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OCF's opinions about HPV and oral cancer

***Continuing research, particularly after the breakthrough paper on HPV16 and oropharyngeal cancers By Dr. Mara Gillison et. al. at Johns Hopkins is being conducted into the relationship of HPV with many other cancer types, and with oral cancers in particular. Speaking historically, at least 25% of those diagnosed with oral cancer have been 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 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 be definitively established, it was generally felt that we could easily define the high risk population. But today the research into the relationship of HPV16 and oral malignancies gives us insights into the origin of cancer in 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 is changing these numbers and ratios dramatically. 

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 cancer in the front (anterior) portion of the oral cavity. Oropharyngeal cancers are those located in the posterior portion of the mouth and pharynx, 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 many decades of stable numbers in the rate of incidence of oral and oropharyngeal cancers, (which are now increasing every year since about 2000, particularly those of the posterior mouth/ oropharynx), it is clear 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. In the foundation's opinion based on more than a decade of solid peer reviewed published science, 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 and no longer representative of the situation in America. Publications now existing in peer reviewed medical journals establish HPV as an equally, if not more important causative agent than tobacco, and its impact will certainly be significantly larger than the 25% of what was previously described as "other causes". The estimates of this HPV percentage of the overall patient population have ranged from 40-80% depending on the source being quoted and anatomical site being discussed. 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 in the US for many years, and been categorized as unknown etiologies for far too long. Because the current treatment protocols for the disease, regardless of etiology are the same, many institutions have been reluctant until just recently to thoroughly explore the causative process. Patients joining OCF’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 oral and oropharyngeal cancer patients. 

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 increasingly 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


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. 

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. 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, despite marketing claims by some companies that do not stand up to scientific scrutiny. So while we are advocates for increased screening, we are also cognizant of the difficulty in the discovery process for this segment of 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 who are informed in the warning signs, who will then self refer when suspect issue arise in the oral environment, to knowledgeable medical and dental professionals for confirmation and diagnosis.

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. Many just label these patients as unknown primaries and proceed with the most aggressive treatments covering large anatomical areas.  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 in patients with no visible symptomology. The primary lesions have been very small - MANY AS SMALL AS 2mm, and buried deep in the tonsil tissues with no surface indications that they are presentWe 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. As of August 2015, 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 oncoprotein E6-E7 DNA involvement 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 likely 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. A paper published in the Journal of the National Cancer Institute following 4000 individuals for four years has now shown what we have always suspected. That HPV vaccinations designed for the prevention of cervical cancers have additional benefits in preventing HPV origin diseases in other anatomical sites, including oral. 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, something already being done in other first world countries with the same vaccines. 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 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.

The following PDF is a scientific argument for using the cervical cancer vaccine to impact other HPV+ cancers.

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 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, 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 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.

Read October 2007 press release from the foundation on this position.

The foundation also believes that studies that are currently being conducted will better elucidate this apparent survival advantage for individuals with HPV positive disease, and in the next few years this will be likely better defined. As treatment modalities for both types have remained consistent, we believe that the change in the causative etiology will prove to be an influencing factor in this survival advantage. This very point was conclusively proven in a June 2010 article by Ang and Gillison et. al. published in the prestigious New England Journal of Medicine.

It is possible that if this is true, treatment modalities for HPV vs. tobacco related tumors could be altered. This is strictly speculation at this point. 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.