Hi everyone,
I'm a cancer researcher with an interest in head and neck malignancies, which includes human papillomavirus (HPV)-induced tumors. I was exchanging messages with one forum member who had questions about HPV and mouth cancer and he recommended polishing up the discussion a little and posting it on the board as an "HPV datasheet." I hope that's ok- some people may find this interesting but it'll be a little long and dense, so here goes…
HPV DATA SHEET
Basic facts:
1) Some strains of HPV are associated with cervical cancer- Most of you guys know this already. Cervical cancer was long known to be associated with risky sexual behavior in women. Originally, a link with herpes virus was proposed, but a German doctor, Harald Zur Hausen, made the connection between cervical cancer and genital warts (condylomata), which are caused by HPV. He won the Nobel Prize in Medicine and Physiology for his work (http://www.nobelprize.org/nobel_prizes/m...es/2008/).
2) The oral mucosa is similar clinically and histologically with cervical mucosa- The epithelium that lines the cervix (and that gets infected with HPV) is pretty much identical to oral mucosa (the 'skin' that lines your mouth). They are so similar that once HPV was found to be associated with cervical cancers, people immediately started looking for the virus in mouth cancers. It took a while to prove the association but now it is known that many (but not all) oropharyngeal cancers (cancers of the oropharynx, or 'back' of your mouth (tonsils, soft palate, base of tongue)) are caused by HPV.
3) Oral HPV infection is sexually transmitted- It's not exactly known how HPV infects the back of the mouth. The obvious answer is through oral sex, but men are more prone to develop HPV-positive oropharyngeal cancers than women (and the nature of oral sex for a man is much less traumatic or invasive than for a woman), so 'deep kissing' is also suspected. Transmission by casual, nonsexual contact is not likely [1].
4) HPV-associated cancers of all kinds (cervical, vaginal, vulvar, penile, anal and oropharyngeal) are on the rise- The rate of HPV-associated mouth cancers soon will or already has exceeded that for HPV-negative oral cancers. Many epidemiologists believe that we might be at the beginning of a true global pandemic of HPV-associated cancers (which I'll talk about below) [2, 3].
5) There are vaccines- Once cervical cancers (and now some oral cancers) were shown to be 'infectious', great efforts were made to develop a vaccine. There are a few vaccines currently in use that protect against the most common "high-risk" serotypes (Gardasil, by Merck, and Cervarix, from GlaxoSmithKline) and they have been shown to work.
Those basic facts provide a foundation for discussion. What follows is more specifics involving the virus, how it works, and some epidemiological information regarding its spread.
Background about the HPV family of viruses:
The human papillomaviruses (HPVs) are a family of small double stranded DNA viruses that generally contain only 8 to 10 open reading frames (ORFs, or stretches of DNA that codes for proteins). HPVs show a pronounced tropism for epithelial cells. Over 120 types gave been discovered so far that are grouped into "low-risk" and "high-risk" viruses, with the "risk" being the chance that an infected cell will become cancerous. Infection of skin or mucosa with a low-risk virus will cause a squamous papilloma, or what we call a wart. In normal, healthy, immunocompetent individuals, these generally go away on their own, but it can take a little time. In any event, they don't cause cancer. The most common low-risk subtypes are HPV 6 and 11. High-risk viruses on the other hand, under the proper circumstances and given enough time, can transform an infected cell into cancer.
The mechanism for cellular transformation is well known but a bit technical, and we don't need to get into it here. Basically, a virus, like all other organisms, wants to make copies of itself. Since it only has 8 or 10 genes it can’t do this on its own, so it needs to get inside a host cell and hijack its replicative machinery, or all the myriad of proteins and resources required to copy DNA and assemble new virus particles. It does this by coding for "early" or E genes, which, as the name implies, are turned on early in the infectious process and go to work forcing the infected host cell to divide. E genes are really good at tricking a host into proliferating, even when it's not normally supposed to, by deactivating 'tumor suppressor' proteins, or proteins coded for by the cell that restrict cellular proliferation. Once the tumor suppressors are degraded and neutralized by the viral E proteins (specifically, E6 and E7), the newly proliferating cells make more viruses but also replicate themselves as well, and 'pile up' on top of each other. Clinically, this causes a raised, bumpy hyperplastic patch of epithelium that we call a wart. The virus finishes the job by coding for "late" or "L" gene products that are the structural proteins forming the capsid or 'outside' of the virus. These proteins spontaneously assemble around a core of DNA and new viruses bud off of the infected cell and are shed into the environment.
In low-risk infections, that's pretty much the end of it. If an infection even starts, your immune system (this would be cell-mediated immunity, mostly controlled by T lymphocytes) will go to work trying to destroy all of the infected cells, while the virus struggles to make 'baby viruses' before it is entirely eliminated. However, in high-risk infections it’s a bit more complicated. In a rare event, one that is unfortunate for the host cell but also the virus, the circular viral DNA that normally hangs out in the cytoplasm will instead enter the cell's nucleus, break open, and integrate into the host DNA. I say "unfortunate" for the virus because when this happens it can no longer reproduce. It's unfortunate for the cell because the break occurs in the viral DNA usually at one place- an area that controls or restricts the behavior of E6 and E7. Once that control is lost, E6 and E7 run wild and the main tumor suppressors in the cell have no chance. The cell will divide in a completely uncontrolled manner- i.e., cancer. It has been shown that over expression of high-risk E6 and E7 proteins in an epithelial cell is sufficient to make it immortal (a hallmark of a cancerous cell in the lab) [4]. The mouth squamous cell carcinomas you hear about associated with HPV are due to infection of oral epithelial cells with high-risk strains, which include 16, 18, 31 and 32. HPV 16 is the most common high-risk virus going around the U.S., while other strains are found in different areas of the world.
HPV and oral cancer:
This seems to be the thing giving men here the greatest cause for concern. Firstly, it is sexually transmitted, so any risky behaviors, the more partners you have, and so on, the greater chance of becoming infected. As I mentioned, HPV-positive oropharyngeal cancers are much more common in men than women. It's not really known why, but most researchers in this field think that it's probably because the female immune system is more used to encountering, and fighting off, HPV, due to the traumatic nature of sex for females. Men are a little more 'naive' when it comes to HPV exposure, and therefore slightly more susceptible. Also, the oropharynx is hard to examine, so much like in the cervix, cancers here have time to develop undetected.
HPV-associated mouth cancers affect a slightly younger population than HPV-negative cancers, which are the kind of cancers found in grizzled old people who smoke and drink heavily. It's a different etiology, different patient population, different location (the alcohol and tobacco-induced lesions usually occur on the lateral surface of the tongue and floor of mouth, not the oropharynx) and a different prognosis. HPV-positive cancers grow rapidly and look more aggressive clinically, but respond better to treatment and have a better prognosis compared to the traditional smoking and drinking-induced HPV-negative cancers. Again, the reasons for this are a little technical, but it's likely because the DNA of the cells in HPV-positive cancers isn't really damaged like it is in tobacco and alcohol-induced HPV-negative tumors (tumor suppressors are lost in HPV-positive tumors, but not through mutation, so they're still there and intact, just at really low levels), so the cells respond a little better to treatment.
People on this board have a right to be concerned because HPV-associated oropharyngeal cancers are on the rise. The annual number of HPV-positive oropharyngeal cancers is expected to surpass the annual number of cervical cancers by the year 2020 [3]. In fact, there's evidence that it already has happened. Indeed, many epidemiologists believe that HPV-associated cancers of all kinds (cervical, vaginal, vulvar, penile, anal and oropharyngeal) are increasing due to a true global pandemic of HPV infection. According to an epidemiological study published in 2011, HPV is responsible for 600,000 cancers a year- more than from any other infectious cause (more than Epstein-Barr virus, more than hepatitis viruses, which are known to promote liver cancer), and a number that is growing [5]. HPV is far and away the most common sexually transmitted infection, with over 20 million annual cases worldwide, outnumbering chlamydia and gonorrhea [6]. From 1984 to 2004, HPV prevalence in oropharyngeal cancers increased by about 225% while the incidence for HPV-negative cancers declined by about 50% (because fewer people are smoking nowadays, as per the Surveillance Epidemiology and End Results (SEER) data from the National Cancer Institute). This could be from better detection techniques (maybe a lot of tumors in the past were HPV positive but we didn't have the technology to prove it) but epidemiologists who do this stuff for a living have shown that there's an approximately 3% annual increase in incidence that is NOT related to detection methods. A Swedish researcher published a paper in 2011 where he noted a significant increase in HPV-positive tonsillar and tongue base cancers and assumed, not unreasonably, that what he was detecting was the beginning of an epidemic of oral cancer caused by HPV [2].
The vaccine:
The vaccine was developed by taking one of the "L" genes (the late genes that code for the outer protein coating of the virus), getting a yeast or other host cell to make it in large quantities, and then allowing the capsid to self-assemble into a "viral-like particle", essentially forming what appears to be a virus on the outside, but with no DNA in the center. The immune system sees this, thinks it's an infection, and mounts an immune response that then protects against subsequent 'real' infections. There isn't a ton of data regarding vaccination against HPV because the studies are new and still ongoing, but early results suggest that it works. People who are vaccinated develop antibodies to the covered HPV subtypes (called 'sero-conversion') and exhibit a reduction in the incidence of genital warts (cancer takes years to develop, so wart formation is a good short-term read-out for efficacy). Most early studies center on a clinical trial in Costa Rica, where results have shown protection against infection at vulnerable sites (cervical, anal, and oral mucosa). For example, in one study they found 15 young women to be positive for the presence of HPV in the control group compared to only 1 in the vaccinated group [7]. It's been so effective that about 40 nations now have incorporated the vaccine into their national health programs.
There really is no downside to the vaccine, except that some people believe that if kids are vaccinated against HPV they will engage in more dangerous behaviors thinking that they are protected (the same arguments against providing condoms in schools or clean needles for drug addicts). I do think men benefit from the vaccine- it protects against mucosal warts, oropharyngeal cancers, and penile cancers, with no downside, except for maybe the cost (I don't know if it's expensive or not, or covered by insurance the way other vaccines are). As for the anti-vaccine crowd, that's an entirely different discussion that I'd rather not get into at the moment, because those people don't argue using facts, and therefore there is no way to debate them.
Questions you may have:
A question I often hear is "My girlfriend/wife/partner had an abnormal pap smear. I may have been exposed. Should I get tested?" The answer is no, and I'll explain why. Firstly, there are a lot of causes for abnormal pap smears, not all of them are due to HPV. Second, even if your partner is HPV positive, you would need to know what 'type' you were exposed to. This can be done, but it involves expensive lab tests that aren't routinely performed, and unless you have a wart (evidence of an active, productive infection), the doctor wouldn't know what tissues to examine or biopsy anyway. And simply detecting the presence of a virus doesn’t tell you anything about the nature of the infection- what we would really need to see is the presence of high-risk E6 and E7 proteins in a cell, a much harder proposition. If by some stroke of luck it is determined that yes, you test positive for a high-risk strain, that knowledge is still of little benefit. If you were exposed to a high-risk HPV there is a chance that an infected cell will wind up in a virally 'unproductive' infection that might lead to cancer, but there's no way of knowing, in a healthy individual, if the virus will be cleared, persist, or become cancer, nor can infected epithelium even be identified in the absence of a productive infection. There is no 'pre-malignancy' test, so as of now the motivation to develop cheap accurate HPV tests just isn't there, because we currently do not alter patient management based on that information. Even in a proven, diagnosed HPV-positive oropharyngeal cancer, despite the evidence that they have a different clinical course and prognosis, surgeons will still treat it like a 'conventional' alcohol and tobacco-induced cancer (though this may soon change).
I hope that helps to clear up any misconceptions. Feel free to respond or PM me if you have any other questions.
1.Gillison ML, Broutian T, Pickard RK, Tong ZY, Xiao W, Kahle L, et al. Prevalence of oral HPV infection in the United States, 2009-2010. JAMA 2012; 307:693-703.
2.Ramqvist TDalianis T. An epidemic of oropharyngeal squamous cell carcinoma (OSCC) due to human papillomavirus (HPV) infection and aspects of treatment and prevention. Anticancer Res 2011; 31:1515-9.
3.Chaturvedi AK, Engels EA, Pfeiffer RM, Hernandez BY, Xiao W, Kim E, et al. Human papillomavirus and rising oropharyngeal cancer incidence in the United States. J Clin Oncol 2011; 29:4294-301.
4.Munger K, Phelps WC, Bubb V, Howley PMSchlegel R. The E6 and E7 genes of the human papillomavirus type 16 together are necessary and sufficient for transformation of primary human keratinocytes. J Virol 1989; 63:4417-21.
5.Tota JE, Chevarie-Davis M, Richardson LA, Devries MFranco EL. Epidemiology and burden of HPV infection and related diseases: implications for prevention strategies. Prev Med 2011; 53 Suppl 1:S12-21.
6.Schiffman M, Castle PE, Jeronimo J, Rodriguez ACWacholder S. Human papillomavirus and cervical cancer. Lancet 2007; 370:890-907.
7.Herrero R, Quint W, Hildesheim A, Gonzalez P, Struijk L, Katki HA, et al. Reduced prevalence of oral human papillomavirus (HPV) 4 years after bivalent HPV vaccination in a randomized clinical trial in Costa Rica. PLoS One 2013; 8:e68329.
I'm a cancer researcher with an interest in head and neck malignancies, which includes human papillomavirus (HPV)-induced tumors. I was exchanging messages with one forum member who had questions about HPV and mouth cancer and he recommended polishing up the discussion a little and posting it on the board as an "HPV datasheet." I hope that's ok- some people may find this interesting but it'll be a little long and dense, so here goes…
HPV DATA SHEET
Basic facts:
1) Some strains of HPV are associated with cervical cancer- Most of you guys know this already. Cervical cancer was long known to be associated with risky sexual behavior in women. Originally, a link with herpes virus was proposed, but a German doctor, Harald Zur Hausen, made the connection between cervical cancer and genital warts (condylomata), which are caused by HPV. He won the Nobel Prize in Medicine and Physiology for his work (http://www.nobelprize.org/nobel_prizes/m...es/2008/).
2) The oral mucosa is similar clinically and histologically with cervical mucosa- The epithelium that lines the cervix (and that gets infected with HPV) is pretty much identical to oral mucosa (the 'skin' that lines your mouth). They are so similar that once HPV was found to be associated with cervical cancers, people immediately started looking for the virus in mouth cancers. It took a while to prove the association but now it is known that many (but not all) oropharyngeal cancers (cancers of the oropharynx, or 'back' of your mouth (tonsils, soft palate, base of tongue)) are caused by HPV.
3) Oral HPV infection is sexually transmitted- It's not exactly known how HPV infects the back of the mouth. The obvious answer is through oral sex, but men are more prone to develop HPV-positive oropharyngeal cancers than women (and the nature of oral sex for a man is much less traumatic or invasive than for a woman), so 'deep kissing' is also suspected. Transmission by casual, nonsexual contact is not likely [1].
4) HPV-associated cancers of all kinds (cervical, vaginal, vulvar, penile, anal and oropharyngeal) are on the rise- The rate of HPV-associated mouth cancers soon will or already has exceeded that for HPV-negative oral cancers. Many epidemiologists believe that we might be at the beginning of a true global pandemic of HPV-associated cancers (which I'll talk about below) [2, 3].
5) There are vaccines- Once cervical cancers (and now some oral cancers) were shown to be 'infectious', great efforts were made to develop a vaccine. There are a few vaccines currently in use that protect against the most common "high-risk" serotypes (Gardasil, by Merck, and Cervarix, from GlaxoSmithKline) and they have been shown to work.
Those basic facts provide a foundation for discussion. What follows is more specifics involving the virus, how it works, and some epidemiological information regarding its spread.
Background about the HPV family of viruses:
The human papillomaviruses (HPVs) are a family of small double stranded DNA viruses that generally contain only 8 to 10 open reading frames (ORFs, or stretches of DNA that codes for proteins). HPVs show a pronounced tropism for epithelial cells. Over 120 types gave been discovered so far that are grouped into "low-risk" and "high-risk" viruses, with the "risk" being the chance that an infected cell will become cancerous. Infection of skin or mucosa with a low-risk virus will cause a squamous papilloma, or what we call a wart. In normal, healthy, immunocompetent individuals, these generally go away on their own, but it can take a little time. In any event, they don't cause cancer. The most common low-risk subtypes are HPV 6 and 11. High-risk viruses on the other hand, under the proper circumstances and given enough time, can transform an infected cell into cancer.
The mechanism for cellular transformation is well known but a bit technical, and we don't need to get into it here. Basically, a virus, like all other organisms, wants to make copies of itself. Since it only has 8 or 10 genes it can’t do this on its own, so it needs to get inside a host cell and hijack its replicative machinery, or all the myriad of proteins and resources required to copy DNA and assemble new virus particles. It does this by coding for "early" or E genes, which, as the name implies, are turned on early in the infectious process and go to work forcing the infected host cell to divide. E genes are really good at tricking a host into proliferating, even when it's not normally supposed to, by deactivating 'tumor suppressor' proteins, or proteins coded for by the cell that restrict cellular proliferation. Once the tumor suppressors are degraded and neutralized by the viral E proteins (specifically, E6 and E7), the newly proliferating cells make more viruses but also replicate themselves as well, and 'pile up' on top of each other. Clinically, this causes a raised, bumpy hyperplastic patch of epithelium that we call a wart. The virus finishes the job by coding for "late" or "L" gene products that are the structural proteins forming the capsid or 'outside' of the virus. These proteins spontaneously assemble around a core of DNA and new viruses bud off of the infected cell and are shed into the environment.
In low-risk infections, that's pretty much the end of it. If an infection even starts, your immune system (this would be cell-mediated immunity, mostly controlled by T lymphocytes) will go to work trying to destroy all of the infected cells, while the virus struggles to make 'baby viruses' before it is entirely eliminated. However, in high-risk infections it’s a bit more complicated. In a rare event, one that is unfortunate for the host cell but also the virus, the circular viral DNA that normally hangs out in the cytoplasm will instead enter the cell's nucleus, break open, and integrate into the host DNA. I say "unfortunate" for the virus because when this happens it can no longer reproduce. It's unfortunate for the cell because the break occurs in the viral DNA usually at one place- an area that controls or restricts the behavior of E6 and E7. Once that control is lost, E6 and E7 run wild and the main tumor suppressors in the cell have no chance. The cell will divide in a completely uncontrolled manner- i.e., cancer. It has been shown that over expression of high-risk E6 and E7 proteins in an epithelial cell is sufficient to make it immortal (a hallmark of a cancerous cell in the lab) [4]. The mouth squamous cell carcinomas you hear about associated with HPV are due to infection of oral epithelial cells with high-risk strains, which include 16, 18, 31 and 32. HPV 16 is the most common high-risk virus going around the U.S., while other strains are found in different areas of the world.
HPV and oral cancer:
This seems to be the thing giving men here the greatest cause for concern. Firstly, it is sexually transmitted, so any risky behaviors, the more partners you have, and so on, the greater chance of becoming infected. As I mentioned, HPV-positive oropharyngeal cancers are much more common in men than women. It's not really known why, but most researchers in this field think that it's probably because the female immune system is more used to encountering, and fighting off, HPV, due to the traumatic nature of sex for females. Men are a little more 'naive' when it comes to HPV exposure, and therefore slightly more susceptible. Also, the oropharynx is hard to examine, so much like in the cervix, cancers here have time to develop undetected.
HPV-associated mouth cancers affect a slightly younger population than HPV-negative cancers, which are the kind of cancers found in grizzled old people who smoke and drink heavily. It's a different etiology, different patient population, different location (the alcohol and tobacco-induced lesions usually occur on the lateral surface of the tongue and floor of mouth, not the oropharynx) and a different prognosis. HPV-positive cancers grow rapidly and look more aggressive clinically, but respond better to treatment and have a better prognosis compared to the traditional smoking and drinking-induced HPV-negative cancers. Again, the reasons for this are a little technical, but it's likely because the DNA of the cells in HPV-positive cancers isn't really damaged like it is in tobacco and alcohol-induced HPV-negative tumors (tumor suppressors are lost in HPV-positive tumors, but not through mutation, so they're still there and intact, just at really low levels), so the cells respond a little better to treatment.
People on this board have a right to be concerned because HPV-associated oropharyngeal cancers are on the rise. The annual number of HPV-positive oropharyngeal cancers is expected to surpass the annual number of cervical cancers by the year 2020 [3]. In fact, there's evidence that it already has happened. Indeed, many epidemiologists believe that HPV-associated cancers of all kinds (cervical, vaginal, vulvar, penile, anal and oropharyngeal) are increasing due to a true global pandemic of HPV infection. According to an epidemiological study published in 2011, HPV is responsible for 600,000 cancers a year- more than from any other infectious cause (more than Epstein-Barr virus, more than hepatitis viruses, which are known to promote liver cancer), and a number that is growing [5]. HPV is far and away the most common sexually transmitted infection, with over 20 million annual cases worldwide, outnumbering chlamydia and gonorrhea [6]. From 1984 to 2004, HPV prevalence in oropharyngeal cancers increased by about 225% while the incidence for HPV-negative cancers declined by about 50% (because fewer people are smoking nowadays, as per the Surveillance Epidemiology and End Results (SEER) data from the National Cancer Institute). This could be from better detection techniques (maybe a lot of tumors in the past were HPV positive but we didn't have the technology to prove it) but epidemiologists who do this stuff for a living have shown that there's an approximately 3% annual increase in incidence that is NOT related to detection methods. A Swedish researcher published a paper in 2011 where he noted a significant increase in HPV-positive tonsillar and tongue base cancers and assumed, not unreasonably, that what he was detecting was the beginning of an epidemic of oral cancer caused by HPV [2].
The vaccine:
The vaccine was developed by taking one of the "L" genes (the late genes that code for the outer protein coating of the virus), getting a yeast or other host cell to make it in large quantities, and then allowing the capsid to self-assemble into a "viral-like particle", essentially forming what appears to be a virus on the outside, but with no DNA in the center. The immune system sees this, thinks it's an infection, and mounts an immune response that then protects against subsequent 'real' infections. There isn't a ton of data regarding vaccination against HPV because the studies are new and still ongoing, but early results suggest that it works. People who are vaccinated develop antibodies to the covered HPV subtypes (called 'sero-conversion') and exhibit a reduction in the incidence of genital warts (cancer takes years to develop, so wart formation is a good short-term read-out for efficacy). Most early studies center on a clinical trial in Costa Rica, where results have shown protection against infection at vulnerable sites (cervical, anal, and oral mucosa). For example, in one study they found 15 young women to be positive for the presence of HPV in the control group compared to only 1 in the vaccinated group [7]. It's been so effective that about 40 nations now have incorporated the vaccine into their national health programs.
There really is no downside to the vaccine, except that some people believe that if kids are vaccinated against HPV they will engage in more dangerous behaviors thinking that they are protected (the same arguments against providing condoms in schools or clean needles for drug addicts). I do think men benefit from the vaccine- it protects against mucosal warts, oropharyngeal cancers, and penile cancers, with no downside, except for maybe the cost (I don't know if it's expensive or not, or covered by insurance the way other vaccines are). As for the anti-vaccine crowd, that's an entirely different discussion that I'd rather not get into at the moment, because those people don't argue using facts, and therefore there is no way to debate them.
Questions you may have:
A question I often hear is "My girlfriend/wife/partner had an abnormal pap smear. I may have been exposed. Should I get tested?" The answer is no, and I'll explain why. Firstly, there are a lot of causes for abnormal pap smears, not all of them are due to HPV. Second, even if your partner is HPV positive, you would need to know what 'type' you were exposed to. This can be done, but it involves expensive lab tests that aren't routinely performed, and unless you have a wart (evidence of an active, productive infection), the doctor wouldn't know what tissues to examine or biopsy anyway. And simply detecting the presence of a virus doesn’t tell you anything about the nature of the infection- what we would really need to see is the presence of high-risk E6 and E7 proteins in a cell, a much harder proposition. If by some stroke of luck it is determined that yes, you test positive for a high-risk strain, that knowledge is still of little benefit. If you were exposed to a high-risk HPV there is a chance that an infected cell will wind up in a virally 'unproductive' infection that might lead to cancer, but there's no way of knowing, in a healthy individual, if the virus will be cleared, persist, or become cancer, nor can infected epithelium even be identified in the absence of a productive infection. There is no 'pre-malignancy' test, so as of now the motivation to develop cheap accurate HPV tests just isn't there, because we currently do not alter patient management based on that information. Even in a proven, diagnosed HPV-positive oropharyngeal cancer, despite the evidence that they have a different clinical course and prognosis, surgeons will still treat it like a 'conventional' alcohol and tobacco-induced cancer (though this may soon change).
I hope that helps to clear up any misconceptions. Feel free to respond or PM me if you have any other questions.
1.Gillison ML, Broutian T, Pickard RK, Tong ZY, Xiao W, Kahle L, et al. Prevalence of oral HPV infection in the United States, 2009-2010. JAMA 2012; 307:693-703.
2.Ramqvist TDalianis T. An epidemic of oropharyngeal squamous cell carcinoma (OSCC) due to human papillomavirus (HPV) infection and aspects of treatment and prevention. Anticancer Res 2011; 31:1515-9.
3.Chaturvedi AK, Engels EA, Pfeiffer RM, Hernandez BY, Xiao W, Kim E, et al. Human papillomavirus and rising oropharyngeal cancer incidence in the United States. J Clin Oncol 2011; 29:4294-301.
4.Munger K, Phelps WC, Bubb V, Howley PMSchlegel R. The E6 and E7 genes of the human papillomavirus type 16 together are necessary and sufficient for transformation of primary human keratinocytes. J Virol 1989; 63:4417-21.
5.Tota JE, Chevarie-Davis M, Richardson LA, Devries MFranco EL. Epidemiology and burden of HPV infection and related diseases: implications for prevention strategies. Prev Med 2011; 53 Suppl 1:S12-21.
6.Schiffman M, Castle PE, Jeronimo J, Rodriguez ACWacholder S. Human papillomavirus and cervical cancer. Lancet 2007; 370:890-907.
7.Herrero R, Quint W, Hildesheim A, Gonzalez P, Struijk L, Katki HA, et al. Reduced prevalence of oral human papillomavirus (HPV) 4 years after bivalent HPV vaccination in a randomized clinical trial in Costa Rica. PLoS One 2013; 8:e68329.