have weakened immune systems are at greater risk of HPV infections. Immune systems can be weakened by HIV/AIDS or by immune system-suppressing drugs used after organ transplants.
Damaged skin. Areas of skin that have been punctured or opened are more prone to develop common warts.
Personal contact. Touching someone's warts or not wearing protection before contacting surfaces that have been exposed to HPV — such as public showers or swimming pools — might increase your risk of HPV infection.
Source: Mayo Clinic
Risk factors specific for oral HPV infections include:
Oral sex. The prevalence of oral HPV infection was increased in subjects who had experience with oral sex as compared to those who did not.
Number of oral sex partners. Those with more oral sex partners had a higher incidence rate for HPV infection.
Smoking. This was significantly associated with oral HPV infections in both men and women
Source: See Shigeshi and Sugiyama Risk Factors for Oral Human Papillomavirus Infection in Healthy Individuals: A Systematic Review and Meta-Analysis J Clin Med Res. 2016 Oct; 8(10): 721–729. doi: 10.14740/jocmr2545w
8) Is there a way to prevent infection with HPV?Open or CloseYes. There are two ways to prevent infection with HPV. One is to be immunized against the virus with a safe and effective vaccine. Note, however, that this will only prevent infection with any of the nine strains that the current vaccine (Gardasil 9) protects against. It does not offer protection against other HPV strains. Click here to learn more about the vaccine.
The other way is to practice safe sex, which means having protected sex (oral, vaginal, and anal) with anyone who might harbor the virus. This means using condoms, dental dams, or other types of barrier protection. However, this does not bring your risk to zero, because the virus can be transmitted by skin to skin contact. For example, HPV can infect areas that are not covered by a condom—so condoms may not fully protect against infection. Simple contact with the shaft of the penis or the labia may be sufficient to transfer the virus.
9) If you’re infected with a cancer-causing strain of HPV, does this mean you will definitely get cancer?Open or CloseNo. In fact the vast majority of people infected will NOT get cancer. Less than 1 percent of people infected with a cancer causing strain of HPV will go on to develop cancer. Most peoples immune systems will prevent this from happening. For example, a study of college-age women showed that approximately 70 percent of women with any strain of HPV infection became HPV negative within 1 year and as many as 91% of them became HPV negative within 2 years, with a median duration of infection of 8 months. When they focused in on the most prevalent cancer causing strain, HPV 16, the 2 year clearance rate was still a very high 72 percent.
If your immune system does not fight off the infection with HPV, researchers believe that it can take between 10 and 30 years from the time of initial HPV infection until a tumor forms. For women, even if severely abnormal cells are seen on the cervix during a Pap smear (a condition called cervical intraepithelial neoplasia 3, or CIN3), these do not always lead to cancer. The percentage of CIN3 lesions that progress to invasive cervical cancer has been estimated to be 50% or less.
10) How many people are newly infected with HPV each year in the US?Open or CloseHPV infection is not a nationally reportable condition, so this number has to be estimated. The NCI and the CDC put the number of new genital HPV infections at 14 million new cases per year. Unlike other sexually transmitted infections, most people infected with HPV will never realize that they’ve been infected, as few will have any symptoms.
11) Do some types of HPV cause genital warts?Open or CloseYes they do. Genital warts usually appear as a small bump or a group of bumps in the genital area. In men, genital warts may be found on the scrotum, on the shaft of the penis, and in and around the tip of the penis. In women, genital warts may be found on the vulva, in the vagina, and on the cervix. In both men and women, warts can be found in the groin and in and around the anus. Oral sex can result in warts around the mouth, in the mouth, on the tongue or gums, and in the throat.
A study done from 2000 to 2005 (before the HPV vaccine was available) showed that the highest incidence of genital warts in both men and women was between the ages of 20 and 24. Slightly less than 1% of the people examined were found to have genital warts. For women, 63% of the warts were on the vulva, and 21% were on the cervix.
Note that the strains of HPV that cause genital warts are DIFFERENT from the ones that cause cancer. The most common HPV strains that cause genital warts in both women and men are 6 and 11, whereas the most common cancer-causing strains are 16 and 18. Both the original Gardasil vaccine as well as the newer Gardasil 9 version provide protection against all four of these strains. That’s because the vaccine was designed to protect those who are immunized with it against both genital warts and cancer. Gardasil 9 also protects against an additional five cancer-causing strains (31, 33, 45, 52, and 58) of HPV.
Source: Camenga et al Incidence of genital warts in adolescents and young adults in an integrated health care delivery system in the United States before human papillomavirus vaccine recommendations. Sex Transm Dis. 2013 Jul;40(7):534-8. doi: 10.1097/OLQ.0b013e3182953ce0.
While genital warts are caused by certain wart causing strains of HPV, an analysis of these warts indicated that they are sometimes co-infected with multiple strains of HPV, including cancer causing strains. In one study of surgically removed anogenital warts, cancer causing HPV types were found in 35% of patients. The prevalence of HPV infection with a single type was 88.4, 9.0% for two types, and 2.6% for three types.
Al-Awadhi et al Association of HPV genotypes with external anogenital warts: a cross sectional study. BMC Infectious Diseases (2019) 19:375 https://doi.org/10.1186/s12879-019-4005-4
12) Is the HPV virus very efficient at causing either genital warts or cancer?Open or CloseIt’s very inefficient. In one study Less than 1% of people screened for genital warts had them, although this number (as well as the study itself) doesn’t tell us what percentage of the people examined were actually infected with the virus. But given how high a percentage of the population is infected with HPV, the virus is not very efficient in causing genital warts. That’s because more than 79 million Americans are currently infected with one or more strains of HPV. To put this in context, the total population of the US in 2018 was about 328 million people, so about 25 percent of the population is currently infected. In addition, about 14 million more people in the US are infected with HPV every year. About 80 percent of the US population will be infected with HPV sometime in their lifetimes. The probability of a woman in the US acquiring an HPV infection sometime in her life is about 85 percent; for men the likelihood is 91 percent.
Source: Camenga et al Incidence of genital warts in adolescents and young adults in an integrated health care delivery system in the United States before human papillomavirus vaccine recommendations. Sex Transm Dis. 2013 Jul;40(7):534-8. doi: 10.1097/OLQ.0b013e3182953ce0.
The vast majority of people infected with HPV will NOT get cancer. Less than 1 percent of people infected with a cancer causing strain of HPV will go on to develop cancer. Most peoples immune systems will prevent this from happening. For example, a study of college-age women showed that approximately 70 percent of women with any strain of HPV infection became HPV negative within 1 year and as many as 91 percent of them became HPV negative within 2 years, with a median duration of infection of 8 months. When they focused in on the most prevalent cancer causing strain, HPV 16, the 2 year clearance rate was still a very high 72 percent.
Source: Ho GY et al Natural history of cervicovaginal papillomavirus infection in young women N Engl J Med. 1998 Feb 12;338(7):423-8.
13) How can I tell if I’ve been infected with HPV?Open or CloseThere’s no easy way to do this because there’s no single exam (such as a blood test) that can be used to determine your HPV status at multiple body sites. There are tests that can be done on specific tissues that develop HPV-associated cancers (i.e. the mouth, anus, vagina, vulva, and penis), but these are simply not done routinely.
For many years, the only screening tests recommended by the U.S. Preventive Services Task Force (USPSTF) for HPV-caused cancers was the Pap test for cervical malignancies. A Pap test looks for changes in cervical cells that indicate that the cells might become cancerous, or already are. A Pap test is NOT the same as an HPV test. The Pap test has been the gold standard for detecting precancerous cells of the cervix (that may develop into cancer) for many years. Recently, however, it has been proposed that the Pap test can be replaced by molecular tests that screen for the presence of the HPV virus. The USPSTF issued its latest recommendations for cervical cancer screening, which now say women 30 and older can drop the traditional Pap tests every 3 years in favor of testing for human papillomavirus (HPV) every 5 years, if they choose to.
Here are the details:
Women 21-29 should receive a Pap test every 3 years to check the cervical lining for abnormal cells.
Women 30-65 should receive either a pap test every 3 years, an HPV test every 5 years, or a combination of both every 5 years.
Healthy women younger than 21 most likely don't need any screening.
Women older than 65 who've had normal testing in recent prior years likely don't need any screening.
Healthy women who've had a hysterectomy with cervix removal likely do not need screening.
14) If you’re already infected with one strain of HPV, can you be infected with another?Open or CloseThe short answer is yes. A study was done looking at women who were referred for HPV testing when they were having cells from their cervixes examined. Twenty four percent of the women were positive for HPV infection, and 19 percent of those infected with one strain also harbored a second strain. The overall percentage of women who were infected with at least two strains of HPV was 4.6 percent. "Women who harbor multiple infections are at higher risk for cervical lesions than those ever infected with one type only and should be followed more closely," said Eduardo L. Franco, Dr.PH., professor of epidemiology and oncology, and director, division of cancer epidemiology at McGill University. The research raises the possibility that in women with multiple infections, their immune systems may be less robust in clearing the infections. HPV 16, the most well known cancer causing strain, was found in 9 percent and 14 of single and multiple HPV infections, respectively.
15) Can the vaccine prevent you from being infected by another strain if you’re already infected with HPV?Open or CloseIn theory the vaccine should prevent someone who is already infected with HPV from being infected by a second strain, providing that the second strain is one of the nine strains that the Gardail 9 vaccine works against. Those who received the earlier vaccines (Cervarix or Gardasil) that only protected against two strains (16 and 18) or four strains (16, 18, 6, and 11), respectively, could also get some benefit from the most recent vaccine, Gardasil 9, that provides protection from an additional seven strains or five strains, respectively. Keep in mind that the most prevalent cancer causing strains (16 and 18) are found in the vast majority of HPV-caused cancers. For example, WHO reports that 70 percent of cervical cancers are linked to these two strains. One study estimated that the Gardasil 9 vaccine may prevent an additional 4.2 percent to 18.3 percent of cancers compared to the earlier vaccine targeted at just strains 16 and 18. Thus, there are diminishing returns in getting the newest vaccine if you’ve already been immunized with the earlier ones. In addition, your insurer may not pay for a second series of vaccine shots if they’re already covered an earlier version of the vaccine. Check with your doctor if you are concerned about this.
16) Can HPV-associated oral cancers have other causes besides the virus?Open or CloseYes they can, but the vast majority of these cancers are caused by infection with HPV. According to the American Cancer Society, cases of oral and oropharyngeal cancers used to be primarily associated with smoking and/or and drinking alcohol, but as the rates of those behaviors has declined, the incidence of oropharyngeal cancers has actually increased. There are other risk factors that increase your likelihood of developing oropharyngeal cancers. These include certain genetic diseases (e.g. Fanconi anemia and dyskeratosis congenital) as well as poor nutrition and a compromised immune system. As with many cancers, some people will have none of these risk factors and will still develop these cancers, and others may have a number of these risk factors as part of their health history, and they will never develop cancer.
17) Since HPV can cause oral cancer, can the infection be spread by kissing?Open or CloseIt is generally believed that this is possible. A 2009 study showed that the risk of contracting oral HPV increased with the number of partners who engaged in open mouth kissing (but had not engaged in oral sex). A similar finding arose out of a 2012 study. However, while many believe that while the virus can be shared via kissing, this is not an efficient route for transmission. Oral HPV cancers are generally thought to arise from viral infections that are passed by oral sex. Note: it is the virus in the mouth (or other parts of the body) that is contagious, NOT the oral cancers caused by HPV.
See Shigeshi and Sugiyama Risk Factors for Oral Human Papillomavirus Infection in Healthy Individuals: A Systematic Review and Meta-Analysis J Clin Med Res. 2016 Oct; 8(10): 721–729. doi: 10.14740/jocmr2545w
18) How does HPV cause cancer?Open or CloseThis is a complex issue, but I’ll give a short answer. There are thought to be two ways this happens. In one pathway, once you are infected with HPV, and if your body does not successfully fight off the infection, the DNA contained in the HPV virus (a member of the papilloma family of DNA viruses) integrates itself into your DNA. Put another way, the genetic material of the virus (its DNA) becomes integrated into and part of your own genetic material (your DNA). At some point the integrated virus begins to express the viral proteins E6 and E7, and it’s these oncoproteins (proteins that cause cancer) that help transform the cell from normal to cancerous. Those seeking greater details can look here.
The second way for the virus to cause cancer is for it to replicate itself inside the cell, but without integration. In these cases the virus appears to be mutated, leading to aberrant expression of he E6 and E7 proteins. There are also examples of cancers where the virus is both integrated and replicating. Which path the virus takes to cause cancer can vary between tissues. For example, viral integration seems to be more frequent in cervical cancer than it is in oropharyngeal cancer. It also appears to vary by viral strain. For example, in a series of cervical cancer samples examined, 76% of HPV16-positive samples have integrated HPV, whereas integration is evident in 100% HPV18-positive samples. Both paths can be taken as well i.e. the virus can be both integrated and episomal in the same tumor.
McBride AA, Warburton A (2017). The role of integration in oncogenic progression of HPV- associated cancers. PLoS Pathog 13(4): e1006211. https://doi.org/10.1371/journal.ppat.1006211
In a separate study, researchers analyzed 75 patients with HPV16+ oropharyngeal squamous cell carcinoma (OSCC). They found that HPV16-human fusion products indicating viral integration in 29 (39%) OSCC. In the remaining tumors (61%) only episome-derived PCR products were detected. When comparing OSCC with or without an integration-derived fusion product, they did not find significant differences in the mean RNA expression of viral genes E2, E6 and E7 or the viral copy numbers per cell, nor did the RNA expression of the HPV-disrupted genes differ from either group of OSCC. They concluded that constitutive, rather than a high level, of expression of oncogene transcripts appears to be required in HPV-related OSCC.
Olthof et al Comprehensive Analysis of HPV16 Integration in OSCC Reveals No Significant Impact of Physical Status on Viral Oncogene and Virally Disrupted Human Gene Expression. PLOS ONE February 2014 | Volume 9 | Issue 2. FREE download
In contrast, Parfenov et al noted that tumors that do and do not have HPV integration display distinct gene expression profiles and DNA methylation patterns.
Parfenov Characterization of HPV and host genome interactions in primary head and neck cancers. PNAS (2014) 111, 15544–15549. FREE download.
Finally, in a fourth study of 186 HPV+ head and neck cancer patients, viral integration only was found in 43% of the cancers sampled. The remainder were either episomal expression of the viral proteins, or mixed (both integrated and episomal). However, no statistically significant difference was found in disease specific survival between patients with HPV-positive integrated vs. extrachromosomal/mixed forms of the virus.
Vojtechova et al Analysis of the integration of human papillomaviruses in head and neck tumours in relation to patients’ prognosis. Int. J. Cancer: 138, 386–395 (2016) FREE download
Bottom line: HPV can cause H&N cancers whether or not it integrates into your DNA.
The E6 and E7 proteins serve as primary targets in the development of a number of clinical therapies aimed at treating HPV-caused cancers. As of 2018 none of these potential treatments have been approved by the FDA for use in patients with HPV-caused cancers.
19) Can HPV infections be transmitted via blood or other body fluids?Open or CloseThis is a bit of a complex issue, as explained here. This mode of transmission has not a big concern in the biomedical community. For example, blood donations are not currently screened for HPV, and the American Red Cross (and other Red Cross societies) do not prevent HPV-positive individuals from donating blood.
Having said that, a paper was recently published suggesting that blood transmission may be possible for papilloma viruses. The study came about after an observation made in 2005 where blood samples from a group of HIV-positive children were also found to be positive for HPV. Because of the age of the children (the usual sexual transmission mode of viral transfer), the researchers wondered if the virus could have come from blood transfusions, which some of the children had undergone. Researchers showed using two different animal models that the virus could be transmitted via blood. Whether or not this holds true for human papilloma viruses remains to be determined. Cladel, N.M. et al, Papillomavirus can be transmitted through the blood and produce infections in blood recipients: Evidence from two animal models. Emerging Microbes & Infections (2019). DOI: 10.1080/22221751.2019.1637072.
Infection through other body fluids like sperm or saliva is considered to be rather unlikely. However, the virus may spread during oral sex if mucous membranes in the mouth touch areas of skin of your partner that have been infected with HPV.
Transmission from the mother to baby via nursing has also been looked at in a couple of small studies. In one study it appeared that the virus might be transmitted via milk in a very small percentage of cases, but it appears to be rare. Milk from lactating women in Australia was examined in a separate study and a few samples were found to be HPV positive. Breast feeding of babies is still encouraged by virtually all organizations, so this is something that women should not be overly concerned about.
20) Can mothers transmit genital HPV infections to their unborn children? Are there any adverse events associated with being pregnant and having HPV?Open or Close
Can mothers transmit genital HPV infections to their unborn children?
Yes. This can lead to a rare disease known as recurrent respiratory papillomatosis (RRP), which can be diagnosed in both children (juvenile onset) and adults (where it may be acquired via sexual transmission, and not present since birth). It is associated with HPV strains 6 and 11 (these are the virus types that cause genital warts, not cancer). Children born with RRP typically develop symptoms of hoarseness and can develop a raspy voice, a chronic cough, and severe breathing problems during their toddler years. It’s treated by surgeries to remove the HPV lesions from the throat, and because it’s virally caused, these lesions can recur. The incidence of this disease is quite rare; only a small fraction of those infected with the virus will develop this condition. The mechanism of viral transmission is unclear, although it has been suggested it occurs in the birth canal since those born via Cesarean section appear to have a lower incidence of the disease. However, Cesarean birth does not prevent the baby from picking up the infection from the mother. There is some evidence that HPV can be transmitted to the fetus across the placenta, but others have been unable to find this mode of transmission. Kids born to moms who have been vaccinated with Gardasil 9 should not develop RRP as the two strains that cause it, 6 and 11, are targeted by the vaccine. This is yet another reason for girls to get immunized against this virus.
The HPV vaccine has been tested as a treatment for RRP. The idea is that the vaccine will prevent ongoing infection of cells by the virus, thereby cutting down on the number of surgeries needed. To date, only small scale studies have been done, but the vaccines appear to be working in these trials. According to the article, “The number of surgical procedures per month was significantly reduced after HPV vaccination compared with before vaccination (estimated mean, 0.06 vs 0.35). The mean intersurgical interval increased from 7.02 months (range, 0.30-45 months) before to 34.45 months (2.71-82 months) after HPV vaccination.” See Rosenberg, T. et al Therapeutic Use of the Human Papillomavirus Vaccine on Recurrent Respiratory Papillomatosis: A Systematic Review and Meta-Analysis. J Infect Dis. 2019 Mar 15;219(7):1016-1025. doi: 10.1093/infdis/jiy616.
In a small retrospective study, only n = 2 (15.4%) of the n = 13 vaccinated patients developed a recurrence of the disease after a mean time of 54.9 months (SD: 9.5 months). All patients who were not vaccinated (n = 11; 100%) developed a relapse after a mean time of 12.3 months (SD: 9.72 months). Mauz et al. HPV vaccination as preventive approach for recurrent respiratory papillomatosis - a 22-year retrospective clinical analysis. BMC Infectious Diseases (2018) 18:343 https://doi.org/10.1186/s12879-018-3260-0 FREE download.
In Australia, which has a very high rate of HPV vaccine usage, the incidence of RRP (or more specifically juvenile onset RRP) was impacted by the vaccine. Rates declined from 0.16 per 100000 in 2012 to 0.02 per 100000 in 2016 (P = .034). Novakovic, D. et al. A Prospective Study of the Incidence of Juvenile-Onset Recurrent Respiratory Papillomatosis After Implementation of a National HPV Vaccination Program. J Infect Dis. 2018 Jan 4;217(2):208-212. doi: 10.1093/infdis/jix498.
Are there any adverse events associated with being pregnant and having HPV?
In a meta analysis that looked at a large number of other studies, the authors found a consistent and significant association between HPV and preterm birth and preterm premature rupture of membranes. They also reported that HPV “may also be associated with intrauterine growth restriction, low birth weight, and fetal death, but findings are limited by suboptimal control of biases.”
Niyibizi, J. et al Association Between Maternal Human Papillomavirus Infection and Adverse Pregnancy Outcomes: Systematic Review and Meta-Analysis. The Journal of Infectious Diseases, jiaa054, https://doi.org/10.1093/infdis/jiaa054
21) Does being infected with HPV interfere with a woman’s ability to get pregnant?Open or CloseNo. According to the CDC, “Having HPV does not make it harder for a woman to get pregnant or carry a pregnancy to term. However, some of the pre-cancers or cancers that HPV can cause, and the treatments needed to treat them, might lower a woman’s ability to get pregnant or have an uncomplicated delivery. Treatments are available for the conditions caused by HPV, but not for the virus itself.”
22) Do people infected with HPV make antibodies against the virus?Open or CloseOnly about half of patients with a known HPV infection at any site will develop antibodies to HPV. There is no reliable test for prior HPV infection if the virus has been cleared from the original site of infection.
Reference: Pytynia KB et al Epidemiology of HPV-associated oropharyngeal cancer Oral Oncol. 2014 May ; 50(5): 380–386. doi:10.1016/j.oraloncology.2013.12.019.
Neutralizing antibodies against HPV can be protective, but these are triggered only after infection and cannot eliminate virus-infected cells. Reference: Roden, RBS and Stern, PL Opportunities and challenges for human papillomavirus vaccination in cancer Nature Reviews Cancer doi:10.1038/nrc.2018.13
23) Should I take an at-home HPV test to find out if I am positive for the virus?Open or CloseNo. There is really no good reason to do this, because the information that you get is not really actionable. What will you do differently armed with this information? Since there is no systemic test (i.e. one that would cover your entire body), you are going to have to choose just one particular tissue for each test (in this case, that would be vagina, vulva, penis, anus, or oral cavity). I do not believe you can do a cervical HPV test at home (SEE BELOW). Say you pick an HPV test for the oral cavity. Let’s say you take the test, and it shows that you (along with an estimated 79 million other Americans) are HPV positive. Even if you are positive for one of the cancer-causing strains of HPV, the likelihood of you actually developing an HPV-caused cancer is less than 1 in 100. With odds that low, why create something to worry about? And it’s easy to get a false negative result (a test says you don’t have an HPV infection, when you actually do) because HPV is hard to detect in the mouth for a number of reasons.
The only situation where it is worthwhile to be tested for HPV at present is in the context of looking for cervical pre-cancers in women, and this should be done in consultation with your doctor. For more information, go to the Screening for HPV Cancers page on this website, and look at the answer to the question Is screening recommended to find HPV-caused cancers?
24) Are gay and bisexual men more likely to develop anal cancer than heterosexual men?Open or CloseYes. According to the CDC, gay and bisexual men are 17 times more likely to develop anal cancer – also caused by HPV – than men who only have sex with women. Anal cancers are also more commonly found in men who are HIV positive, presumably due to having a weakened immune system. An estimated 61% of HIV-negative and 93% of HIV-positive gay and bisexual men have anal HPV infections, compared to 50% or less of heterosexual men. More information can be found here at the National LGBT Cancer Network.
25) Do lesbian women have an increased incidence of cervical cancer compared to heterosexual women?Open or CloseLesbians may be slightly more likely to develop cervical cancer, in part because they are less likely to be vaccinated against HPV. The 2006-2010 National Survey of Family Growth examined responses of women and girls between the ages of 15 and 25 who were asked about HPV vaccination. Of the over 3,200 participants involved, 84 percent reported having heard of the HPV vaccine, and of this informed population, only 28.5 percent had actually initiated the series. The study cannot say why lesbians have higher rates of cervical cancer, but the proposed explanation has to do with decreased cervical cancer screening with Pap tests as well as lower rates of HPV vaccination.
26) Can you get anal cancer if you don’t engage in anal sex?Open or CloseAnal sex is a risk factor for developing anal cancer. According to the HPV and Anal Cancer Foundation: “People who engage in anal sex are at a higher risk of developing anal cancer because they are at a higher risk of skin-to-skin contact in the anal region and contracting an anal HPV infection. Because HPV is a skin virus that is transmitted very easily, anal intimacy is not necessary to contract anal HPV or to develop anal cancer. In addition, men who are uncircumcised are at a higher risk of developing a persistent HPV infection.”
27) Is there an association between HPV infection and prostate cancer?Open or CloseMaybe. There have been several meta-analysis studies suggesting that infection with HPV 16 is associated with an increased risk of developing prostate cancer. However, more work needs to be done to establish if this is really the case.
Yin B et al Association between human papillomavirus and prostate cancer: A meta-analysis Oncol Lett. 2017 Aug; 14(2): 1855–1865. doi: 10.3892/ol.2017.6367
Russo GI et al Human papillomavirus and risk of prostate cancer: a systematic review and meta-analysis. Aging Male. 2018 Mar 23:1-7. doi: 10.1080/13685538.2018.1455178.
28) Exactly what types of head and neck cancers does an HPV infection cause?Open or CloseThe standard answer to this question is that HPV causes squamous cell carcinomas (SquamousCC). The vast majority of head and neck cancers, whether or not they are HPV positive, are SquamousCC. However, I came across a pathology paper that indicated that a very small percentage of head and neck cancers (again, whether HPV positive or negative) are actually small cell carcinomas (SmallCC). Only a very small number of head and neck cancers have ever been shown to be SmallCC, and the outcomes for patients with HPV+ types of this cancer are much worse than for those with HPV+ SquamousCC.
Squamous cells are thin, flat cells that are found in the tissue that forms the surface of the skin (the epidermis, which is the outermost layer of skin). The vast majority of head and neck cancers are SquamousCC, but the majority of SquamousCC are NOT head and neck cancers, but skin cancers. These skin cancers are NOT caused by HPV but by UV damage to the DNA in the skin cells.
Reference: Allison DB et al Cancer Cytopathology 2018. Characteristics of HPV-Related Small Cell Carcinoma of the Oropharynx. DOI: 10.1002/cncy.22078
Note: HPV has also been found in about 32% of patients who have been diagnosed with sinonasal squamous cell carcinoma (SNSCC), according to a study published online Dec. 30, 2019 issue of Cancer. https://doi.org/10.1002/cncr.32679
Jamie R. Oliver, from the New York University School of Medicine in New York City, and colleagues used the National Cancer Data Base (2010 to 2016) to identify 6,458 SNSCC cases and assess patterns of HPV testing and its association with survival in patients with SNSCC. Only 23.6 percent of patients (1,523) were tested for HPV, 62.1 percent of whom had advanced-stage tumors. HPV-positive SNSCC accounted for 31.5 percent (447 of 1,418 cases) of the final study cohort. Patients that had HPV-positive SNSCC were younger (median age, 60 years versus 65 years) and were more likely to have high-grade tumors (55.3 versus 41.7 percent) and tumors attributed to the nasal cavity (62.2 versus 44.0 percent). HPV-positive SNSCC was associated with significantly improved overall survival (hazard ratio, 0.45), including in propensity score-matched (hazard ratio, 0.61) analyses that controlled for clinicodemographic and treatment factors. This survival advantage matches up with oropharyngeal HPV-caused tumors, because patients with these have a much greater overall survival rate than those with HPV- oropharyngeal cancers.
29) People who are diagnosed with cervical, vaginal, vulval, penile, oral, or anal cancers must have gotten them from sex, right?Open or CloseWrong. While HPV-caused cancers represent the majority of cases of the cancers named above, the incidence is not 100 percent. Studies have been done to estimate the percentage of these cancers that are believed to be caused by the virus. These percentages are 99% for cervical cancer, 90% for anal cancer, 75% for vaginal cancer, 70% for vulvar cancer, 60% for penile cancer, and 70% oropharyngeal cancer.
Put another way, people can and do develop cancers in these tissues that have other causes besides HPV. Therefore, no single cancer case can be attributed to being caused by HPV acquired during sexual intimacy unless it has specifically been tested for the presence of the virus.
30) Is there any good news you can share regarding HPV-caused cancers?Open or CloseIt’s hard to come up with good news regarding cancer, but consider this. The risk of dying of head and neck cancer is about 70 percent lower if your tumor is HPV positive compared to those tumors that are HPV negative. Put another way, HPV positive head and neck cancers respond better to treatment than those that are HPV negative, resulting in improved levels of both progression-free and disease-free survival.
Reference: O’Rorke et al Human papillomavirus related head and neck cancer survival: a systematic review and meta-analysis. Oral Oncol. 2012 Dec;48(12):1191-201. doi: 10.1016/j.oraloncology.2012.06.019. Epub 2012 Jul 28.
One other preliminary piece of good news. It looks like a new drug in clinical trials, Tipapkinogen Sovacivec, is capable of clearing HPV infections in women with early stage cervical precancers. This molecule fits the definition of a therapeutic vaccine against HPV, which is distinct from the prophylactic vaccine (Gardasil 9) that is currently used to prevent HPV infections. You can read about it here.
Here are the highlights of the study:
Tipapkinogen sovacivec completely resolves CIN 3 lesions significantly more frequently than placebo. It completely clears HPV16 viral DNA associated with CIN 2/3 significantly more often than placebo. It has significantly greater complete resolution rates of CIN 2/3 regardless of HR HPV type. It offers 36% complete resolution or partial response of CIN2/3 associated with all HR HPV types.
Here is how it is supposed to work:
“The modified vaccinia virus Ankara (MVA) is a highly attenuated replication-deficient strain of vaccinia virus used widely as a gene-delivery system of vaccines. TS has inserted genes that code for three proteins: human cytokine IL-2, and modified forms of HPV 16 E6 and E7 proteins that have been rendered non oncogenic. MVA by itself contributes to the immune reaction by the induction of an Interferon-alpha response . Upon sub-cutaneous injection, TS infects the surrounding cells. The expressed HPV16 E6 and E7 proteins are then processed and presented by dendritic cells which are co-activated by the viral infection. These dendritic cells migrate to the draining lymph-node and present E6 and E7 peptides to the naive T-cells present in the lymph-node, which should allow development of a targeted cell mediated immune response.”
Harper, D. et al. The efficacy and safety of Tipapkinogen Sovacivec therapeutic HPV vaccine in cervical intraepithelial neoplasia grades 2 and 3: Randomized controlled phase II trial with 2.5 years of follow-up. Gynecological Oncology 2019. https://doi.org/10.1016/j.ygyno.2019.03.250
You can find the paper for FREE here.
31) What’s the most unusual disease associated with HPV infection?Open or CloseEpidermodysplasia verruciformis (EV), also known as treeman syndrome (because the extremities of people afflicted with this resemble tree limbs). According to Wikipedia, “ EV is an extremely rare autosomal recessive hereditary skin disorder associated with a high risk of skin cancer. It is characterized by abnormal susceptibility to human papillomaviruses (HPVs) of the skin. The resulting uncontrolled HPV infections result in the growth of scaly macules and papules, particularly on the hands and feet. It is typically associated with HPV types 5 and 8, which are found in about 80% of the normal population as asymptomatic infections, although other types may also contribute. The condition usually has an onset of between the ages of one and 20, but can occasionally present in middle age. The condition is also known as Lewandowsky–Lutz dysplasia, named after the physicians who first documented it, Felix Lewandowsky and Wilhelm Lutz. The cause of the condition is an inactivating PH mutation in either the EVER1 or EVER2 genes, which are located adjacent to one another on chromosome 17.”
The EVER genes belong to a novel gene family, a transmembrane channel-like (TMC) family, and are responsible for properly functioning zinc homeostasis.
Kalinska-Bienias et al The EVER genes – the genetic etiology of carcinogenesis in epidermodysplasia verruciformis and a possible role in non-epidermodysplasia verruciformis patients. Advances Dermatol Alergol. 2016 Apr; 33(2): 75–80.
The following strains of HPV are thought to be capable of causing epidermodysplasia verruciformis: 5,8,9,12,14,15,17,19,20,21,22,23,24,25,36,37, 38, 46, 47, 49, 75, 76, 80, 92, 93, 96. Source: Graham, S. The human papillomavirus replication cycle, and its links to cancer progression: a comprehensive review. Clinical Science (2017) 131 2201–2221 https://doi.org/10.1042/CS20160786 FREE download.
32) With six different types of cancer already associated with HPV infections, will cancer of the vocal cords and esophogeal cancer join this list?Open or CloseIt’s certainly possible. A 2019 report from the Massachusetts General Hospital (MGH) described finding HPV infections in all tested samples of vocal-cord cancer from 10 patients who had been diagnosed at age 30 or under. Most of them were non-smokers. The story is very similar to the one for oropharyngeal cancers, which used to be primarily associated with smoking, but are now more frequently associated with infection with high-risk HPV strains. The vocal cord cancers also used to be correlated with smoking, but non-smokers now make up nearly half of the vocal cord cancers. “Of 353 patients treated for vocal-cord cancer during the entire period, none of the 112 treated from 1990 to mid-2004 were age 30 or younger. But 11 of the 241 patients treated from 2004 to 2018 were 30 or younger – 3 were age 10 to 19 – and only 3 of the 11 were smokers. Put another way, about 1% of the total patients with HP-positive vocal cord tumors were under 20, with another 4% of these patients in the 20-29 years old age group. Analysis of tissue samples from the tumors of 10 of the 11 younger patients revealed high-risk strains of HPV in all of them.”
The median age for being diagnosed with most HPV cancers (except cervical cancer) is in the late 50’s to early/mid 60’s. For laryngeal cancers (of which vocal cord tumors are a subset), the median age for diagnosis is 65, which fits in the other HPV caused cancers. It’s very unusual to have HPV associated cancers in people so young. On the other hand, the incidence of laryngeal cancer has been falling for decades. This, as with oropharyngeal cancers, mostly reflects a decrease in smoking. It may be that this decrease has allowed this subset of HPV+ cancers to be revealed.
“The male to female rate ratio for laryngeal cancers was substantially higher in the glottic region (9.2 among whites and 11.8 among blacks) than in other subsites (approx. 3-5 in both races).” According to Yang et al in Differences in the sex ratio of laryngeal cancer incidence rates by anatomic subsite. J Clin Epidemiol. 1989;42(8):755-8.
This preponderance of male to female cancers is similar to what is seen with oropharyngeal cancers.
“The authors note that these high-risk-HPV-associated vocal-cord cancers greatly resemble recurrent respiratory papillomatosis (RRP), a benign condition caused by common, low-risk strains of HPV. Benign RRP of the vocal cords has been a well-known HPV disease for more than a century, and it is very remarkable that there is now an HPV malignancy that looks so similar, creating diagnostic and therapeutic confusion,” says Steven Zeitels, the Eugene B. Casey Professor of Laryngeal Surgery at Harvard Medical School. “It should be noted that these HPV-associated vocal-cord carcinomas are NOT a malignant degeneration of the benign disease.”
The report appears in a special supplement on innovations in laryngeal surgery that accompanies the March 2019 issue of Annals of Otology, Rhinology and Laryngology.
Finally, a meta-analysis of previous studies showed “HPV infection, especially infection due to the high-risk type HPV-16, was found to be significantly associated with the risk of laryngeal squamous cell carcinoma.” In a majority of these studies, the predominant strains of HPV found in the tumors were high-risk i.e. cancer causing strains. See
Li et al Human Papillomavirus Infection and Laryngeal Cancer Risk: A Systematic Review and Meta- Analysis. The Journal of Infectious Diseases 2013;207:479–88
HPV has been shown in a study to increase the risk of developing esophageal cancer 3 fold. However, only 35% of the tumors studied were positive for HPV, so that means HPV cannot be the only cause. As the authors put it: “Uncertainty around the aetiological role of HPV in OSCC is due largely to the small number and scale of appropriately designed studies. Our meta-analysis of these studies suggests that HPV increases the risk of OSCC three-fold. This study provides the strongest evidence to date of an HPV-OSCC association.”
Liyanage, S. et al The Aetiological Role of Human Papillomavirus in Oesophageal Squamous Cell Carcinoma: A Meta-Analysis. PLOS one 2013. FREE download.
33) Is there an association of infection with high-risk HPV strains and the development of cardiovascular disease (CVD)?Open or CloseA recent report suggests there is. A study of cardiovascular disease in women from South Korea showed that infection with high-risk (cancer causing) strains of HPV were significantly associated with an increased risk of developing CVD, especially in obese individuals and those with metabolic syndrome, indicating that high-risk HPV might affect CVD risk with possible effect modification by obesity and metabolic syndrome. Note that correlation does not prove causation, and we also don’t know if this result applies to other groups aside from Korean women. Further studies we be required to figure that out. Look here to learn more about these types of cohort studies, and what their strengths and weaknesses are.
Reference: Eun-Jeong Joo et al High-Risk Human Papillomavirus Infection and the Risk of Cardiovascular Disease in Korean Women: A Cohort Study
Originally published in Circulation Research Feb. 2019
34) I heard that a study had been done that a recent clinical trial showed that robotic surgery for oropharyngeal cancer was associated with MORE side effects than radiation treatment. What’s the story?Open or CloseThis was indeed the primary finding of the study, but there were a number of caveats. The data has not yet been published; what’s been presented so far was shown at a medical conference. Here’s what we know:
The seven-year multi-center study, led by researchers at the Lawson Health Research Institute, compared robotic surgery (TORS) or radiation therapy as treatments for oropharyngeal cancer (cancer affecting the back of the throat, tonsils, soft palate and base of the tongue). Starting in 2012, researchers recruited 68 throat cancer patients at six medical centers in Australia and Canada, including the London Health Sciences Centre’s London Regional Cancer Program (note: this is in London, Ontario, Canada; it is NOT in London, England). Radiation therapy can cause side effects, and patients receiving radiation therapy often report problems swallowing, a reason that the robotic surgery option rose in popularity. Many assumed that robotic surgery was going to give a better quality of life for patients as measured by swallowing ability. This idea was tested in a randomized trial where these two treatments were tested against each other.
Researchers discovered the radiation patients had less swallowing difficulties than the surgery group. Forty per cent of surgery participants reported mild decline in their swallowing ability compared to only 26 per cent of radiation patients. The study also found no difference in survival rates between the patients who received the robotic surgery and ones who received radiation only. So that settles the issue, right? Unfortunately, no. There are a number of caveats that prevent us from making this conclusion:
1) the study was quite small by current standards. It will need to be tested in a much larger population of patients.
2) the primary outcome that was measured here was swallowing ability. While this is important, the study did not look at other potentially negative outcomes that might be associated with large doses of radiation to the neck. These include the later formation of other cancers, damage to blood vessels that can lead to future strokes, and skin problems arising from the radiation.
3) While the data indicated that there were no survival differences between the two groups, we really need to see much longer term data before we can reach that conclusion.
It should also be noted that the robotic surgery option is only available to patients who have small oral tumors. Those that are large, or have spread to the lymph nodes in the neck, cannot be treated solely with robotic surgery. These patients may get chemotherapy and radiation, or surgery plus chemotherapy and radiation.
There’s also a second generation TORS robot in clinical trials (phase II). It uses a single port i.e. the arms all come through one small opening, which has some theoretical and practical advantages. Data was positive in the phase II trial. You can read more about it here: Holsinger, F.C. A Next-Generation Single-Port Robotic Surgical System for Transoral Robotic Surgery: Results From Prospective Nonrandomized Clinical Trials. JAMA Otolaryngol Head Neck Surg. Published online September 19, 2019. doi:10.1001/jamaoto.2019.2654. FREE download.
35) Can Turkey Tail (and other mushrooms) eliminate the HPV virus from your body?Open or CloseNot likely. I had never heard of this hypothesis and so I looked it up. The idea is apparently based on data from a single publication in an obscure medical journal. The actual name of the mushroom is Trametes versicolor, also known as Coriolus versicolor. Here’s the abstract from this paper:
“This preliminary randomized study investigated the efficacy of medicinal mushrooms, Trametes versicolor (TV), Ganoderma lucidum (GL), and Laetiporus sulphureus (LS), on the clearance of oral human papillomavirus (HPV, serotypes 16 and 18). Among 472 patients who underwent oral swabs for gingivitis, 61 patients were positive for HPV16 or HPV18. Twenty patients were included in group 1 (LS) and 41 patients were included in group 2 (TV+GL) for 2 months. Polymerase chain reaction (PCR) for HPV was performed at inclusion and after 2 months. In group 1, the clearance was equal to 5% after 2 months of treatment. In group 2, the clearance was equal to 88% (P<0.001). The detection of HPV16 or HPV18 could become relevant in routine since positivity is frequent and because a harmless and costless treatment may exist. The use of TV+GL for the clearance of oral HPV deserves further investigation.”
We can’t conclude that Turkey Tail mushroom really had any effect on HPV clearance for the following reasons:
1) There was no control group (i.e. people who were positive for HPV, but received no treatment at all). As a result, we don’t know what the rate of clearance is in the absence of any mushrooms. Other research has clearly demonstrated that the majority of people with HPV infections clear it without any intervention whatsoever (see FAQ9 above). Perhaps that is what is happening in group 2, and the lower rate in group 1 is because Laetiporus sulphureus actually inhibits clearance of HPV. We simply can’t tell here.
2) Turkey Tail mushroom was not used alone in group 2, where it was combined with Ganoderma lucidum. Thus, we can’t say that any effects seen are due to the Turkey Tail alone. It could be due to the Ganoderma lucidum, or the combination of the two is required. We can’t draw any firm conclusions.
The fact that this was reported in 2014, and no subsequent papers on the subject have been published, suggests that no real effect of the mushroom was seen, the initial report was not followed up, or it was simply not confirmable.
Donatini, B. Control of oral human papillomavirus (HPV) by medicinal mushrooms, Trametes versicolor and Ganoderma lucidum: a preliminary clinical trial. Int J Med Mushrooms. 2014;16(5):497-8.
36) Viruses need to bind to specific receptors on the surface of cells to gain entry. What protein(s) does HPV bind to in order to get into cells?Open or CloseThere are a number of different proteins that have been shown to bind to HPV virions, with the most prominent one being heparin sulfate proteoglycans (HSPGs). However, there are other proteins that also bind to the virions, including CyPB (PPIB), alpha 6 integrin (ITGA6), tetraspanins (TSPAN1), GFR (EGFR and FGFR2) and A2t. One group of investigators has suggested that all of these proteins may play a role in how the virus gains entry to a cell. In their study, these scientists looked at genetic variants of these various receptor proteins to determine if there were variants that may inhibit or enhance the binding and entry process. Their findings suggest that HPV receptor and associated gene variants may influence the susceptibilities to HPV type-specific infection and cervical lesion progression. If confirmed, this information might have value in cervical cancer screening and therapy.
Zou, J. et al Variants in human papillomavirus receptor and associated genes are associated with type-specific HPV infection and lesion progression of the cervix. Oncotarget. 2016 Jun 28; 7(26): 40135–40147. Published online 2016 May 20. doi: 10.18632/oncotarget.9510. FREE download.
37) What are some of the psychological issues associated with HPV infections?Open or CloseThere are a number of these issues, and they can cause serious problems. These include:
1) fear of developing an HPV cancer
2) damage to relationships over how one partner came to acquire an HPV infection. It is nearly impossible to tell this most of the time as you could have been infected decades before this becomes apparent.
3) concerns about engaging in sexual relations with a new partner and spreading the virus
4) shame about having acquired a sexually transmitted disease, even though most people will get and HPV infection sometime during their lifetime
See this story about dealing with HPV infection-induced anxiety, as well as this collection of stories (written by both men and women) on the website of the American Sexual Health Association.
38) Scientists like to develop animal models for many different diseases. Are there any animal models for HPV-driven cancers?Open or CloseYes. Scientists in 2019 developed a mouse model for HPV 16 caused head and neck cancers. The details about how they did this are highly technical, you can find the details in the article via the link below. Their goal was to develop a model where new drugs and other treatments could be tested.
This was certainly not the first model system developed to study this, as the authors clearly point out. Numerous other models exist, but each brings to it some particular issues that may potentially result in cancers that aren’t a good model for human cancers. The same can be said for this study as well. These other models are listed in the graphic below, which was taken from the S4 supplementary material from this paper:
Carper, M. et al An Immunocompetent Mouse Model of HPV16(+) Head and Neck Squamous Cell Carcinoma. Cell Reports 29, 1660–1674 November 12, 2019 https://doi.org/10.1016/j.celrep.2019.10.005 (FREE DOWNLOAD)
39) HPV positive cancers are generally more responsive to radiation treatments than HPV negative cancers. Why is this, since HPV is what caused the cancer in the first place?Open or Close
Three-year (36-month) Kaplan–Meier estimates showing overall survival versus HPV status for oropharyngeal squamous cell carcinoma. Figure from Schache, A.G. et al Clinical Cancer Research DOI: 10.1158/1078-0432.CCR-11-0388 Published October 2011The greater survival of HPV+ cancer patients is thought to be due to a process known as DNA repair, which HPV infections interfere with. From a paper on this subject:
“Cancers associated with the human papillomavirus, including oropharyngeal, anal canal, cervical, and vulvar carcinomas, constitute about 4.5% of all solid tumors. In many cases, they can be readily cured with radiotherapy, which is the mainstay of treatment. HPV-associated cancers are more radiosensitive than HPV-negative cancers, but the mechanism of this radiosensitivity is unknown. Across all of oncology, HPV association is one of the only validated molecular biomarker of radiosensitivity. Here, we demonstrate that the HPV16 E7 oncoprotein alters DNA double-strand break repair pathways by promoting error-prone, microhomology-mediated end-joining and suppressing nonhomologous end-joining. These results characterize the molecular mechanism of this unique biomarker in cancer therapy and suggest therapeutic vulnerabilities.
Squamous cell carcinomas (SCCs) arising from aerodigestive or anogenital epithelium that are associated with the human papillomavirus (HPV) are far more readily cured with radiation therapy than HPV-negative SCCs. The mechanism behind this increased radiosensitivity has been proposed to be secondary to defects in DNA repair, although the specific repair pathways that are disrupted have not been elucidated. To gain insight into this important biomarker of radiosensitivity, we first examined genomic patterns reflective of defects in DNA double-strand break repair, comparing HPV-associated and HPV-negative head and neck cancers (HNSCC). Compared to HPV-negative HNSCC genomes, HPV+ cases demonstrated a marked increase in the proportion of deletions with flanking microhomology, a signature associated with a backup, error-prone double-strand break repair pathway known as microhomology-mediated end-joining (MMEJ). Then, using 3 different methodologies to comprehensively profile double-strand break repair pathways in isogenic paired cell lines, we demonstrate that the HPV16 E7 oncoprotein suppresses canonical nonhomologous end-joining (NHEJ) and promotes error-prone MMEJ, providing a mechanistic rationale for the clinical radiosensitivity of these cancers.”
Leeman, J.E. et al Human papillomavirus 16 promotes microhomology-mediated end-joining. PNAS October 22, 2019 116 (43) 21573-21579; first published October 7, 2019 https://doi.org/10.1073/pnas.1906120116