The Human Papilloma Virus (HPV)

The human papilloma virus (HPV) is a DNA virus that infects the epithelial cells of skin and mucosa. The moist epithelial surfaces (squamous cells) include all areas covered by skin and/or mucosa such as the mouth, throat, tongue, tonsils, vagina, cervix, vulva, penis and anus. Transmission of the virus occurs when these areas come into contact with a virus. It is established now that sexual contacts, both conventional and oral, are means of transferring the HPV virus through direct skin to skin contact. There may be other means of transmission that are yet unknown.

The leading cause of oropharyngeal cancer is from HPV, a very small number of oral cavity cancers also occur from HPV. The HPV family contains almost 200 strains, and it is one of the most common viruses in the United States. It is important to understand that of all these, only nine are associated with cancers. Of the nine that are high risk, only one is strongly associated with oropharyngeal cancer, HPV16. A handful or more are associated with benign growths (warts) and the vast majority we have no evidence, other than they exist, that they harm us in any way.

There is lack of Indian data .
The CDC says that up to 80% of Americans will have HPV infections in their lifetime and 99% will clear these infections without consequence, or even knowing that they had the infection, as it produces no symptoms they will notice.

The body’s immune system is usually able to get rid of an HPV infection and many infections come and go without causing any problems, or an individual even knowing they were infected. The information provided is not meant to scare you. Oropharyngeal cancers while increasing rapidly in incidence, are still a very small risk in our world. It is meant to educate you about the risk factors and signs and symptoms of oral and oropharyngeal cancer. An informed individual will be able to self-discover something which is going wrong and bring it to the attention of a medical or dental professional for the earliest possible diagnosis of a problem.

Since OCF-Oral Cancer Foundation first met Dr. Maura Gillison at the ASCO meeting in 1999, where she delivered her paper which correlated HPV infections as the likely cause of the increase in oropharyngeal cancers we were seeing clinically in the US, and that papers subsequent publication in 2000, OCF-Oral Cancer Foundation has been heavily engaged in the HPV issue, both as funders of research to understand it better, and as advocates later for preventative measure like the cervical cancer vaccine. Since then further research has been conducted into the relationship of HPV with many other cancer types, and with oropharyngeal cancers in particular. Historically, at least 25% of those diagnosed with oral cancer are non-smokers. From papers dating several decades ago, many organizations, the foundation included, have stated that the other 75% of those diagnosed have used tobacco in some form during their lifetimes. Many years of tobacco use, manifested itself in the later decades of life (with an average occurrence time of about 60 years of age) as oral/oropharyngeal cancers. Historically this information has been true. As smoking was the number one causative agent in oral cancers for so long, and the relationship of HPV had not yet been definitively established, (the research was early) it was generally felt in the early 2000’s that we could easily define the high-risk population by sorting out tobacco users. But today the research into the relationship of HPV16 and oral malignancies gives us unchallenged evidence as to the origin of cancer in many of those diagnosed individuals who did not smoke and were moderate alcohol consumers. Along with American’s changing behaviors both in tobacco use and sexual practices, all of this is changing these numbers and ratios dramatically of those who come to the disease in dramatic ways.

While the foundation speaks in public service messages about “oral cancers” for simplicity during public dialog, our cancers of interest are distinctly divided into two separate diseases based on anatomical site and etiology. Oral cancers are actually those cancers in the front (anterior) portion of the oral cavity. Oropharyngeal cancers are those located in the posterior portion of the mouth and oropharynx, and usually include the tonsils, the tonsillar pillars and crypts, the base of the tongue, and the back of the oropharynx itself.

Given the decline of tobacco use over the last twenty years in the US, (the historic primary cause of the disease) and the stable (or increasing in the 2004 – 2008 period) rate of incidence of oral cancers, particularly those of the posterior mouth/ oropharynx, it is likely that the 75% -25% statement which has been made by everyone at least since the Blot paper published in 1988, is no longer an accurate representation of the situation. It has been the foundation’s opinion, that HPV is playing a greater role in the incidence rates of the disease, and the now decades old Blot and Mashberg papers which presented these percentages are outdated. We now (2017) have an abundance of peer-reviewed published scientific evidence of this change. Unfortunately, the information people obtain in many parts of the web and from organizations who pay less attention to the changing science, much misinformation still live in this environment. We believe the rates stated on many websites no longer are representative of the actual realities of oral cancer etiology in the US today. Publications now existing in peer-reviewed medical journals establish HPV as a more important causative agent than tobacco in oropharyngeal cancers, and its impact will certainly be significantly larger than the 25% of what was previously described as “other causes.” A number closer to 70% would more accurately describe its impact in that anatomical site today. Most recently there was a study published in Sweden that looked at their current population of oral cancer patients and in that group, 60% were HPV positive. The foundation believes that the ratio of HPV+ disease rates have been significantly under-reported.

Because until recently the treatment protocols for the disease, regardless of etiology were the same, many institutions were reluctant until just recently to thoroughly explore the causative process. So data has been skewed for years from under-reporting and thorough exploration of the causative etiology. Patients joining OCF-Oral Cancer Foundation’s large support group for oral cancer patients, even today report that their treating institutions have not tested their biopsy specimens for the presence of HPV even when the primary is in an anatomical site characteristically known for HPV disease to occur. This leads us to believe that national numbers are short of giving us an accurate view of the extent of the problem. Whatever the percentage, there is little doubt the HPV is the driving force behind the rapidly escalating numbers of oropharyngeal cancer patients. Today (2017) the treatments for HPV+ patients are changing, lesser radiation exposure protocols are being clinically trialed at numerous locations, the most surprising was the early 2-year results from Mayo Clinic on a 50% reduction that had identical outcomes at two years to those who received the normal dose of radiation. Neck dissections, so commonplace in treatment are now being done are in fewer cases as the disease responds so well to radiation alone. Clearly positive testing of tissue samples for the presence of HPV involvment is mandatory given these new opportunities to reduce the morbidity of treatments. We also have today published science showing a clear survival advantage to those HPV+ patients when compared to a tobacco etiology group that can be as large as a 30% improvement.

The foundation, in lectures, news interviews, and in written opinions has often expressed this premise since 2001. We strongly believe that in a younger population of non smoking oral cancer patients, that HPV is presenting itself as the dominant causative factor, particularly in the oropharynx anatomical locations. Since the historic definition of those who need to be screened is now changed by this newly defined HPV etiology, and is no longer valid, it is NOT POSSIBLE to definitively know who is at risk for the development of the disease, and who is not. Simply stated, today

ANYONE OLD ENOUGH TO HAVE ENGAGED IN SEXUAL BEHAVIORS WHICH ARE CAPABLE OF TRANSFERING THIS VERY UBIQUITOUS VIRUS NEEDS TO BE SCREENED ANNUALLY FOR ORAL CANCER.

For this reason we are STRONG promoters of OPPORTUNISTIC annual screenings to catch this disease at its earliest possible stages, when it is most vulnerable to EXISTING treatment modalities and survival rates are the highest. We believe that this will bring the oral cancer death rate down as early detection and diagnosis takes place, and will reduce the treatment associated morbidity to patients who do present with oral cancers. If you combine that professional diligence with a public self-discovery and self-referral program like OCF-Oral Cancer Foundation’s “Check your Mouth” program, (www.checkyourmouth.org) there exists a strong opportunity to find precancers in the anterior mouth, and early finds of cancers in the oropharynx, which ultimately would be of benefit. Earlier stage of disease development at time of discovery and onset of treatments, leads to lesser treatment related morbidity, fewer long-term negative quality of life issues, and ultimately better long-term survival rates.

While encouraging a more robust national screening policy, we are painfully aware that in HPV+ disease, early discovery is very problematic. Disease from this etiology does not present in the same manner as tobacco origin disease. Tobacco disease reveals itself often even in precancerous stages through tissue changes, such as leukoplakia, erythroplakia, and other visible lesions, tissue discolorations, ulcerations, and palpable tissue indurations. HPV disease seldom, until very late stages of progression, produces visible lesions. Often it is first found as an enlarged painless cervical (neck) lymph node, which is never a primary location but a metastasis from the primary in the oropharynx. While there are some screening techniques and patient history questions that will help in finding HPV cancers, they are very nuanced clues, rather than overt signs and symptoms. As of yet there are no adjunctive devices that assist in this process. No light-based technology or other method of early discovery has been found to be valuable in the early discovery of this origin disease. So while we are advocates for increased screening, we are also cognizant of the difficulty in the discovery process for this segment of posterior oral cancers. For this reason, the foundation believes that as in many other cancers, we need to educate the public on the early signs and symptoms, so that self-discovery can take place by individuals informed in the warning signs, who will then self refer to knowledgeable medical and dental professionals for confirmation and diagnosis. It is not a difficult process and takes less than 5 minutes once a month at home. A video and description of how to do this at home exists at (www.checkyourmouth.org)

Anecdotally we are hearing from numerous treatment facilities that the incidence of patients with positive neck metastasis and no visible primaries intraorally is becoming increasingly common. Some institutions have adopted a policy of bilateral tonsillectomies in these patients with occult oral environments. At at least one prominent NCI designated institution they are reporting finding approximately 70% of these tonsils to be positive for SCC. The primary lesions have been very small – MANY AS SMALL AS 2mm. (It is possible for conventional scanning technology to miss something this small.) Note that it is highly uncharacteristic of a lesion this small to be spinning off metastasis in other cancer types, but in the lymphoid tissue of the tonsils and that which covers the base of the tongue, those tissues are directly connected to a lymph fluid drainage system leading into the lymph nodes of the neck. Hence the first sign of an enlarged, painless node in the neck and what is apparently to an examiner an occult or symptomlesss oral environment. We are concerned that data on this experience is not being reported, even though it appears to be an increasingly common presentation. Should it prove that these HPV16/SCC positive tonsils (which appear visually normal in the intra oral environment) are becoming commonplace, this does not bode well for pre-malignant early detection by methods that we are currently using. No currently available adjunctive device, using tissue auto fluorescence, tissue reflectance, or brush cytology, is capable of assisting in the early discovery of these disease states as pre-cancers. There is also no evidence that the current swish test to collect exfoliated cells to test for the presence of HPV16 has any value in this process. This test finds episomal HPV infections, and it is the persisting long-term infections that have cascaded into E6-E7 DNA involvement in the cells that are of concern. In an HPV world, the adjunctive devices on the market today, mostly sold within the dental industry, do not show efficacy in finding early HPV+ oral/oropharyngeal cancers.

It is worth mentioning that the new cervical cancer vaccines approved for use in pre-sexual individuals for the prevention of cervical cancer being developed and marketed by pharma giants Merck and GlaxoSmithKline, will have a positive collateral impact in the world of head and neck / oral cancers in the next couple of decades, as these young, vaccinated individuals do not develop HPV related malignancies in sites far removed from the cervix. Antibodies developed from vaccination are not isolated to a particular anatomical site, but circulate systemically. The foundation is a strong supporter of the use of the vaccines, and encourages their use in young males as well as females. We appeared before the CDC for three consecutive years to fight for the use of these vaccines in a non gender based manner, allowing young boys to be vaccinated as well. With our partners at the HPV and Anal Cancer Foundation, and the American Academy of Pediatrics, we finally obtained a new recommendation from the CDC encouraging the vaccination of young males. While the foundation has written to the FDA expressing this viewpoint, the manufacturer’s, without a long-term definitive clinical trial approved by the FDA related to H&N; infections and cancers, are prohibited from talking about oral and head and neck cancers in relationship to their vaccines, and what impact their vaccines may have on them. OCF-Oral Cancer Foundation strongly believes that elimination of a causative agent (HPV16) by preventing infection from it with a vaccine, will subsequently prevent any disease that agent may have produced in the protected individual. This is simple scientific extrapolation, and a view shared by many in the science community. Already we are seeing in the national, on going study NHANES, a reduction in HPV infections in females since the advent of vaccination, both as cervical and oropharyngeal infections.

Argument against this position from some doctors

Some doctors, (not the core researchers on this subject) believe that if we eliminate HPV16 as the causative agent through vaccination, that another oncogenic version of HPV will just take its place. In science circles this is referred to as the strongest swimmer theory. It goes like this. Imagine 50,000 sperm swimming towards an egg to fertilize it. Whichever one gets there first, fertilizes the egg and no others can enter. Now imagine that you are able to knock out that strongest swimmer. What would happen is the second strongest swimmer would reach the egg instead, and take care of the job. Likewise, if you take out the second strongest swimmer, the third strongest would accomplish the task, and so on. The reason this does not apply to HPV16 and oral cancer in our opinion, is that we have seen no other contenders in the pack. HPV16 is it. Cervical cancers are a different situation, 16 and 18 are the dominant causes about 70% of the time, and we sometimes see other oncogenic HPV’s cause cervical cancers in association with them. We do not see this occurring in oropharyngeal cancers. We seldom see other oncogenic HPV DNA in oral cancer tissues other than HPV16. The other reason we believe in the vaccine, is that in the cervical cancer model, the vaccine DOES NOT protect from the other oncogenic HPV’s, such as versions 31, 33, 35, 45, etc. So while we have knocked out the primary cervical cancer causing versions (16 and 18 ie. the strongest swimmers) no other secondary tier oncogenic HPV’s have jumped in to replace them in the years that the vaccine has been in use. If this were happening, the vaccine would be useless, cervical cancer rates would remain the same, and that is not the experience that we are observing in the years since the introduction of the vaccine and its protection.

What does the HPV16 etiology mean for opportunistic screening?

We certainly still need to be engaged in opportunistically screening entire patient populations in the dental, ENT, RDH, and general medicine environments. Tobacco is not going away as a cause, and it is still a major problem with many new unknowns entering the marketplace, like dissolvable tobacco products, vaping, and others marketing themselves as “harm reduction strategies.”

But the mechanisms of oral cancer detection need to be altered to some degree, and dental and medical professionals need to not only get up to speed on these new issues, but be increasingly involved. As a primary example, with these occult oral environments common in HPV+ patients, and tissue changes we historically look and feel for not so readily available to us in the examination, what NEW things must we incorporate?

Palpation of the neck has never been more important.

Unfortunately, this is where we are seeing many first presentations, and recognition by the patient, that something is amiss. A hard/firm, enlarged, painless, fixated node in the neck that has been present for over 21 days should be sampled by fine needle aspiration biopsy at minimum. Painless is the keyword here. If this were from a tooth abscess, ear infection etc. draining into cervical nodes, it would be tender to the touch. Another sign is an irregular and asymmetrical trigome (the shape visualized in the posterior of the mouth formed by the base of the tongue, and the tonsillar pillars on each side). Lack of symmetry and swelling on one side, which is simultaneously painless when palpated, is a cause for concern, and is not associated with other disease states. This is frequently associated with a positive finding in the cervical nodes on the same side.

The foundation also believes that studies that are currently being conducted will better elucidate all the mechanisms behind the survival advantage for individuals with HPV positive disease, and in the next few years, this will be likely better defined.

There are also therapeutic vaccines under study which may be able to suppress viral loads and prevent recurrences in patients with HPV positive tumors. The results from these has yet to be published, and we are far from knowing definitively that this is possible.

For those with an interest in the science of all this, the relevant peer-reviewed science articles, many of which OCF-Oral Cancer Foundation has financially co-sponsored the work on, appear in their original full formate on another page in HPV section of the OCF-Oral Cancer Foundation website.