My name is Ben Giuliatti. I'm an early career thyroidologist at the University of Rochester and it's a privilege to be here with all of you today. I'd like to thank Steve Hammes, my mentor, and the Annual Meeting Committee for the invitation to come speak with you today. So the topic for today is what's new-ish in the treatment of differentiated thyroid cancer and I added ish partly because new is a matter of perspective and thyroid cancer management like many areas of clinical medicine has been a moving target over the last especially 15 years. I have no disclosures other than the fact that I tried to get them to change the name to meet the assistant professor to lower everybody's expectations and differentiate me from the more esteemed faculty giving the other talks but I promise to make up for being junior faculty with an abundance of effort and enthusiasm. So we have two poll questions. We'll go through two cases as part of this conference today. So I'll ask you to take a snapshot with your barcode reader and then the case will come in a couple of slides. So I'll give everyone a moment to do that. Great and if you that's not working you can go into the app and go to the live polling section. All right in terms of learning objectives let me just start the timer here. So today I'd like to focus on two ends of the thyroid cancer risk spectrum. So we'll spend most of today talking about patients with low risk disease and we're gonna focus on the practical management of patients for the general or non specialized endocrinologists and I think focusing on low-risk thyroid cancer specifically differentiated thyroid cancer is really important because they're most of the patients that we see in our clinics and so we'll talk a little bit about these new methods although some of them are really not new in terms of hemothyroidectomy and active surveillance although we're looking at them with new light in because of recent data and we'll talk a little bit about the thermal and other ablative methods. We'll then spend the last part of this talk talking about patients with more advanced disease because while they are relatively uncommon in our clinics they certainly give us I think the most worry and are the patients that I at least stay up at night worrying about. My father would call it agita. So these are the patients who we really think a lot about and there's been a ton of developments in terms of new therapies and ways of thinking about advanced disease but again we'll address this from the lens of a non-specialized endocrinologist. So before we get started let's just define what differentiated thyroid cancer means because even that something as fundamental as the definition has been a moving target over time. So traditionally it's included papillary and follicular thyroid cancers because even though they're distinct in terms of their biology and behavior they share a lot of common characteristics and are often managed with the same tools and both have an excellent prognosis. What's new I would say or new-ish I guess since it's a around seven years old now is this idea of some thyroid cancers being particularly indolent. So now it's been excluded the encapsulated follicular papillary thyroid cancer is now called NFP or a non-invasive neoplasm and they remove carcinoma from the name to really highlight the fact that whether or not you think this is a carcinoma or a neoplasm or a carcinoma in situ or whatever you think it is it's an incredibly indolent tumor that is completely treated usually with hemithyroidectomy and so the idea of changing it from carcinoma to neoplasm regardless of the biology is to really avoid overtreatment which we'll talk a lot about in the next few slides. And last but not least this is actually very new the WHO just came out with their 2022 fifth edition for thyroid endocrine tumors and they divided in terms of benign low-risk types of tumors which NFP is included as a neoplasm and then within malignancy they stratify of course using traditional histopathologic phenotypes or definitions but also the addition of these molecular diagnostics and I think that's really important especially as we talk about trying to identify patients who have more advanced disease and treating them these molecular alterations including them in the definition is a really powerful way I think for us to make our definitions more sophisticated and of course herthal cell carcinoma has actually been removed from being a subtype of follicular thyroid cancer because of its unique genetic contributors. So an obligatory slide on thyroid cancer epidemiology as most of you know the incidence of thyroid cancer has been really dramatically increasing especially over the last 15 years but most of this increase is accounted for by small papillary thyroid cancers and accordingly there is no or at most a tiny tiny little increase in incidence-based mortality and when you see this increase in incidence without mortality it really strongly suggests over diagnosis and recent estimates put it up to maybe 80 to 90 percent that most of these small papillary thyroid cancers may be due to missed or over diagnosis and this data is from a recent study looking at seer 18 registry data just shy of 200,000 patients but what's interesting if you look at this trend here is finally I think we're making strides in the problem of over diagnosis in terms of using different ultrasound thresholds for people to even be performing FNA in the first place and this trend towards conservatism has been a steady trend especially over the last 10 years or so and what's interesting when you dive into these data you actually see that this drop in incidence is actually just that it's decreasing the incidence of these small localized and rather innocent papillary thyroid cancers but if you look in more detail there actually seems to be a small uptick in larger tumors and there is some suggestion of a very mild or tiny increase in mortality although that's debated so that's something that as we think about where to thread the needle in terms of over diagnosis versus appropriate treatment that's something we continue to grapple with so why has management been evolving especially over the last 15 years well really I think we're getting a better sense of this problem of over diagnosis so we have these clearer indications to perform ultrasounds in the first place and stricter FNA criteria I think our clinical and histopathologic features have been refined over time as we try to stratify patients with lower versus higher risk disease and we'll spend one slide talking about that and I think really the hallmark is this idea that a risk-adapted strategy triaging lower risk tumors for more conservative management is safe and successful because for a long time we didn't know which tumors were truly the lowest tumors or at least there was debate about that we've certainly been better at recognizing and understanding the extent of morbidity of over treatment and I think the improved understanding of the molecular pathogenesis of thyroid cancer certainly plays a role in helping us stratify and become more sophisticated and of course using those molecular features to help find new systemic diseases is also impactful so let's start with low-risk differentiated thyroid cancer which we'll spend most of our time on today so I'd like to start with the case so if you could pull up your polling so this is a genuine case that I saw in clinic a 78 year old man who presented for evaluation of a multi nodular goiter was into incidentally found on chest CT for new onset hemoptysis he had no next symptoms whatsoever no radiation exposure no family history of thyroid cancer he had significant medical comorbidities so he was had COPD on maximal medical therapy and two liters of oxygen and a number of other conditions including heart failure hypertension hyperlipidemia etc and in terms of the data we saw when we saw him in clinic he was coming from an outside hospital he had a normal TSH and free T4 and the ultrasound at the outside hospital revealed a well demarcated right 1.4 centimeter hypoechoic taller-than-wide nodule with microcalcifications and it was in the anterior and mid aspect of the the thyroid lobe there was no obvious radiographic extrathyroidal extension and additional nodules included a 1.2 centimeter relatively low risk complex nodule and a left 2.5 centimeter low risk complex nodule there were no nothing on the report about neck nodes which is fairly common so we did an ultrasound guided FNA in our clinic of the 1.4 centimeter nodule on the right and this was Bethesda 5 suspicious for papillary thyroid carcinoma and the left 2.5 centimeter was not unexpectedly benign so which of the following is the most appropriate initial management strategy for this patient so the first option is thyroid ultrasound to get a better sense of nodule size volume and to look better at the local regional nodes referral to interventional radiology for radiofrequency ablation referral to thyroid surgery for consideration of a right hemi or a total thyroidectomy if you can't get the technology to work shout it out or raise your hand excellent I think this is a great spread and one thing we'll talk a little bit about is that there are multiple right answers here and I'll give you a little bit of information about how we can try to make this decision making and that's really what we'll talk about for the next couple of slides thanks for your input so we define differentiated thyroid cancer what about low-risk differentiated thyroid cancer and this depends so even something as simple as that definition have multiple different criteria we can use if you use the TNM staging system from the AJCC 8th edition you know stage 1 has a disease specific survival of 98 to 100 percent at 10 years Macy's pioneered by the Mayo Clinic in the early 90s a Mesa score less than 6 and these are the contributors to the Mesa score had a 20-year disease specific survival of 99 percent but I think in the modern environment many of us use the ATA risk of recurrence system because the prognosis for most patients with thyroid cancer is excellent and so recurrence while not necessarily as clinically impactful as mortality that's obviously a very hard outcome this is really more relevant for most of our patients who will not die of thyroid cancer so when we look at the ATA guidelines this risk adapted strategy defines PTCs and FTCs based on no local regional local regional tissue invasion local Mets or distant Mets either on axial or I-131 imaging conventional histologies in terms of not having high-risk cytologies like tall cell hobnail columnar variant even these are a little bit of a moving target with new definitions all macroscopic tumor is resected in the initial surgery and there's no obvious macroscopic or I think a little bit more debated microscopic invasion of parathyroidal soft tissues and then no suspicious lymph nodes on ultrasonography and small volume micrometastases at most and then for FTC a lot of this comes down to the blood vessels so less than few for foci of vascular invasion is important in terms of defining low risk and this is one of my favorite graphs from the guidelines because it really gives a sense that even though we're creating categorical variables in managing these patients and helping us figure out what to do next risk is truly a continuum or a spectrum and I think is with any risk spectrum it's really important to be particularly careful with patients who are right at the borders or the thresholds in between these different groups so if you look from here at the very bottom unifocal papillary thyroid microcarcinoma is defined by one centimeter has an incredibly low risk of recurrence whereas when you start getting up into minor extra thyroid extension or having multiple lymph nodes you're starting to get at this threshold and this is particularly important because as we've recognized over diagnosis and over treatment it's really led to this trend of downstaging in the AJCC system and increasing conservatism but as I showed you before there's maybe the suggestion of a small uptick in mortality and we know that even patients with low-risk disease around one to two percent of them will actually end up having distant metastases and when my goal is not to scare all the clinicians in the audience or make us lose even more sleep at night I think one of the major questions is can we do better in terms of really refining this system and so I'd like to highlight some new data in that context so in the last couple of years a retrospective study out of Italy with over 2,000 patients with PTC one-year follow-up not very long when you're dealing with incredibly long life expectancies and a great prognosis but what they found looking at minimal or microscopic extra thyroid extension is that it really didn't predict the initial response to treatment but when you stratified it and included extra thyroid extension and a tumor greater than two centimeters it was a significant odds ratio higher that patients would have recurrence at one year. So maybe it's not just one criteria, but how those criteria interface together that is impactful in terms of risk. If you look at this retrospective study from Sloan Kettering with over 6,000 patients with PTC, they looked at 10-year disease-specific survival. So not just minimal or microscopic, but macroscopic extrathyroidal extension noted at the time of surgery into the strap muscles. And what they found is that if you had no extrathyroidal extension, 99% survival at 10 years. But when you start to see extrathyroidal extension into muscle, or you see it into other structures, and interestingly, even when you just look into the ETE into muscle, if you're an adult over the age of 55, that modulated the risk and made it even higher. So this idea that as we refine our criteria, maybe some of these patients are ones that we should be redefining as intermediate risk to triage them for more upfront therapy. Multifocality has been a big issue in terms of trying to define, okay, you could have a ton of little one millimeter metastases throughout the thyroid, or you could have three giant one, two, three centimeter nodules. Are all these patients the same? Because the guidelines just say multifocality. So if you look here at this systematic review and meta-analysis from Korea of 26 studies, over 33,000 patients with PTC, the multifocality recurrence rate was certainly higher, but it was highest in pediatric patients, those with greater than or equal to three foci of disease, or larger foci greater than one centimeter. So again, maybe we can be refining these criteria in the next iteration of the guidelines. Margins are also debated. So in this case, retrospective out of Miami of the National Cancer Database, over 14,000 patients showed that a microscopic positive margin led to a higher rate or risk of death. And then interestingly, another recent study out of the JCAM, which is a multicenter study looking at BRAF V600E, which all of us know many papillary thyroid cancers have this very common mutation. But what's interesting when you look at these data is that the hazard ratio for death is 5.76 if you have lymph node mets and are BRAF V600E positive. But if you do not have the BRAF V600E mutation, then there is no increased risk even despite having some lymph node metastases. So this idea that these different criteria modify each other, and as we define our criteria, we may need to do better than just a simple list. All right, we'll talk now about hemithyroidectomy in terms of treatment strategies, and I'd love to highlight the wonderful debate by Dr. Tuttle and Sosa about these various strategies. So lobectomy, so lobectomy, I'm saying the talk is about what's new. Lobectomy is not new at all. They were very frequently performed for a very long time. And most patients did well until really the 50s when controversy around the role of surgical management and newly emerging radioactive iodine that was pioneered at the Mass General Hospital in the early 40s. And so there were two key studies that really changed the tide in terms of this management. One by Vijay Varma at the University of Michigan in 1970 showing giving this new radioactive iodine, although I guess it wasn't new by the 70s, after operation led to a 20-fold drop in mortality. And then, of course, Ernesto Mazzaferri's landmark study from 1977 showing the post-op I-131 reduced risk of recurrence. And really, over the ensuing decade or two, there was a huge shift in saying that, okay, we can't do hemis anymore because we gotta give radioactive iodine in order to reduce mortality and recurrence. One of the problems with some of these studies with the benefit of hindsight and the retrospectoscope is that really there wasn't a lot of criteria to define risk or to risk stratify these patients, which is something we're really getting increasingly good at, as I said on the last slide. But then there was a paradigm shift with increasing data showing that for most patients, when we really do a good job refining low and intermediate risk, most patients don't seem to need this. They do well anyways. And same thing that we're seeing increasing data around the adverse effects and the secondary malignancy risk of I-131. So because of that, the 2009 ATA guidelines no longer recommended RAI for everyone, and really, especially for people with low-risk disease, made it more optional. And then if you don't need to give radioactive iodine for everyone, you don't have to remove the entire thyroid for everyone. So really, lobectomy came back as the pendulum as such a common thing in medicine. So what's new? I'd like to, before we talk about lobectomy, just talk about a couple of studies that have looked at radioactive iodine, because even that topic, who do we give radioactive iodine in, in patients with low or intermediate-risk disease? So in this wonderful study by Dr. Kitahara's group, and I encourage you to check out her lecture from the 12th, retrospective, looking at over 27,000 patients, really focusing on younger patients under the age of 45, in between 75 and 2017, with really quite good follow-up, 15 years, they showed a solid tumor relative risk increase of around 25%, and then a heme malignancy risk of 51%. So this is, of course, a relative risk, but I think we're better understanding now the role of radioactive iodine in this very small, but I think clinically significant, uptick in other cancers. We know, based on multiple data, and this is a systematic review and meta-analysis from Ireland, that when you look at low- and intermediate-risk patients with DTC, and you have follow-up greater than 12 months, we see that low-dose radioactive iodine, which I wouldn't really consider less than 81 to be low-dose, I guess I'd call that a medium dose, but was just as effective as higher dose in terms of recurrence rates, and the success of rendering thyroglobulin undetectable in terms of facilitating follow-up. And then I think there are two major studies that have come out just recently that have recapitulated, and now a lot of them are, or the goal is to get some prospective data. So, you know, Mayo actually has been sounding the alarm for many years about really, many patients don't need radioactive iodine. And I think, again, with the retrospectoscope, a lot of that is that the patients that Dr. Mazzafferi was treating, many of those were low-volume surgeons who were doing the surgeries, whereas at Mayo they had some of the world experts. So I think a lot of this came down to who is your population? Who are the people that might benefit versus not? But when they looked at their impressive 60-year experience, they showed really no change in terms of role of radioactive iodine in terms of reducing mortality or recurrence when you use the MESA score that I mentioned before to risk-stratify patients. And then last but not least, hot off the press from France, finally, prospective data, so a randomized phase three trial looking at over 700 patients with DTC and randomizing them to radioactive iodine or null treatment and showing that RAI was non-inferior to low-dose radioactive iodine in terms of structural or biochemical recurrence, excellent response to therapy, and quality of life except for some of the usual expected issues in the RAI group. And I'd love to point you out to the Martinique conferences because these are wonderful conferences if you want to read more about radioactive iodine as we try to figure out in whom we should be using it. So who are the candidates for lobectomy? And I tried to make this talk as practical as possible, so all of this is in the chapter, but really just giving you some bullet points. And I think as endocrinologist, I would often defer to the surgeon to discuss this with patients, but I'm getting more and more consults in clinic either from low-volume surgeons who are trying to grapple with who they should be doing less upfront treatment in. And I'd say also patients after we diagnose them by FNA are asking about, do I really need to have my whole thyroid out because, you know, Dr. Google. So here in terms of ideal candidates, so you can really stratify by ideal and reasonable candidates. So obviously someone who has no contralateral disease or nodularity, no abnormal lymph nodes. So it's really important to do a good lymph node exam on all of your ultrasounds. Smaller nodules, especially without extrathyroidal extension. No obvious clinical risk factors. Indeterminate cytopathology with use of molecular testing where appropriate. Strong preference for hemithyroidectomy if the patient wants it. And low operative risk, even if one or more surgery is needed to do a completion. But I think the ones I'm getting a lot of patients in clinic where they have contralateral nodules and there's always this dilemma, do we do the whole total thyroidectomy or do we just follow them? Because it's now on us as endocrinologists to do all the post-op follow-up and we can't really trust thyroglobulin and then we're dealing with ultrasounds as well. But I think even when you look at these data, so these patients, most of them do incredibly well. So it's more the inconvenience. So just to summarize the pros and cons, and I actually give this to my patients as a handout, here are some of the reasons why to consider or not consider a HEMI. So obviously there's a lower likelihood of needing post-operative levothyroxine and here are some of the clinical predictors that help you figure out whether or not the patient may have a higher or lower risk of needing levothyroxine. A lower risk of recurrent laryngeal nerve injury. Obviously you can't ding all the parathyroid glands or both recurrent laryngeal nerves if you limit your surgery to one side of the neck. And we'll talk about how so much of thyroid cancer is in relying on your local team and knowing the people around you. So a lot of this comes down to the availability of surgical expertise. Potential savings in cost and quality of life. And really no increased risk of mortality as far as we can tell. But then of course, what have we lost in doing lobectomies? Well, you can't do radioactive iodine. So we're gonna miss if we don't properly select those one to two patients who have distant mets where we only would have found them on the iodine scanner. Potential need for a second surgery if intraoperatively or afterwards we see the pathology shows higher risk features. So two surgeries instead of one. And of course, decreased sensitivity of thyroglobulin in detecting tumor persistence. And then there's debate about whether or not there's a small increased risk of recurrence. So let's say somebody gets a lobectomy and now you're sitting with them with the pathology in clinic and trying to decide do we need to send them back for a completion? I don't wanna belabor the point, but in terms of looking for these criteria, there are some people where we do have to send them back. And I think that's really important because again, we're the ones who are gonna be following these patients longitudinally. So if you see higher risk features, you see new abnormal central lateral compartment lymph nodes, a markedly elevated postoperative thyroglobulin, especially if above one, a positive margin. That's a little bit controversial, but I just showed you some data saying we should probably be taking these seriously. But if you look at the field as a whole, it seems like posterior more than anterior and wide rather than focal margins seem to be more impactful in terms of recurrence risk. And then of course, multifocality is controversial, but as I mentioned, maybe we can do a better job at defining which are the higher risk versus the lower risk multifocal tumors. So what's new with lobectomy? So in terms of this study that was done out of Sloan Kettering with over 6,000 patients, they showed that after propensity matching, lobectomy versus total thyroidectomy when you properly select them had a similar overall survival, disease-specific survival, and risk of recurrence. So really very, I think, compelling data, although it's retrospective, that these patients do very well. What about need for levothyroxine? Well, this is a bit of a kicker. So let's say somebody only has a 20% chance of needing levothyroxine if you use the reference range. Well, according to the ATA guidelines, if they're low risk, we should be targeting a TSH less than two. So when you use that criteria, up to 80% of people have a TSH greater than two, and actually a lot of them end up starting levothyroxine. So are we really doing as well as we think we are? And what should be the TSH target? Should we be using this low risk TSH target? So lots of folks are working on this to try to figure out in whom, or what TSH targets we should aim for. And this is a retrospective study out of China with over 2,000 patients. But just to sort of cut to the chase, about a little less than half were intermediate risk, but most of the patients that were low risk actually had microscopic, or PTMC, microcarcinomas. But what they found is no matter what your TSH was, there did not seem to be a significant effect in recurrence-free survival, albeit with a little bit limited follow-up. And I think a lot of this debate is sort of nicely captured in this wonderful short commentary by Biscoff and Hamart and Thyroid of this year, looking at what should we be aiming for. So more to come on this. So what's new with lobectomy otherwise? Well, quality of life has been an increasingly important metric that we use. And so there's a number of studies looking at do patients fare better, or are they worrying more about their cancer because they had a lower, or less upfront surgery? If you look at this great study done out of Omaha, Nebraska, you can see that when you look at total thyroidectomy for cancer, it's a higher rate of... a higher worry in people who get hemithyroidectomy. So I think this is an active area of research and more will come. So as we think about hemithyroidectomy, I don't know if any of you have seen this sort of cute phrase, but that medicine is cyclical or that there's a pendulum. So in 2000 BC, here eat that root, all the roots heathen, say this prayer, all the prayer superstition, drink this potion, the potion snake oil, swallow this pill, that pill is ineffective, here's this antibiotic. And then in 2022, that antibiotic is artificial or unnatural, eat this root, you know. So I think a lot of this lobectomy is coming back just as many of these treatments. So let's talk about active surveillance and there was a wonderful talk again by Dr. Tuttle, who's one of the world experts in this. I am not going to try to compete with him. But just to summarize some of his data, I will say that there is a large subclinical reservoir, small, and by that I mean mostly subcentrometric thyroid cancer, papillary thyroid cancer in healthy adults. And one of my favorite studies, the mortality in patients who had these small papillary thyroid microcarcinomas was actually, or I should say their survival was 102%. In other words, they did better than the people who did not have papillary thyroid carcinoma because they're healthy and live a healthy lifestyle and were more likely to access healthcare. So sort of interesting that these patients do so incredibly well. And therefore, do they really need even a lobectomy? And so I think as we have a better sense of this over-diagnosis that is occurring, we know that maybe we should be doing less. And so another study showed that up to 30% of patients have subclinical or occult PTC at autopsy, which is 1,000-fold higher than the patients who have clinically significant disease that come to our attention as endocrinologists. And that's really incredible. And so based on these observations, which are not new, they're actually have been around for a long time, there were three major pioneers in this idea of active surveillance, mostly out of the Japanese experience with Dr. Miyayuchi and Ito out of Kuma Hospital in Kobe, Japan, looking at over 1,200 patients with papillary thyroid microcarcinoma and really incredible data that at 10 years, only 8% of these, these are biopsy-confirmed thyroid cancers group, 92% didn't if you use a three-millimeter size threshold. And even though almost 4% of them developed new lymph node mets during surveillance, there was no death and the patients did very well with the salvage surgery compared to an upfront one. And this experience was recapitulated by Dr. Tsuchitani in Tokyo, Japan. And then in really in the early 2000s, once the Japanese had really pioneered the experience at Sloan Kettering, looking at patients with a little bit, maybe up to a little bit larger tumors, knowing there is no sink or sank, biological cutoff in size, even that's a spectrum. But then when you look at 25, we had even better data in terms of only 4% of them grew. But this is because Americans are a little bit more prissy and we probably would not do active surveillance unless someone else did the work for us. So we'll go through and talk a little bit about active surveillance, because now it's no longer experimental. These data are really compelling. And if you look at the most recent ATA guidelines, you can see that if you have a microcarcinoma without any adverse features, or so you only need one of these criteria, patients have high, short, or long-term surgical risk, comorbidities, or short life expectancy. These are the patients we should consider watching it. So Dr. Brito and Tuttle and colleagues have really given us a wonderful framework of how to approach active surveillance. And so they divide it into three different variables, the patient factor, the tumor or the nodule factors, and then the medical team factors. And in terms of ideal, they rank it in terms of ideal, appropriate, or inappropriate. Who are the ideal patients for active surveillance? Well, older, I'll say, wiser individuals, those who are accepting of an active surveillance philosophy and really don't, they're minimalist in terms of wanting interventions, patients who are reliable and adherent to follow-up, those who have a high risk of surgery, particularly people with significant comorbidities like our patient I mentioned before. And what about the tumor factors? Well, small tumors, I think that's obvious based on these experiences, looking at mostly 10 to 15 millimeter tumors. Having a two millimeter rim of normal thyroid tissue around it, no evidence of extra thyroid extension radiographically, no nodal mets, no high-risk features. But what's interesting is they say this, no high-risk molecular features, but to date, we still don't know exactly what molecular features are more predictive of higher risk. Maybe BRAF E600E plus a TURP promoter mutation, but even that is something they're really working out as they do molecular testing for these patients. And then the medical team factors, and I say comfortable because comfort is only something you get when you've been doing something, and so if you're going to start active surveillance, you have to start somewhere, and that involves being a little uncomfortable. But I think having high-quality nexogenography available, having ancillary support to make sure these patients are following up, and having a multidisciplinary team I think are really valuable features of when you think the time is ripe to try this. And then of course, there's less ideal, but appropriate based on the data that have come out of Dr. Tuttle's research as well as from Japan. So maybe a little bit larger, maybe patients who are a little bit younger, multifocal tumors, indistinct tumor margins or nodules that you can't really crisply measure over time, but you can get at least a ballpark. PET-positive thyroid nodules if somebody had it incidentally discovered. And then here, a non-critical subcapsular nodule location. So again, all these are in the chapter. Don't feel the need to write them down or worry too much about the details. But I think when you're approaching these patients in clinic, I always have to pull out these lists in terms of figuring out who's appropriate or not. So what about practical implementation? Well, they recommend baseline thyroid sonography with normal measurements. And this is not something a lot of us do, but tumor volume calculation. And tumor volume has been found to be a very helpful way of following these and in determining whether or not to abort active surveillance. So that's something that you can either use the ATA nodule volume estimator or calculator on the website, or actually use the ellipsoid formula, which I almost failed calculus, so I've been using the calculator. So you can do serial thyroid sonography every six months for two to three years, and then annually if it's stable. And I think for most of us, especially me worrying about these patients I'm caring for, what are the indications to abort it? So obviously, if we see significant growth, at least in one dimension, an increase in volume, new evidence of lymph node metastasis, or new evidence of invasion through the thyroid capsule. These are the reasons to stop. And I actually had one patient who we tried this in recently, his tumor doubled at the six month mark. And he had new lymph node metastases that appeared. But the reason we did active surveillance is because he had stage four lung cancer and actually ended up going on hospice because of doing very poorly for that. So even though he progressed, we decided to perform active surveillance and he was very grateful in terms of his time not needing to spend time recovering or dealing with this. So what's new in this space? Again, I don't wanna belabor too many of these points, but since the talk is what's new and it's a little bit of an ambitious topic, we'll at least highlight some recent questions. And I think with active surveillance, there's more questions than answers. But one of the questions are, are there molecular predictors? I had mentioned that before. And here in the study in 2019, they showed that when you look at the ones that progressed versus the ones that didn't, there were some differentially expressed genes, but no particular oncogenes, no mutations or fusions, just differential expression. So maybe we can be incorporating expression analyses from some of our commercial or research platforms and looking at these. Is there an optimal TSH to reduce progression during active surveillance? We know that a high TSH, at least in this retrospective study, predicted a volume increase and a progression-free survival is lower if the TSH was above 2.5. Is there a maximum safe size and how does location impact risk? Well, the study from Dr. Tuttle's group showed that if you have a nine millimeter or larger PTC and it's in one of these three locations, there is a higher risk of progression and of needing to abort surveillance. So it's location, location, location. And will patients adhere to this? So I don't wanna belabor the point, but again, I think there's really an importance in looking at quality of life for these patients who are getting less surgery to make sure we're doing right by them. So here, a sign that most patients do very well and have high quality of life, but maybe they have a little bit of upfront anxiety about active surveillance that fades with time, at least according to this data from Dr. Suchitani out of Tokyo. And then really, we have no prospective data to really compare surgery to active surveillance, although at least in the retrospective studies that have been done, they look to be fairly similar. All right, and then we'll just finish up. So I'm gonna spend just a very short period of time on image-guided ablation. And the reason is we don't have a lot of data on this in thyroid cancers. Most of the data for image-guided ablation is actually in benign thyroid nodules. But there's been a flurry of new statements, consensus statements and guidelines around these new technologies, which I give you the references here. But really when we talk about what does this mean, it's ethanol ablation or some flavor of thermal ablation. And when we're looking at candidates for this, it's really, I think, a niche technology, although it's becoming more popular and more common. But really when you have cancers that require treatment despite high anesthetic or surgical risk or refusing surgery, but also refusing active surveillance or patients who really place high value on avoiding a surgical scar. And while again, I don't wanna go into too much detail here, really when you look at the studies, there is not a lot out there in terms of looking at using these technologies in malignancy. But most of the studies that are out there look at microcarcinomas or small, low-risk thyroid cancers. And then the other area where there's sort of interesting use is the ablation of local regional lymph nodes that again, somebody really doesn't want to or can't undergo surgery. And here's just a summary of the pros and cons in looking at these various technologies. I don't wanna go over with them, but just to highlight, they are done with local anesthesia, sometimes conscious sedation, if you do thermal ablation, there's no scar. They're generally low cost, although thermal ablation is a little bit variable in terms of insurance coverage. And there are some complications. There's no such thing as a free lunch. Right, so back to case number one, which a summary is there for you. So I'll give you a little bit more information because all those options were good. He's got a suspicious 1.4 centimeter nodule. It has four millimeters of normal thyroid tissue around the rim. When we did our upfront ultrasound at our evaluation, no suspicious lymph nodes. He lives 10 miles away, not too far from Rochester, New York and he always attends medical appointments. And he really does have a minimalist philosophy. So while all of these management strategies could be appropriate depending on your team and what you're comfortable with, this is what we ultimately decided. And actually this is my first case of active surveillance when I joined the faculty at the U of R around four years ago. So he's been doing very well since then and really chose it. But I'll tell you, if we didn't have a great high volume surgeon and he didn't wanna watch it, I would be sending him for a HEMI to try to minimize risks of surgeries. With our really wonderful high volume surgeon, we tend to push for total thyroidectomies because the risk is much lower with experience. But this Latin phrase, which I won't try to pronounce means know thyself, which is something that know yourself, know your team and that'll help you take good care of these patients. You know, I just realized now I'm seeing this blown up. I'm not a fundamental scientist. I know we're in the basic science pavilion, but I'm pretty sure that's not how hormones work. Isn't that a synapse? At least thyroid hormone doesn't, I think so. All right, let's talk. So we'll spend our last five minutes together on advanced disease. Cause again, this is something that's rare, but I wanna hit a couple of important points for the community endocrinologist. All right, so this is a 59 year old woman. She's got a neck mass, total thyroidectomy seven years ago. She had a minimally invasive four centimeter FTC, less than four foci angioinvasion. No recent surveillance, no radioactive iodine, no other medical history. On ultrasound, she had a three centimeter nodule in the right bed, now seven years later. And FNA was suspicious for a follicular neoplasm. The TSH is 2.2 on levothyroxine. And she has a thyroglobulin of 0.24. She has a revision surgery by our local high volume surgeon and they see an angioinvasive now, follicular thyroid cancer in the bed. And then to fast forward, she had a whole body scan and she was empirically given 100 millicuries of radioactive iodine because of this being now a higher risk tumor recurrence. No uptake other than the central neck on the post-op scanning and her thyroglobulin was undetectable afterwards. We'll fast forward several years, she gets a CT chest for shortness of breath. They find many pulmonary nodules, the largest of which was one centimeter and the FNA was thyroid. She had a whole body scan to look at these nodules and they did not concentrate iodine and they were really indolent for over seven years and most one to two millimeters a year growth. But then she presented with sudden hemoptysis and shortness of breath and at least three of these foci have grown a lot. So what would you do? Excellent. So we'll talk about why this is what I did, although we'll talk a little bit about these other options too. So this case I think is a very clear case of advanced disease. Somebody with distant metastases that are progressing and now causing symptoms. How many of you have struggled with dealing with some patients where you're trying to figure out are they advanced or not? Do I need to be doing more? Do I keep an eye on them? I know I certainly have. Great, so a significant number in the audience. So that definition of advanced disease is really important and thanks to this recent consensus statement that came from the AHMS as well as ITOG recently, they accomplished the ambitious feat of trying to define what constitutes advanced disease and how should we be using these newer systemic therapies. And so in this article they achieved consensus in defining it as large locally invasive tumors, especially when involving critical structures, the presence of distant mets, and anticipated imminent threat from tumor extent. But where it was a little bit more debated is patients who have gross residual disease, those with a rapid growth trajectory either by thyroid globulin or structurally, poorly differentiated or aggressive histologies and failure to respond to radioactive iodine and TSH suppression. So these are all things that I think many of us worry more about these patients, but as we try to triage who should be getting these newer therapies, these are the things to think about. And I think it's so important as endocrinologists, there's a subset of endocrinologists who have really developed expertise in using these new therapies, but most of us need to partner with a good oncologist who has the infrastructure and the ability to give these. So I think as endocrinologists, most of us should be focusing on who do we refer and when do we refer. And so I think for a lot of these therapies, they are best studied in patients with progressive radioiodine refractory disease. So again, I've given a lot of definitions, but even the definition of RAI refractory is debated. And so this is a wonderful excerpt from the Martinique conferences, really saying that there's no hard and fast somebody's refractory or not in terms of saying, should I give radioactive iodine or not? Really there are criteria that make you think they will respond less or more, but really using hard and fast rules probably isn't the right thing to do. So just to give you some of these criteria, no uptake in tumor foci. So we could say that for our patient, uptakes present but in some, but not others, or is lost. Or in this case, the presence of metastases that progress despite getting a treatment. And my usual rule, and I won't say that this should be in the guidelines is if you're not sure, give a God's honest dose of radioactive iodine to see if it helps either in thyroglobulin or structural disease changes. And here's a wonderful figure from this article looking at all the different factors to think about, about whether or not to give more radioactive iodine or to do it up front. And I think now we've understood that the reason why some tutors become radioiodine refractory is because of the molecular pathogenesis of thyroid cancer and the accumulation of either various alterations or different expression profiles that turn it into RAI refractory disease or poorly differentiated or anaplastic thyroid cancers. And we're doing a better job at mapping this out, although a lot of this is active research. And now we have all these different systemic therapies that are approved in thyroid cancer. The stars are the ones that are approved for differentiated thyroid cancer. And then this is actually for tumor agnostic, any tumor that has an N-track fusion. And so the real question is, when do you use these? We have all these different options and you can generally divide them by ones that are sort of nonspecific multi-kinase or angiogenic inhibitors versus those that are genotype specific for particular oncogenes present in the tumor or fusions. So really the problem is that these are not a panacea. These are not curative. They are really palliative therapies and responses are variable, even when you stratify patients with similar molecular profiles. And as I mentioned, treatment is mostly tumor-static and palliative, although that can be very impactful for patients to buy time. Adverse effects are significant, although some of the newer therapies seem to have fewer of them and more mild effects. And really the major problem is that resistance is nearly inevitable. So the main way of doing this has always been to save it for the last minute. But I think now we're realizing who are the people we should be using this in. And so again, I use this term refer because I think most of us are not gonna be prescribing these, but we'll be relying on a local oncologist who we trust to do the actual nuts and bolts of it. But these I think are the criteria to use. Failure to respond to current treatments, failure to respond to locally ablative therapies to try to spot weld tumor as it persists, if it's amenable to it, tumor foci that are big or are really close to a critical structure, rapid growth trajectory, although we know that using a structural growth, so on imaging of 20%, there's some data to support use of them in this setting, but where people wonder what do you do when the thyroglobulin's going up and up and up. And then here, presence of symptoms, so in our patient's case, hemoptysis and shortness of breath. Great. So I'm gonna skip this out just because we're running out of time, but I just wanna highlight one thing. I don't wanna go into all these different therapies, but I do wanna clue you into one thing that hits closer to home for us as endocrinologists, and that's these re-differentiation protocols. Many of these MAP kinase pathway therapies have been shown to restore sodium iodide symporter activity. And that's really impactful in that you can do a one-two punch basically, giving these therapies that have side effects for a shorter period of time to try to trigger iodide uptake. This is from Dr. Alan Ho's New England Journal study, Landmark, in 2013. Now the response doesn't always look as good as the imaging does, but I think this is a very promising modality that we're going to be seeing more and more data on. And as you can see, there are certainly lots of studies looking at this. And then of course, there's novel agents that are coming out that I won't go over. But one last slide here. So this is an interesting study. Dr. Ho again, and a multicenter trial looking at, okay, those studies were looking at known metastases and trying to trigger iodine uptake into them. This is actually looking at using it in a neoadjuvant, or I guess a adjuvant for patients with high-risk disease, using this to boost radioactive iodine uptake before their first treatment. And in this case, it was somewhat disappointing. We didn't see much of a benefit, but I think it's still really promising that we're going to be doing more research and finding out who best and what are the characteristics that might predict a response to this novel re-differentiating therapy. So in this case, we referred to oncology because she was really sick and she ended up starting Lenvatinib and actually had improvement in her hemoptysis and did very well. So my last slide is just with the continuously changing environment of thyroid cancer. It's particularly important to realize the guidelines are ever-evolving. And so this is a quote from my mentor, Gil Daniels at the MGH, co-written with Peter Topp. Clinical guidelines are recommendations produced by experts on best available evidence. If all questions were answered, we wouldn't need guidelines, just a list of references. So just appreciate the guidelines are never gospel. You know, they're updated periodically unlike the gospels and modified, but like the gospels, they're somewhat faith-based. And I think it's ironic that I'm quoting my faith in Dr. Daniels to highlight this excerpt from his manuscript, but just a sense to, if you're ever struggling in the outpatient setting managing these patients, appeal to Eminence, send them to someone who really treats a lot of these patients and can help in a team-based approach. So thanks so much for your attention. Sorry for going a couple of minutes over. Thank you.

treatment

differentiated thyroid cancer

evolving

low-risk

management strategies

active surveillance

ablative methods

risk stratification