Kendal Williams, MD (Host): Welcome everyone to the Penn Primary Care Podcast. I'm your host, Dr. Kendal Williams. Head and neck tumors and head and neck cancer is the eighth most common cancer in the world. And in the last decade or two, we've had a change in the epidemiology of these cancers with more and more being associated with human papillomavirus infection.

And this has sort of changed the whole dynamic about how we think about head and neck cancer, certainly from the days when I trained, when it was all about, risk factors were tobacco and alcohol. The risk factors have changed and the treatment of these tumors have changed. So for that reason, I brought on an expert to talk to us about it.

Dr. Robert Brody is an Assistant Professor of ENT and Head and Neck Surgery at Penn and the VA. He is a Head and Neck Surgical Oncologist and a Microvascular Reconstructive Surgeon, who not only performs clinical work in the OR and in the clinic, but also does research as well. Rob, thanks for coming onto the podcast.

Robert Brody, MD: Well, thanks for inviting me onto the podcast as well, Dr. Williams, a pleasure to talk about what I think is an important topic to me and hopefully, the audience as well.

Host: And please don't call me Dr. Williams.

Robert Brody, MD: Well, thank you. Thank you very much, Kendal.

Host: Only my patients are allowed to do that. So talk about area. You know, this came to my attention when I had a couple of my patients actually come back to me and were under treatment with your group, for HPV associated head and neck cancers.

You know, just to give some context on this, you know, I trained late 90s, early 2000s, went to medical school, graduated from Penn in 1995. You know, during that period really, when we thought about head and neck cancers, we were mostly talking about squamous cell cancers, which I know are still the most predominant cancers, but it was often just associated with alcohol and tobacco use. And now we've seen this change, right?

Robert Brody, MD: Yeah, I mean, if you look at it historically, a large proportion of cancers of the upper air digestive tract, as we call it, the UADT is the abbreviation we use, you know, that consists of the nasopharynx, the nasal cavity, the oropharynx, the larynx and the hypopharynx as well.

 And about 90, 95% of those cancers are squamous cell carcinomas. Classically they're caused by combination of smoking and drinking. However, in our oral cavity cancer patients, about half of our patients have never smoked before, and it can also be due to chronic trauma, sometimes due to kind of chronic biting or chronic injury to the lining of the oral cavity.

And most importantly, there is an epidemic of HPV associated oropharyngeal cancers, or cancers of the tonsils, that has really been growing over the past 20, 30 years, upwards of 25 to 40,000 patients are being diagnosed every year with oropharyngeal cancer. And 90 percent of those patients are due to HPV or human papillomavirus.

Host: Is this because of a changing nature of the virus? Is the virus changing? I mean, our habits in relation to exposure to this have probably not changed that much. So, I'm just curious why you think the uh HPV associated cancers are increasing.

Robert Brody, MD: It's hard to say exactly. But there is a lot of research epidemiologically that occurred in the nineties, two thousands. I mean, literally we didn't know that HPV caused cancers until the late seventies, and primarily when people think of HPV associated cancers, they think of cervical cancer, as well as some anorectal cancers.

 HPV associated throat cancer is actually more common than all of those cancers currently. The thought, in many circles could be that it could be due to changes in behavior, such as oral sex. Over the course of the past 20 or 30 years, there's been a shift in that type of behavior. However, you know, I always talk to patients and I say that you know, HPV infection due to, oral infection occurs in about 5% of the population. And there's a few studies that say that it could be increased due to oral sex, but you can also pass it along from sharing a drink or also coming out of the birth canal.

 A lot of children actually, can have respiratory papillomatosis, which is also caused by a strain of HPV. And these are not cancerous lesions. These are benign lesions of the larynx. And they occur just from being born in someone who may have had an infection in the cervical area. So the same type of infection could be passed on with other subtypes of HPV.

Host: HPV16 is the subtype that is the most associated with oropharyngeal cancers, right?

Robert Brody, MD: Yeah, you know, there's a variety of subtypes of HPV, 16 is the predominant one that occurs in oropharyngeal cancer. There's also subtypes, 18, 31 and a few other oncogenic ones. There's also benign papillomas that can occur from subtypes 6 and 11. So, the most common HPV vaccine that is currently given out to ideally children between the ages of around 9 - 13; that vaccine includes all of those subtypes, both the types that cause benign lesions, as well as the most common types that cause malignant lesions, including subtypes 16 and 18.

Host: We should probably assume that over the coming decades, we'll see, just as we've seen a spike in it, we'll see a reduction because of the HPV vaccine, right?

Robert Brody, MD: Yeah, it's very interesting. I mean, if you look in Australia where the uptake of the HPV vaccine is incredibly high, nearing 100%, you've actually already seen a substantial drop in that respiratory papillomatosis, which you see in infants; it's almost dropped to zero over the past five to 10 years.

Having said that, you know, when you think about cervical cancer, women are oftentimes diagnosed with cervical dysplasia and cervical cancer in their teens and 20s or early 30s. Why PAP smears are more often performed in that age group. However, the diagnosis of HPV associated throat cancer is oftentimes in the median age of around 60 to 65.

So the theory is that for some reason, people are being infected in likely their teens and 20s. And it's taking about 30 to 40 years for this to ultimately become a malignancy of the throat. I commonly describe it to patients more as like getting chicken pox when you're younger, and then you'll end up having the shingles in your 60s, you know, it kind of reactivates in some way.

Not a kind of an apples to apples comparison, but in terms of the time lag, it's a similar type of theory where you get infected when, again, you're in your teens or 20s. And for some reason, it takes about 30 to 40 years for these mutations to build up and result in cancer.

Host: So, I thought the way we would do this is to actually, kind of go through the various sections of the anatomy, the nasopharynx, the oropharyngeal area, because they, it turns out, they actually are a little different in terms of the types of cancers you see in those various cavities. Let's start with the oropharynx.

So, this is the mouth, the tongue, the cavity in the back of the throat until you get to the epiglottis, right? That's the oropharyngeal area. Something roughly that?

Robert Brody, MD: I always think of it kind of like that cross section that you see when you're in medical school, where they show you that sagittal cut through the head where, you can see the circumbellate papillae, if you haven't heard that word for many years, those taste buds that are kind of in the shape of a V on your tongue.

 The oral cavity is composed of the oral tongue or that anterior two thirds of the tongue. When you think about your anatomy where the facial nerve, has the chord of tympani and it innervates the anterior two thirds of the tongue, that's kind of the oral tongue. So the oropharynx is the area which is the base of the tongue, the area behind those circumbellate papillae.

And so the oropharynx consists of that base of tongue, which also has the lingual tonsils on the back. Then you have the palatine tonsils, which are the tonsils that we classically think of as tonsils. And those are the ones that kids have taken out when they're younger, or some adults who have really chronic sore throats get those palatine tonsils removed.

Then you also have the adenoid tonsil,or the adenoids. And all of those combined, consist of Waldyer's ring, which is again, probably hearkening back to med school and, and those eponymous names that you get. And so your oropharynx is that lingual, tonsil, base of tongue, palatine tonsil, and then the soft palate as well.

So the uvula and the soft palate, that area in the back of your throat is the oropharynx. The area in front of that we would call your oral cavity, which is, again, there's like kind of sub areas that we talk about, which is the oral tongue, the floor of mouth, the hard palate. And then we also talk about the alveolus which is, the alveolar mucosa, which is where your teeth are along the gingiva there.

And then you have your gingivo buccal sulcus, which is this little sulcus between your gingiva and your buccal mucosa. And then you also have your lip or the kind of the oral cavity component of your lip. So a lot of terms there to throw around.

Host: No, it's very good. Because, you know, this is anatomy. We don't think about that much. And just going through that was, is actually very helpful. And so, let's talk about the oral cavity and also the oropharyngeal cavity in terms of sort of cancers.

 When we talked about HPV, we talked about oropharyngeal. Are they exclusively in the oropharyngeal area? Or are they in the anterior oral cavity as well? How does that all fit?

Robert Brody, MD: Yeah. I mean, the only research that has really shown a consistent track record of causing cancers of the upper air digestive tract, is that HPV occurs in the tonsils or the palatine tonsil or the lingual tonsil generally. When I'm talking about HPV associated cancers, I'm generally discussing oropharyngeal cancer.

There are cancers that we biopsy in the oral cavity, in the larynx, the nasopharynx, even the nasal cavity as well, where there are HPV associated cancers and we can see that they stain for a marker for HPV. However, when we talk about HPV associated cancers, we're generally talking about oropharyngeal cancer.

And the really important reason for that is that when you have non HPV associated cancers or cancers that either do not stain, or have kind of the appropriate workup that show HPV causing the cancer; they tend to do worse than HPV associated cancers. And so the cure rate for HPV associated oropharyngeal cancer is quite high.

The cure rate is literally curing the local tumor or the tumor that can spread to the neck. We generally have five year control rates of over 90%, whereas when you have these cancers caused by smoking or just unfortunately due to other reasons like chronic trauma; those cancers do not have the same cure rate. It's closer to around 60 percent or so for five years, to sometimes 70 percent depending on the stage.

Host: Even though they're both essentially just squamous cell cancers, right?

Robert Brody, MD: Exactly. There's squamous cell cancers, but there's this thought that the HPV infection kind of gets caught in these tonsillar crypts and the crypts are only occurring in the lingual tonsils or the palatine tonsils, you know, when you think about someone with like one of these tonsil infections or chronic tonsillitis.

There's all these kind of nooks and crannies that are within that tonsillar tissue. I rarely use this term, but the tonsillar fauces, like F-A-U-C-E-S. And the thought is that these cancers form within those little crypts, and so they actually present differently than non HPV associated cancers.

So, usually a non HPV associated cancer, or a smoking induced cancer, is kind of this ulcer that forms on the tongue or the cheek or one of these areas in the upper air digestive tract. That ulcer can be painful, it can bleed, it's oftentimes the first thing that a patient notices. Either they have kind of an infection, they feel like they, it's not healing, it's an ulcer that's not healing, and so they go to see their doctor and they'll get a biopsy.

Whereas for HPV associated cancers, oftentimes, the first thing you notice is it's a gentleman in his early 60s and he's been shaving, and he notices that he has a lump in his neck, actually. So, he actually doesn't even know that he has a tumor of the tonsil. We only discover that when they come into my office and I see it with a scope.

So, what they're first noticing is actually a neck mass, which is, it can be a bit troubling to just notice a neck mass crop up.

Host: You know, it's interesting because I, I want to get into this a little bit on the clinical presentation piece because, in our office, you know, patients come to us first. The guy who notices a neck mass while shaving comes to us. So, I want to go into a little bit, because it does appear that they present a little differently.

Like you said, HPV associated present with neck masses in areas maybe that we're not paying a lot of attention to. Whereas, somebody who has, who chews tobacco or smokes and then has an oral cancer may present as an ulcer, as you said. The other thing I noticed when I was reading about this was actually, ear discomfort is a common symptom that brings people in, but it's not with the HPV associated ones. It was more with the sort of classical ones that were due to smoking and alcohol. I don't know why that is.

Robert Brody, MD: Yeah, I like to think of the ear pain as, especially if I'm talking to, this medical audience here, I think of it as that referred pain. So I think classically, you think of referred pain as like gallbladder pain, where you have a pain in your shoulder. So in the same way, you know, if you have an ulcer in the oral cavity or kind of along that general vicinity, it oftentimes presents as an ear pain in the same way that when you talk about kind of the taste sensation being the corda tympani.

Which runs from the facial nerve through the ear and then towards the tongue. There's a lot of interesting innervation in the head and neck. And so you have this referred pain to your ear when you have an ulcer or lesion that's in the oral cavity or the oropharynx, or even the nasal cavity or nasopharynx, or larynx as well.

It could either be due to that referred pain or you can have a tumor of the nasopharynx or the tonsil where literally a mass that's blocking the eustachian tube. Either you have this referred pain or you literally have the pain that you would have if you had really bad cold block your eustachian tube. You're literally having ear pain because there's a lack of equalization of pressure between the back of the nose and the middle ear.

And so, you're getting this ear pain, the same kind of pain that you would get in a plane if you had a cold, where you're changing pressure quickly, but you can't pop your ear. So, two different kinds of pain that you can get in your ear, and both can be a harbinger of malignancy in the head and neck.

Host: Yeah, that's interesting. You know, that's a little bit of a clinical pearl for me because I didn't think about ear pain as really being, I didn't think about cancer as being high on my differential when I think about ear pain, but obviously I need to be much attentive to my oropharyngeal exam and head and neck exam when somebody comes in with ear pain because normally I would focus on the ear or some sort of referred TMJ pain or something like that.

Robert Brody, MD: Local symptoms. So, if you had a tumor, if you go from top to bottom, like a tumor in your nose, can have just chronic nosebleeds, and that could just be due to the season and having dry air, or it could be a tumor, so you always want to be a little bit careful about that for persistent nosebleeds.

Nasal obstruction, so it's blocking off one side of the nose. That could be another sign, as well as a change in smell, because it's blocking off your olfactory tract. Again, that ear pain, because you can have a tumor in the nasopharynx. The most common presenting symptom for nasopharyngeal carcinoma would be ear pain or a blockage back there.

 Then you go down into the oropharynx, and you'll think of, again, just having a neck mass, which we can get into later, because it's its own topic. You can also just have a feeling of globus sensation, or like when you swallow, it's hard to clear, or just a chronic cough, because this mass is kind of touching or tickling your voice box, and then certainly in the voice box, hoarseness certainly should warrant presentation to be seen by any ear, nose, and throat doctor to look at the voice box, as well as, alterations in swallowing or dysphagia. We skipped over the oral cavity there because we were going from the back of the nose into the back of the throat, but again, in the oral cavity, any kind of chronic ulcer that's not going away within days.

As well as chronic dental issues, where you feel like you're having a chronic ulcer around your tooth or tooth pain, certainly that can be due to dental infection. But it could also be due to the initial presenting symptom of the head and neck cancer. And so an ear, nose and throat doctor, obviously we partner very closely with primary care doctors, but there's also a lot of common cause that we have with our oral surgeons as well as with, honestly dermatologists as well, because they sometimes also are the first people that people present to. So the first specialist someone presents to with a head and neck cancer as well.

Host: Yeah, and dentists, I imagine, you know, they're the ones that are sort of sitting there with the patient's open mouth looking there with full lights on the subject, maybe picking up things.

Robert Brody, MD: Whenever I go to the dentist, I'm always waiting for them to say clear to their dental hygienist to say that they did the oral cavity exam and it always makes me very happy to know that they're taking care of, you know, hundreds and thousands of patients and ensuring they don't have a tumor there. Although you talk to most dentists and most dentists will only find about one or two tumors a year, with their oral cavity exam but it just shows the importance of having a high level of concern. They're not diagnosing many but the impact they have when they diagnose one or two patients a year is massive because any delay would result in a much worse outcome.

Kendal Williams, MD (Host): Yeah, as we'll talk about, getting it early is important. I just wanted to kind of highlight a couple of other anatomical areas because the tumors there are a little different. So, you mentioned the nasopharyngeal. We talked about HPV associated tumors, but, worldwide we see EBV, Epstein Barr virus associated tumors that can present in the nasopharynx, or they almost exclusively present in the nasopharynx, I believe, right?

Robert Brody, MD: In Eastern China, Southeast Asia, that's the most prevalent type of cancer that you're oftentimes seeing, especially due to Epstein Barr virus, kind of like I mentioned before, where someone gets an HPV infection early in life. In the same way, you can get Epstein Barr virus or mononucleosis.

And then it can, for some reason either cause a type of oncogenic, in fect, oncogenic reaction that results in someone getting a nasopharyngeal cancer and that can present as either nasal obstruction or that can also present as a neck mass. I would say that we don't see nasopharyngeal carcinoma as frequently, in the United States.

But we do see it. I would say that I see it probably about one tenth of the time that I see oropharyngeal cancers or oral cavity cancers, but again, it should always be on the differential.

Host: And are those patients that are presenting with it born abroad, or are they born here, or does it, is it a mix?

Robert Brody, MD: You see a mix of both. The EBV related one is oftentimes, someone who was born abroad. You see it, again, in kind of East Asia as well as Sub Saharan Africa, but you can see it also in people who have not been born in those areas and have lived in the U. S. their entire lives.

Host: And then, you know, as we go sort of down the anatomy, we get into the laryngeal cancers, the larynx, and so forth. And you mentioned that, they can present with hoarseness and dysphagia and other things. Those are not so much HPV associated, right, as you get more distal there?

Robert Brody, MD: You can see HPV associated cancers in the region; that's more rare. I would say that the vast majority of the time it's a patient who's a smoker. And so if you look at the incidence of the different types of head and neck cancers over the past 40 to 50 years, you'll see a big upswing in oropharyngeal cancers, but you'll actually see a steady and slow decline in laryngeal cancers and hypopharyngeal cancers, both of which are caused by smoking, and both of which have decreased over the past 30 or 40 years as behaviors have changed.

You do see, actually, that's more of a prominent change in men, actually, because the rate of men smoking has decreased substantially. It's a bit of a slower decrease in women because women actually started smoking more, and then also have changed their behavior and began smoking less as well.

 That's also a lot of what you'll see in the United States. I always look at the American Joint Commission on Cancer's facts and figures, which has a new report usually every year, and they kind of give the incidence of various head and neck carcinomas, and other types of cancers.

And you can kind of see what the rates of cancers are. But, you know, if you look in other countries, like in India, oral cavity cancer is the most common cancer, more common than breast cancer, actually. And similarly in Taiwan, and that's due again to behaviors of smoking and drinking, and also, either betel nut or betel quid use, which is a type of chewing tobacco, with an additional additive.

And you'll see that in many patients in America as well, patients who might be from South Asia or from Taiwan, and they've chewed that for about 10 or 20 years in their youth, and they haven't chewed for about 10 or 20 years, but they still have a much higher rate of oral cavity cancers as well.

Host: So, any of these cancers, you know, the nasopharyngeal, oropharyngeal, laryngeal can present with a neck mass, and I think that's probably the most common reason patients might come to see us as primary care, saying, hey, I noticed this. You know, as you're thinking about neck masses, what's your approach to that?

I don't want to get too much down the rabbit hole on this, but just some general pearls, I guess, about what to biopsy, when to biopsy, that kind of thing.

Robert Brody, MD: Some general pearls would be that when you see a neck mass, especially one that's been persisting for a long time, I think you have to make sure it's not a cancer. When you think about back to med school and learning about the workup of a neck mass, you always want to think about various causes, which can range from a congenital neck mass, like a branchial cleft cyst, or an infectious etiology. You can see neck masses due to infections, especially with certain types of mycobacterium, but especially in an adult, not a child, you want to always assume that it could be a malignancy and kind of rule that out.

The most common location to see a neck mass from the upper air digestive tract would be in what's called the jugulodigastric chain, which is just kind of a fancy term for the area right in front of the sternocleidomastoid muscle, or the area kind of right below the jaw and right behind the Adam's apple, the larynx.

And so if you feel a mass there, you want to make sure that you're getting a biopsy of that. Generally, you want to start with an ultrasound actually to get an idea of whether this is just kind of normal lymphadenopathy. The common terms that make me feel really good when I get an ultrasound of a neck mass that could maybe move me more toward a distant inflamed lymph node versus a neoplasm or a carcinoma, would be that there's a normal fatty hilum and that it has kind of that normal kidney bean shape.

And certainly if someone has a prominent lymph node, you can kind of feel it, if it's under 1.5 centimeters or under 1 centimeter, that's very reassuring. So certainly in primary care, and I see it all the time, just from friends and coworkers, they'll feel a small little lymph node almost like the size of a kidney bean and they'll feel it kind of in the back of their neck or in the supraclavicular area just above their clavicle, behind their sternocleidomastoid muscle.

It's not uncommon to have a slightly swollen lymph node there, especially in the setting of a cold. However, if you have a lymph node that's feeling like it's greater than one or, you know, certainly 1.5 centimeters. and it's a bit larger and it's growing, or it's not going away, it's not waxing and waning, that would certainly warrant an ultrasound.

And then if there is a concerning feature on the ultrasound, to move towards a fine needle aspiration.

Host: One of the pearls I learned just from prepping for the podcast was that it's not necessarily reassuring if it's cystic on ultrasound, right?

Robert Brody, MD: Yeah, actually HPV associated cancers most commonly present as a cystic lymph node. And that can also make the diagnosis with a fine needle aspiration quite difficult. Oftentimes if you have a cystic lymph node like this, you'll send someone for a fine needle aspiration and they'll only be able to aspirate the fluid as opposed to any of the tissue itself.

And so, you might get some squamous cells that look atypical, which is a common term you'll see, and you won't get a diagnosis of a carcinoma. When you see that the fluid has an atypical squamous cell in it, you might say to yourself, oh, let's hope for the best, let's be optimistic, it could be a branchial cleft cyst, which it could be because you could have squamous cells which are coming off the lining of a branchial cleft cyst. But again, you know, you have to think about common things being common. In an adult, it's more common to have a regional metastasis from a throat cancer than a branchial cleft cyst. That's more a diagnosis of exclusion. You want to make sure that you're ruling out a cancer before you go ahead and just reassure someone they have a branchial cleft cyst.

The question becomes if you have a fine needle aspiration, which is equivocal, you don't know if it's actually signs of there being a tumor or not, then I would move towards certainly sending this patient for referral with a specialist, specifically one of our ear, nose, and throat colleagues, and they can kind of both examine the oral cavity oropharynx, upper air digestive tract to make sure there's no primary tumor.

 And then they can also move towards repeating a fine needle aspiration or moving towards other types of biopsies to confirm the diagnosis.

Host: So, I can imagine if I feel something and I'm, I'm not sure, I do an ultrasound on it, I decide to do a fine needle aspiration, which I don't know that I would do, by the way. I mean, I just, but let's say I did do it. If I were not here at Radnor I didn't have ENT downstairs, I probably, but, you know, I mean, our podcast goes to rural America and people don't have ENT around the corner.

So let's say you do a fine needle aspirate. It's negative. No cells. How reassured should I be?

Robert Brody, MD: You know, what realistically happens here is that you can do it yourself certainly, but you can also send it to either a specialist who can take the biopsy as well and then send that off to a laboratory. You can order an ultrasound guided fine needle aspiration from a radiology group. But at the end of the day, this is a difficult diagnosis.

 So, if you have a persistent lymph node that's not going away, certainly after weeks, then they should be seeing someone for further evaluation, and oftentimes that again would be, an ear, nose, and throat specialist, or an oral surgeon as well, although, again, both of our groups tend to see this. Either we would repeat that fine needle aspiration or we would move towards doing an open biopsy to get the diagnosis.

There are other types of biopsies that one can do as well, which would be a core biopsy. A core biopsy uses this thing called a core needle, which is usually about 18 gauge, so much larger, and it gets a larger piece of tissue that can actually be examined by histology. And they can actually look at the architecture of the tissue because it's such a large needle biopsy.

When you get a fine needle aspiration, you're kind of pulling individual clumps of cells out and then a pathologist or a cytologist is having to look at those cells to get a diagnosis and it be more difficult. In addition, by the way, to upper air digestive tract cancers, a neck mass like this could also be a thyroid cancer.

 Oftentimes what one can do is a thyroglobulin washout to see if the patient has thyroglobulin in that lymph node, because there should not be thyroglobulin in that lymph node. And then also an ultrasound of the thyroid itself can also ensure that there's no concerning lesions or nodules of the thyroid, which could have also sent off a regional metastasis to the neck.

Host: So, I think that's probably where us as primary care physicians would jump off the train. And, you know, if somebody gets you and gets the diagnosis, now let's assume we, we take this sort of theoretical patient through this. They're diagnosed with a cancer of the head and neck. Let's talk about how you treat those now.

 It looks like the staging systems, this is actually where it gets kind of complicated because it really depends on the type of tumor and all the staging systems vary depending on the exact type and the anatomy and so forth.

Robert Brody, MD: Yeah, it's one of the best things to question your resident about, or your med student, to see if they've been reading the book. So, yeah, again, I think once you have this, let's say a neck mass and you've biopsied it, again, we talked about there's a wide differential diagnosis that can range from squamous cell carcinomas to thyroid cancers to salivary gland cancers as well that can arise from the parotid glands, the submandibular glands.

But when you have one of these squamous cell carcinomas, again, which are about 90 to 95 percent of tumors of the upper air digestive tract, there's this staging system, the AJCC staging system, and it's kind of similar to other staging systems. At the end of the day, the staging system is meant to be for prognostication.

It's meant to help the patient better understand what stage they are, which then helps them kind of understand how well they're going to do with treatment. But at the end of the day, we use staging as a way of communicating, but one of the main reasons for it and the main reasons why these people kind of sit around the table and come up with the system is to help with prognosis, to try and stratify patients into different groups.

So, you know, a stage one patient does really well, a stage four patient does poorly, and that's by definition, that's how the staging systems exist. For a very long time, we were using the same staging system for HPV associated cancers as we were for non HPV associated cancers or kind of HPV negative cancers.

And the issue is that when you have a lymph node from, let's say, a tongue cancer or a larynx cancer, if you have a tumor in those two sites and it spreads to the neck, so you have a regional metastasis, or if you have a smoking induced cancer of the tonsil that's spread to the neck; the prognosis drops by quite a lot.

I mean, the prognosis, if someone has a localized tumor in their tongue, in their oral tongue, and it has not spread anywhere, that is small tumor, that's a stage one, they have a very high rate of cure, over 80 percent for five years, if not higher. When it starts to spread to the neck, that tends to drop closer to 60 percent or lower.

So, a large proportion of our patients with oropharyngeal cancer that's caused by HPV, they'd be coming into our office, the presenting symptom would be a lymph node in their neck. They might not even know that they have a tumor in their throat at the time. And we're telling them that they have stage 3 or 4 disease because as soon as you have a tumor from the upper air digestive tract, from the tongue, the tonsil, the larynx, as soon as that spreads to the neck, in the more classic staging system, you're immediately a stage 3 or 4 cancer.

 So that scares people to be told that they're a stage 3 or 4 cancer, especially when the prognosis for HPV positive cancer is fantastic. They actually changed the staging system for HPV positive cancer. And so all my patients who were stage three or four, the vast majority are now stage one or two. Because again, with treatment, they should expect a very good prognosis.

Kendal Williams, MD (Host): Let's talk about treatment. Obviously, I think surgery is complicated, but it is what it is. You remove the primary tumor, I admire you for choosing this career to operate in this space. It's a complicated space, right? And, there's a lot going on there that, it's really impressive as I was sort of prepping for this podcast and thinking about doing cancer in those areas. It's, it's a pretty big deal, Rob.

Robert Brody, MD: Yeah. I mean, I think, you know, as a surgeon, I think it's important to both know when to operate and when not to operate. When you look at throat cancers and head and neck cancers in general, it really impacts people's quality of life substantially. A lot of what you know a person views as their identity is related to the various aspects of the head and neck.

So your speech, your ability to hear, your appearance, your ability to sit at the dinner table with your family and friends and eat a meal and focus on conversation and then communicate. Your ability to breathe even. It's important to be able to treat these cancers in such a way that you're providing the patient not only with a high rate of cure, but you're also providing them with the best possible quality of life going forwards.

 So it's important for us to do surgeries that provide the best quality of life that are minimally invasive when they can be. And when they have to be maximally invasive, that we are doing the best possible reconstruction that we can, and that when we can't do surgery, that we have the best possible non surgical therapies as well.

So when you think about the oropharynx, specifically the tonsils and the throat, about 30 or 40 years ago, there weren't very easy ways of accessing that area, unless you literally did very complicated surgeries where you had to cut the jawbone and almost open up the jaw and then get a good view into the back of the throat.

My partner and my mentor, Dr. Gregory Weinstein, and then Dr. Bert O'Malley, who was our prior Chair in ENT department. He hired me, so I'm very indebted to him. And he also trained me as well. The two of them, in, in addition to one of our residents who came up with the idea originally, they really invented this new type of robotic surgery, which is able to remove tumors from the back of the throat in a minimally invasive fashion and really revolutionized the field because we were able to now remove these tumors in such a way that we can preserve a lot of function and a lot of quality of life related issues, while getting a negative margin around the tumors. You know, if you kind of break it down, the two main treatments for HPV associated oropharyngeal cancer are non surgical therapy and then surgical therapy with pathology dictated adjuvant therapy.

It's a mouthful. But what that means is that we do surgery, and then depending on what comes out, you know, whether our margins are negative, whether there's a lot of lymph nodes in the neck or only one lymph node or zero lymph nodes, that we can then give either nothing, so you have surgery and you're done, or you might need some radiation afterwards, or you might need chemoradiation afterwards as well.

The goal is to basically look at these tumors and see kind of where the tumor is sitting, see whether it's spread, and if it's spread, how far has it spread, and then, we have a multidisciplinary group which includes radiation oncologists, medical oncologists, neuroradiologists, pathologists.

We have palliative care, nursing, all in one large multidisciplinary tumor board. And then we decide, you what is the best treatment for that patient? Because, as I said before, we have a very high chance of curing that patient and giving them a very long life after we cure their cancer. And our goal is to both cure their cancer at a high rate, but also give them the best possible quality of life.

So at the University of Pennsylvania, we try to provide the most advanced, non surgical therapy using proton therapy and using intensity modulated radiation therapy, which is the most advanced radiation that we have, and use the best chemotherapy drugs that are available, although chemotherapy tends to be platinum chemotherapy, which is kind of an older type of chemotherapy.

So we try and use the most advanced forms of non surgical therapy, but we also try and we have really been leading the field in providing the most advanced surgical therapy, in concert with the best adjuvant therapies as well. And so we've completed multiple clinical trials. The initial surgical clinical trials, as well as two additional low dose radiation clinical trials.

And now we actually have a third clinical trial where we do surgery, and then we do a very low dose of radiation after surgery if the patients are candidates. And that is, only two weeks of radiation, which is compared to the classical version of post op radiation, which is six weeks. That's a mouthful there.

 So, happy to kind of break that down for you if you think there'd be value in that. But it's really kind of, hopefully I've conveyed the complexity that goes into thinking about how to best treat a patient with throat cancer; which again ranges from chemoradiation or radiation alone to minimally invasive surgery and then again, low dose radiation or low dose radiation with chemotherapy.

Host: You know, the patients I would have seen as a medical student would probably all have tracheostomies, after this, you know, treatment for head and neck cancer, or at least those are the ones that I saw. How often are you having to do that level of care, you know, do a tracheostomy so that you can really do advanced surgery on the neck?

Robert Brody, MD: I think that most people, when they think of head and neck cancer patient, they think of someone with a laryngectomy or, you know, all the commercials that you see that tried to get people to quit smoking 20, 30 years ago, where, you know, it'd be a black and white commercial. And there'd be someone with this kind of hole in their neck and they'd be using that electrolarynx, that kind of robotic sounding voice.

 So that is a laryngectomy stoma, which is kind of the term for having your larynx removed. So we still do that, and we have newer techniques that create a much better voice, but then going from that laryngectomy stoma, you have what's called a tracheostoma. So many people will think of a tracheostoma as what you see in a patient who's critically ill, like in the ICU. And oftentimes, you're doing a tracheostoma or tracheotomy in that scenario just to help ventilate the patient. However, in a patient with head and neck cancer, many of them have, if not, healthy lungs, because many patients have COPD because of a history of smoking, at the very least, many of them don't require ventilation.

So, what we're doing the tracheotomy for is to just provide an ability to breathe if you have a tumor that's obstructing the upper airway. So when you think about it, certainly a large larynx cancer might require a tracheotomy, a very large oropharyngeal cancer or tonsil cancer might require a tracheotomy.

However, if we're doing non surgical therapy or if we're doing kind of minimally invasive surgeries, we're oftentimes able to avoid a tracheotomy. Or if we do have to do a tracheotomy, It's more for the safety of the patient during their treatment, and the goal is to remove that tracheotomy tube as soon as possible.

And so many of the surgeries that we do that require a tracheotomy, which oftentimes are larger operations of the oral cavity or larger operations of the oropharynx where we're doing very complex reconstructions, and we expect a lot of swelling postoperatively; in those scenarios, we'll do a tracheotomy.

And the hope is that once the swelling comes down, we can remove that tracheotomy tube either in the hospital or we can take it out in the office, usually within a few weeks. In patients who are not getting surgery but who are getting chemoradiation because they have a very large tumor and they're hoping to avoid an overly morbid surgery like a laryngectomy, sometimes we have to do a tracheotomy to give them kind of just the ability to breathe; while we're treating them with chemoradiation. Let's say in the instance of a very large larynx cancer, which is small enough to be treated without a laryngectomy. So it's usually treated with chemoradiation when it's large enough that if you have a tumor of the voice box, which is the entryway to your windpipe or your trachea, there are various ways to treat that. And sometimes the tumor can be so large that we're literally doing a tracheotomy to save that person's life because they can't breathe. At that point in time, if the goal is to shrink that tumor away, but to try and preserve the voice box;

and there's no way to do that surgically, then chemoradiation is oftentimes given. And sometimes that chemoradiation, in about half of cases, if not more, it can shrink away that tumor and the tumor can shrink away enough that you can eventually remove the tracheotomy tube.

At the end of the day, for the myriad of very diverse head and neck cancers that can occur, a tracheotomy tube will be performed just to provide safety for the patient to breathe.

Host: You talked earlier about prognosis, we talked how HPV associated have a good prognosis overall. I mean, obviously, the more it's spread, the lower the prognosis within any one category. We haven't talked about chemo. You did mention that chemotherapy is platinum based.

 I know also they use checkpoint inhibitors, pembrolizumab, and others that are being used that are trials probably at Penn being done, looking at treatment with chemotherapy for those tumors, with some improvements, I think, right?

Robert Brody, MD: There's really a lot of interest in a variety of ways of treating head and neck cancers. Interestingly, the most common type of chemotherapy used in head and neck cancer is a very old type of chemotherapy, which is a platinum agent cisplatin. Study after study has shown that cisplatin actually provides the best way to cure.

 So cisplatin or platinum containing chemotherapy agents are kind of the gold standard actually. We've tried to move away from cisplatin in the past to other types of drugs like cetuximab which is an EGFR antibody, and studies have shown that it, although it does work, it does carry morbidity and it does not work as well as cisplatin.

 Whenever we can, we actually still provide cisplatin with our medical oncologists, obviously, as the ones who are primarily driving that care. In addition to these gold standards, there have been multiple trials trying to give checkpoint inhibitors, like PD 1 inhibitors, in a neoadjuvant setting, which, unfortunately, it's not a magic bullet. The response rate is under 20 percent if you're being optimistic, actually, for these types of checkpoint inhibitors in isolation.

 So there are newer clinical trials where they're trying to combine checkpoint inhibitors with other types of immune microenvironment modulating drugs. In addition to that, there have been some trials related to HPV vaccines. So, one of the companies that's been spun out of Penn, Inovio actually has an HPV vaccine that they've been working on over many years.

And there's actually some interest in mRNA vaccines against HPV as well, which are very nascent in their development. Checkpoint inhibitors, as you already mentioned though, are very useful in the metastatic setting. So, I have had many patients, who have unfortunately had distant metastases of their head and neck cancer.

Luckily, many of our patients only have local cancer in the actual tongue, as we've discussed, oropharynx, larynx, local disease, or regional disease in the neck. But when it spreads distantly, it can spread to the lungs, it can spread to the bones. And unfortunately, many of our patients that I see have distant metastatic disease, but, fortunately, many of them have responded to immunotherapy.

And oftentimes those patients will be on immunotherapy for one or two years. Some of them will be on this therapy for even longer as the initial approval for immunotherapy and PD1 inhibitors has only been around for about five to seven years. We're still trying to figure out the exact time that a patient should be on these medications when they have a response.

Host: I'm curious, HPV vaccines for patients with established cancer?

Robert Brody, MD: The common question I get is, should I be vaccinated against HPV if I've been diagnosed with a, an HPV associated head and neck cancer? There's not much data to suggest that if you got the vaccine after being diagnosed that it will improve your outcome, or that it will prevent a recurrence.

 Again, the theory is that you've probably had that infection for about 30 to 40 years. Similarly, many patients are worried that they might be infecting their spouse, you know, actively when they have this diagnosed cancer, or their children. And again, I would say that this was likely an infection that occurred possibly even many decades before.

 At the end of the day, the most important thing is to have the HPV vaccine prior to exposure, which would be, you know, at a younger age, before you end up, having any sexual relations.

Host: This has been great. This is a whole area that there's a lot of dynamic changes occurring, both in the treatment of head and neck cancers generally, but then this whole aspect of HPV associated ones, which is, really, I think, relatively new. At least for those of us that trained 20 years ago. So I really appreciate you coming on. This has been really educational. And if we get further interest in this topic, I'd like to have you back at some point.

Robert Brody, MD: Oh, it was an absolute pleasure being here and thank you so much for the opportunity to join you.

Host: And thanks again to the audience for joining the Penn Primary Care Podcast. Please come back next time.

disclaimer: Please note that this podcast is for educational purposes only. For specific questions, please contact your physician. And if an emergency, please call 911 or go to the nearest emergency department.