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BackTable / ENT / Article
HPV-Related Cancer Detection: Clinical Evaluation & Diagnostic Strategies
Iman Iqbal • Updated Jul 17, 2024 • 39 hits
HPV-related cancers, driven by viral infections, represent a significant health concern globally. In particular, HPV-associated oropharyngeal cancer affects the tonsils and base of the tongue, presenting distinctive diagnostic and treatment challenges. In recent years, the landscape of HPV-related malignancies has undergone a significant transformation, with the incidence of oropharyngeal cancers in men now surpassing cervical cancers in women.
Understanding the complex pathogenesis of these cancers, where only a subset of HPV-exposed individuals develop malignancies, underscores the need for advanced diagnostic tools and tailored treatment approaches. Dr. Mihir Patel, an otolaryngologist and expert in Transoral Robotic Surgery (TORS), discusses diagnostic strategies and innovations like TORS, ctDNA, and PET scans in improving detection rates and guiding targeted therapies, aiming to reduce treatment morbidity and improve outcomes for patients facing these increasingly prevalent cancers.
This article features excerpts from the BackTable ENT Podcast. We’ve provided the highlight reel in this article, and you can listen to the full podcast below.
The BackTable ENT Brief
• HPV-driven oropharyngeal cancers have become more prevalent in men than cervical cancers are in women. Affected demographics include middle-aged white males with a history of multiple sexual partners and no smoking history.
• Screening for oropharyngeal cancer is challenging due to the virus's ability to remain latent and undetected in the tonsils, complicating traditional screening methods.
• HPV squamous cell cancers predominantly occur in the tonsils and base of the tongue, influenced by lymphoid tissue composition and lack of a basement membrane.
• Diagnosis often follows the discovery of a neck mass post-stressful event, utilizing antibiotics, CT scans, and fine needle aspiration.
• Transoral Robotic Surgery (TORS) is crucial for isolating primary tumor sites, reducing the need for extensive radiation, and ensuring low recurrence rates.
• Circulating tumor DNA (ctDNA) testing, PET scans and narrow-band imaging (NBI) enhance diagnostic accuracy and guide treatment decisions based on primary tumor location.
• The surgical approach for unknown primary tumors focuses on locating and treating the primary tumor starting with ipsilateral tonsil removal, potentially extending to the base of the tongue and utilizes TORS for real-time pathological assessment, followed by selective neck dissection if necessary.
Table of Contents
(1) HPV Oropharyngeal Cancer: Epidemiology & Screening Challenges
(2) Enhancing HPV Tumor Detection with ctDNA and Advanced Imaging
(3) Identification & Removal of Primary Tumor Sites with Transoral Robotic Surgery (TORS)
(4) Targeted Approaches to Identifying & Treating Unknown Primary HPV Oropharyngeal Cancer
HPV Oropharyngeal Cancer: Epidemiology & Screening Challenges
HPV-driven oropharyngeal cancers now surpass cervical cancers in incidence among men, highlighting a significant shift in the epidemiology of HPV-related malignancies. The population that is most affected includes middle-aged white males with no smoking history and multiple lifetime partners.
There are also challenges in screening for oropharyngeal cancer due to the virus's ability to remain latent and undetected in the tonsils. The location of HPV-related tumors in the deep tissues of the tonsils further complicates screening by making traditional methods like swabs ineffective.
Despite more than 90% of the population being exposed to HPV, only a small subset develops cancer, underscoring the complexity of HPV pathogenesis. Emerging diagnostic tools, such as liquid biopsies, hold promise for early detection, but much remains to be understood about the triggers that cause latent infections to progress to cancer.
[Dr. Mihir Patel]
Today, HPV oropharynx cancers, that's what we see the most in terms of our mix of head and neck subsites or sites. More than oral cavity, more than larynx. I remember as a PGY2, so about 20 years ago, Maura Gillison, who is one of the clinicians credited for linking the association of HPV to squam cell cancers, which at the time were considered stage 4 cancers, she linked that to the human papillomavirus…
What I'm getting at is what she noted was that these patients were younger, 55, 60-year-olds. They were mostly white males, no smoking history.
We know that's the most common risk for head and neck cancers. A lot of them were graduates of college, well-educated. She noted that many of them had more than five intimate lifetime partners throughout their life. That is how all of this transpired. That's what we see today. It has just taken off as an epidemic in some way or form, if you want to think about it. Because in 2018, the incidence of HPV-driven cancers in men surpassed HPV-driven cancers in women. It was primarily driven by oropharynx cancers. Yes…
There's pretty good research to show that a number of these patients have HPV antibodies many years before they actually develop cancer. We're talking about infections from years ago that likely have developed. What makes this tricky is that it is very difficult to screen the tonsil area. More than 90% of the people in the population have had an HPV infection at some point in time. Only a few of them cause cancer out of the hundreds of types or over 100 types of HPV subtypes, only about 12 of them can cause cancer.
How do you screen for all those people? That's what makes it tough. There are some very interesting liquid biopsies coming down the road, ways to think about possibly screening. At one time, people were looking at swabs to try and do that, but that also is very difficult. The swabs are similar to what you would do for strep throat. The reason that's difficult is when the cancer develops, it develops not on the surface of the tonsil, but near the bottom of the tonsil or the deep part of the tonsil.
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Enhancing HPV Tumor Detection with ctDNA and Advanced Imaging
Circulating tumor DNA (ctDNA) is a significant advancement in diagnosing HPV oropharyngeal cancer. This test helps identify HPV-driven cancers, particularly in patients presenting with new neck masses, and aids in locating the primary tumor, typically in the tonsil or base of the tongue. This information guides the treatment plan, along with CT scans PET scans, which collectively enhance the accuracy of locating the primary tumor.
PET scans can detect tumors in 40-50% of cases, direct laryngoscopy and biopsy increase this to 55-60%, and TORS can boost detection rates to 70-85%. Precise identification of the primary tumor allows for targeted radiation therapy, reducing the morbidity associated with broader radiation treatments that were common in the past. Advancements in imaging, such as narrow-band imaging (NBI) during flexible laryngoscopy, further improve the ability to detect subtle mucosal changes and localize tumors effectively. This technique enhances the accuracy of examinations and contributes to higher detection rates.
[Dr. Mihir Patel]
Their ctDNA is essentially that the tumor is shedding in the bloodstream and HPV has tagged it. We can look at specific sequences to determine that it's an HPV-driven cancer. Essentially that's what's being done. It's taking pieces of tumor that have been released into the bloodstream, and identifying and linking that to HPV virus. This isn't uncommon. There are other cancer diseases that do this, including lymph colon cancer. I think they're working on this in lung cancer. We are a few steps behind, but we're there and it's emerging.
[Dr. Ashley Agan]
Would that ctDNA look the same for someone who has HPV cervical cancer?
[Dr. Mihir Patel]
It does work for cervical and anal cancer as well.
…
Looking at how often you can identify the tumor, and the different modalities of tests that we can use to help us identify it. A CT scan will find the cancer, let's say the primary specific, about 23% of the time in a PET scan on the order of 40 to 50%.
If you take a patient for a direct laryngoscopy and biopsy, you can increase that to about 55 to maybe 60%. Now if it's a true unknown and you have no idea of where it is after all these imaging modalities, using TORs can help increase that from 50 to 60 to potentially 70, 80, 85. I think most institutions report about 80 to 85% identification rate, which is really remarkable when you think about it.
…
There are some opportunities that we can use at the time of our flexible laryngoscopy. Some scopes have narrow-band imaging, which is basically a combination of blue-green light and it causes the mucosa to look a little different than white light. You can see slight and subtle variations in the mucosa and ulcers that you might not see otherwise. This is something that has been developed and studied in the GI literature, which is what they use to look for dysplasia or polyps or things of that nature.
Identification & Removal of Primary Tumor Sites with Transoral Robotic Surgery (TORS)
HPV squamous cell cancers predominantly occur in the tonsils and base of the tongue, rather than other areas of the head and neck like the larynx or hypopharynx. The tonsils and tongue base are particularly susceptible due to their lymphoid tissue composition and lack of a basement membrane, which facilitates viral persistence and cancer development.
Typically, these cancers are identified after patients notice a swollen node in their neck after a stressful event. Diagnosis involves antibiotic treatment, CT scans, and fine needle aspiration. Confirming HPV-driven cancer requires the presence of HPV DNA and in situ hybridization, in addition to p16 positivity. Using protocols and liquid biopsies for circulating tumor HPV DNA has significantly improved diagnostic accuracy.
Transoral Robotic Surgery (TORS) plays a crucial role in isolating primary tumor sites and reduces the need for extensive radiation. The process involves removing the tonsil or tongue base and checking margins during surgery. If the tumor is not immediately visible, the chance of recurrence is low. Monitoring circulating tumor DNA levels after surgery helps ensure comprehensive treatment and guides further care, which may involve radiation, especially when multiple lymph nodes are involved.
[Dr. Ashley Agan]
The HPV squamous cell cancers are usually in the tonsils or base of the tongue. Oropharynx is that primary subsite. Why is that the primary site and not larynx or hypopharynx or somewhere else in the head and neck?
[Dr. Mihir Patel]
This was a source of debate for some time because there were times when cancers from the tongue or the larynx were removed and they have p16 positivity, which was considered at that time, a circuit marker for HPV. If you ask HPV researchers, they're going to say, "It can't just be p16 positive. We need to know that there's HPV DNA in that specimen and we need to look at in situ hybridization." There's got to be really three ways to look at it to determine if it's truly HPV driven.
When you distill it down, we've come to realize that there's just something about the tonsil and the tongue base, specifically that histologically they're different. They are lymphoid tissue. Primarily it's an immune-rich environment where you would think a virus would like to be. What causes all of the quick spread, so to speak, is that there's really no basement membrane in those areas. That's why we often see a small cancer there, but that's not how they're noticed.
…
It takes a couple of things that helps me in my mind understand the unknown primary. One, you've got to know that you're dealing with an HPV cancer, and usually clinically there are a lot of things that help you determine that. Before p16 was sometimes positive, sometimes not. Clinically, you still have to really look at the patient and say, "Okay, is this someone who's likely to have an HPV-driven cancer?" That's one of the things that I would always think about in my mind.
The second thing that's new now is that we can actually do a liquid biopsy and get circulating tumor HPV DNA. If that's positive, that is highly sensitive and highly specific for knowing that you've got an HPV-driven cancer. Then I talk to patients and I tell them, "Look, this is likely in your tonsil or your tongue base, and we are going to do a real-time investigation to try and find it." That's where TORS has really helped. It's really helped us deescalate therapy for these patients and that's where I also tell them. We're not going to have to radiate your entire throat to try and treat this.
What we're going to do is we're going to take out the tonsil. We're going to go look at it at pathology, and if pathology sees it then we will clear the margins. If not, we'll transition to removing the tonsil off the back of your tongue or the tongue base. If we see it, clear the margin. If we don't see it, I don't want you to be disconcerted because the chance of it coming back is very low. In our series, we haven't seen that happen yet. Now because they present with a neck node, the majority of these patients are going to get radiation. In fact, all of them do.
Because of the size of the lymph node or there tends to be multiple lymph nodes, we also remove those at the time of surgery. They've gotten completed treatment for what we call an unknown primary. The nice thing now is you can also get a circulating tumor DNA level after surgery. If it goes to non-detectable, that's another way of telling the patient, "Look, I believe we have cleared this surgically and now we need to continue with our standard of care postoperative radiation treatment."
Targeted Approaches to Identifying & Treating Unknown Primary HPV Oropharyngeal Cancer
When taking patients to the OR with an unknown primary tumor, the goal is to locate and treat the primary tumor, often starting with the removal of the ipsilateral tonsil and potentially moving to the base of the tongue if necessary. If neck nodes are present, surgery may address them unless they are overly aggressive or bilateral. The process typically begins with TORS for efficient real-time pathological analysis, followed by neck dissection if needed.
In searching for the primary tumor, the procedure focuses on the ipsilateral side, as the risk of contralateral tumors is low. Pathologists play a crucial role, examining the removed tissue closely during surgery through frozen sections and afterwards with permanent sections. Aggressive searches on the opposite side are generally avoided to minimize unnecessary morbidity.
For patients where the primary tumor remains unidentified, treatment usually involves adjuvant therapies like radiation or chemotherapy. Modern radiation protocols target specific areas, reducing the need for extensive radiation that previously caused significant morbidity. Despite the unknown primary status, modern treatments achieve high cure rates, often exceeding 90%, due to the effectiveness of adjuvant therapies and the nature of HPV-driven cancers.
[Dr. Ashley Agan]
When you're taking patients to the OR in the unknown primary situation, the goal of surgery is finding the primary. Then potentially if you find it, getting a good excision, yes?
[Dr. Mihir Patel]
Yes. The goal is to find it and in fact just treat it completely. I think it just depends on the degree of how aggressive the neck nodes are. If they're really aggressive or they're on both sides, I typically don't tackle that. If it's just four nodes or less, then we'll tackle the neck at the same time. The majority of times that's what we're doing when we take patients back for an unknown primary.
…
The reason I do the transoral robotics portion first is because we send that specimen to pathology to be analyzed for margins and getting real time data. While they are doing that, then we transition to removing the lymph nodes of the neck. It just helps with efficiency.
[Dr. Ashley Agan]
Got you. When you're looking for your unknown primary, do you have a system as far as, I do ipsilateral tonsil first, and then I move on to basal tongue. Let's say you're going in and you really have no preoperative hints as to where it might be. How do you start that search?
[Dr. Mihir Patel]
I always start with the tonsil. 60% of the time, it's going to be there. If they've had a tonsillectomy, obviously it makes it a lot easier. You start with the tongue base. One of the things that has changed my practice was that meta-analysis I referred to before that essentially noted that the risk of the contralateral tongue base having the primary, so contralateral to the neck node, is only 3%.
I just didn't feel like it was worth the risk of causing, even though you're taking a small amount of tissue, there's pretty good data and slick literature to show that even a lingual tonsil does because some dysphagia permanently.
…
The chance of it being in the contralateral tonsils is near 0%, very unlikely.
[Dr. Ashley Agan]
Let's think of a couple of different scenarios. For the patient who has their TORs, and let's say it's the small percentage where you don't find it. I guess, can we unpack a little bit of how pathology is looking at the tonsils and the lingual tonsils. They're doing some frozens at the time of surgery, but then they're also going to do some permanent sections too, right?
[Dr. Mihir Patel]
They will. They will. We are very fortunate to have dedicated head and neck pathology faculty for every single one of our frozen sections. The first thing is that this whole process requires a team from not only the oncologists, but even within the OR, and they are instrumental. I never really understood how important pathology was until I was an attending. I realized that we had just developed a system and working with them is how we came across this.
…
Once we take out the lingual tonsil, typically we'll just check the edges. Then we'll just do what we call shave margins, look at the edge to make sure that we haven't cut across cancer. If all that's clear, we typically don't always bread loaf the remaining tissue. We just wait for the permanent pathology. Because if it's a two or three millimeter cancer, which I have seen, when you run a frozen section, you are at risk of losing that tissue when you're doing the frozen section. Find balance.
Podcast Contributors
Dr. Mihir Patel
Dr. Mihir Patel is an otolaryngologist head and neck surgeon and assistant professor with Emory Healthcare in Atlanta, Georgia.
Dr. Ashley Agan
Dr. Ashley Agan is an otolaryngologist in Dallas, TX.
Cite This Podcast
BackTable, LLC (Producer). (2024, May 21). Ep. 172 – HPV & Oropharyngeal Cancer: Evolving Insights & Implications [Audio podcast]. Retrieved from https://www.backtable.com
Disclaimer: The Materials available on BackTable.com are for informational and educational purposes only and are not a substitute for the professional judgment of a healthcare professional in diagnosing and treating patients. The opinions expressed by participants of the BackTable Podcast belong solely to the participants, and do not necessarily reflect the views of BackTable.
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