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HPV Infection in Pathogenesis of Head and Neck Cancers

Insights From: Ezra Cohen, MD, UC San Diego Moores Cancer Center; Robert L. Ferris, MD, PhD, FACS, University of Pittsburgh Cancer Institute; Jared Weiss, MD, University of North Carolina School of Medicine
Published: Tuesday, Mar 29, 2016


Transcript:

Ezra Cohen, MD:
We’ve begun to recognize that HPV-positive and HPV-negative cancers are distinct groups. We know now that molecularly they’re distinct, they’re different cancers biologically. And that translates into differences in clinical profile, presentation, and some other things that we’ve seen in the clinic. In fact, it was the clinical observations first that gave us a clue that something different was going on. HPV-negative cancers are the typical head and neck cancer. These are tobacco-associated cancers for the most part, not exclusively.

There are some non-smokers that can get HPV-negative cancers, but they’re associated with tobacco use. Alcohol use can act synergistically with tobacco, although alone it usually is not a major risk factor. Tobacco really becomes that. There are some other minor risk factors for head and neck cancer as well, and there are some genetic syndromes that can predispose patients, such as Fanconi anemia, but that’s fairly rare. Those are the HPV-negative subgroup and they can occur in the oral cavity, the oral pharynx, hypopharynx, and larynx.

Whereas, for HPV-positive tumors, we see a little bit of a different scenario. Here we see patients who are usually non-smokers and non-drinkers. And that is what clued us in to the fact that something different was happening. We began to ask ourselves, why are these patients getting cancers of the tonsil and the base of the tongue when they have no apparent risk factors? Several years later, we discovered that these cancers harbored a virus called the human papillomavirus, and that virus appeared to be the etiologic agent for these cancers.

HPV-positive patients tend to be younger. They’re about a decade younger than their HPV-negative counterparts. Interestingly, the male to female ratio is 3:1, and we’re beginning to discover why that is. There may be differences in the ability of men and women when exposed to the virus to actually clear it. And apparently from the data that we have, women are better at clearing the virus than men are. We don’t know the reasons behind that yet. In addition, we know that HPV-positive cancers are associated with sexual activity. This is a sexually transmitted disease, just like any other HPV-related malignancy, cervical cancer, anal cancer, penal cancer, HPV-positive head and neck cancer is, no exception. These are associated with sexual contact.

Then with respect to the incidence, we see dramatic differences. Whereas, especially in the United States, people got the message that smoking is bad for you and began to stop smoking about two, maybe three decades ago. With that, we’ve seen a lower incidence of smoking related head and neck cancers, especially those of the larynx, which is the classic smoking-related head and neck cancer. In the meantime, we’ve seen an increase in HPV-positive oral pharynx cancers. In fact, that increase has been dramatic.

It’s been about 3% per year for the last 30 years, and if you add all that up, we’re getting to the point where HPV-positive cancers in the United States in numbers are going to overtake the HPV-negative cancers. And what’s alarming, if you look at the incidence and the epidemiologic data, is that the incidence curves are not flattening out at all. In fact, if anything, they’re becoming more acute, suggesting that we’re only at the beginning of this epidemic of HPV-positive oral pharynx cancers.

Robert L. Ferris, MD, PhD, FACS: When we talk about HPV in head and neck cancer, we think of it as a new subset of patients, and to some extent it is. But, if you go back to the 30s and 40s, about 10% of head and neck cancers actually had HPV DNA, HPV infection. When we looked in Pittsburgh in the early 80s, it had gotten up to 20% or 30%. This is not of all areas of the head and neck. Interestingly, the HPV subset is restricted to an area called the oropharynx. That’s not the front part of the mouth or tongue and it’s not way down in the voice box. It’s in the middle, the tonsil and the base of the tongue, tonsils that many of us had removed when we were kids. But there’s also tonsil tissue, that lumpy part in the back of the tongue where if you stick your finger back there, you’d gag yourself. That lumpy part is also tonsil tissue and that seems to be where the HPV infects, preferentially, and turns into cancers, turns the cell into a malignant tumor. The increase from 20%-30% of the oropharynx, not of the voice box and not of the front part of the mouth, that increase has gone from 20% up to 80%. So, the vast majority of tonsil and base-of-tongue tumors, the oropharyngeal carcinomas are now HPV-driven. This increase has been seen with a rate of about 5% per year every year, to where HPV-positive head and neck cancers have essentially now equaled and overtaken the HPV-positive cervical cancers in the US.

Ezra Cohen, MD: Screening for HPV oral pharynx cancer is a little bit tricky, whereas for the cervix we have a wonderful test that’s been developed over the last several decades and now involves testing at the molecular level for the actual virus. That’s a lot more challenging to do in the oral pharynx, and the reason behind that is it goes back to the biology of HPV. First of all, the oral pharynx is not the most readily accessible site. We should predicate all of these statements remembering the fact that HPV-positive oral pharynx cancer occurs almost exclusively in the tonsil and the base of tongue, and these are areas that are difficult to get at with a brush or some sort of instrument that could scrape off the layer of cells or the first layer of the mucosa. So, anatomically it’s a little bit more challenging. But, more importantly, when we think about where the HPV virus resides and where these cancers start, we realize that it’s in the crypts of the tonsils and the lymphatic areas of the base of tongue.

If we remember back to medical school in our histology classes, we remember that the tonsil is essentially a type of lymph node and its histological structure is made up of crypts and surrounding a very dense lymphatic infiltrate. The HPV virus actually infects the cells at the base of those crypts. And so even if we were able to scrape off the surface layer, we actually wouldn’t get to the cells that the HPV virus resides in. It’s been quite challenging to come up with a screening test for HPV oral pharynx cancers. Some people have used oral rinses, and those are somewhat helpful in the sense that at least we can identify an individual who harbors a high-risk HPV infection in the oral cavity or in the upper air digestive tract. But the problem with that is that when we look at population studies that have done that, we recognize that there are somewhere in the range of about 1-2 million people in the United States that are infected, that have an oral infection for a high-risk HPV strain. If you do the numbers, we realize that a very small fraction of that will actually develop head and neck cancers, so it doesn’t become a great screening tool.

Transcript Edited for Clarity
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Transcript:

Ezra Cohen, MD:
We’ve begun to recognize that HPV-positive and HPV-negative cancers are distinct groups. We know now that molecularly they’re distinct, they’re different cancers biologically. And that translates into differences in clinical profile, presentation, and some other things that we’ve seen in the clinic. In fact, it was the clinical observations first that gave us a clue that something different was going on. HPV-negative cancers are the typical head and neck cancer. These are tobacco-associated cancers for the most part, not exclusively.

There are some non-smokers that can get HPV-negative cancers, but they’re associated with tobacco use. Alcohol use can act synergistically with tobacco, although alone it usually is not a major risk factor. Tobacco really becomes that. There are some other minor risk factors for head and neck cancer as well, and there are some genetic syndromes that can predispose patients, such as Fanconi anemia, but that’s fairly rare. Those are the HPV-negative subgroup and they can occur in the oral cavity, the oral pharynx, hypopharynx, and larynx.

Whereas, for HPV-positive tumors, we see a little bit of a different scenario. Here we see patients who are usually non-smokers and non-drinkers. And that is what clued us in to the fact that something different was happening. We began to ask ourselves, why are these patients getting cancers of the tonsil and the base of the tongue when they have no apparent risk factors? Several years later, we discovered that these cancers harbored a virus called the human papillomavirus, and that virus appeared to be the etiologic agent for these cancers.

HPV-positive patients tend to be younger. They’re about a decade younger than their HPV-negative counterparts. Interestingly, the male to female ratio is 3:1, and we’re beginning to discover why that is. There may be differences in the ability of men and women when exposed to the virus to actually clear it. And apparently from the data that we have, women are better at clearing the virus than men are. We don’t know the reasons behind that yet. In addition, we know that HPV-positive cancers are associated with sexual activity. This is a sexually transmitted disease, just like any other HPV-related malignancy, cervical cancer, anal cancer, penal cancer, HPV-positive head and neck cancer is, no exception. These are associated with sexual contact.

Then with respect to the incidence, we see dramatic differences. Whereas, especially in the United States, people got the message that smoking is bad for you and began to stop smoking about two, maybe three decades ago. With that, we’ve seen a lower incidence of smoking related head and neck cancers, especially those of the larynx, which is the classic smoking-related head and neck cancer. In the meantime, we’ve seen an increase in HPV-positive oral pharynx cancers. In fact, that increase has been dramatic.

It’s been about 3% per year for the last 30 years, and if you add all that up, we’re getting to the point where HPV-positive cancers in the United States in numbers are going to overtake the HPV-negative cancers. And what’s alarming, if you look at the incidence and the epidemiologic data, is that the incidence curves are not flattening out at all. In fact, if anything, they’re becoming more acute, suggesting that we’re only at the beginning of this epidemic of HPV-positive oral pharynx cancers.

Robert L. Ferris, MD, PhD, FACS: When we talk about HPV in head and neck cancer, we think of it as a new subset of patients, and to some extent it is. But, if you go back to the 30s and 40s, about 10% of head and neck cancers actually had HPV DNA, HPV infection. When we looked in Pittsburgh in the early 80s, it had gotten up to 20% or 30%. This is not of all areas of the head and neck. Interestingly, the HPV subset is restricted to an area called the oropharynx. That’s not the front part of the mouth or tongue and it’s not way down in the voice box. It’s in the middle, the tonsil and the base of the tongue, tonsils that many of us had removed when we were kids. But there’s also tonsil tissue, that lumpy part in the back of the tongue where if you stick your finger back there, you’d gag yourself. That lumpy part is also tonsil tissue and that seems to be where the HPV infects, preferentially, and turns into cancers, turns the cell into a malignant tumor. The increase from 20%-30% of the oropharynx, not of the voice box and not of the front part of the mouth, that increase has gone from 20% up to 80%. So, the vast majority of tonsil and base-of-tongue tumors, the oropharyngeal carcinomas are now HPV-driven. This increase has been seen with a rate of about 5% per year every year, to where HPV-positive head and neck cancers have essentially now equaled and overtaken the HPV-positive cervical cancers in the US.

Ezra Cohen, MD: Screening for HPV oral pharynx cancer is a little bit tricky, whereas for the cervix we have a wonderful test that’s been developed over the last several decades and now involves testing at the molecular level for the actual virus. That’s a lot more challenging to do in the oral pharynx, and the reason behind that is it goes back to the biology of HPV. First of all, the oral pharynx is not the most readily accessible site. We should predicate all of these statements remembering the fact that HPV-positive oral pharynx cancer occurs almost exclusively in the tonsil and the base of tongue, and these are areas that are difficult to get at with a brush or some sort of instrument that could scrape off the layer of cells or the first layer of the mucosa. So, anatomically it’s a little bit more challenging. But, more importantly, when we think about where the HPV virus resides and where these cancers start, we realize that it’s in the crypts of the tonsils and the lymphatic areas of the base of tongue.

If we remember back to medical school in our histology classes, we remember that the tonsil is essentially a type of lymph node and its histological structure is made up of crypts and surrounding a very dense lymphatic infiltrate. The HPV virus actually infects the cells at the base of those crypts. And so even if we were able to scrape off the surface layer, we actually wouldn’t get to the cells that the HPV virus resides in. It’s been quite challenging to come up with a screening test for HPV oral pharynx cancers. Some people have used oral rinses, and those are somewhat helpful in the sense that at least we can identify an individual who harbors a high-risk HPV infection in the oral cavity or in the upper air digestive tract. But the problem with that is that when we look at population studies that have done that, we recognize that there are somewhere in the range of about 1-2 million people in the United States that are infected, that have an oral infection for a high-risk HPV strain. If you do the numbers, we realize that a very small fraction of that will actually develop head and neck cancers, so it doesn’t become a great screening tool.

Transcript Edited for Clarity
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