This virtual, live-panel discussion reviews the implementation and practical application of Penn Medicine’s evidence-based Thyroid Nodule FNA Pathway. Experts from endocrinology, radiology, pathology and primary care address the critical decision-making points along the pathway.
Dr. Kobaly's physician profile See Dr. Jalaly's physician profile See Dr. Sauder's physician profile See Dr. Langer's physician profile See Dr. Jaeger's physician profile All right, well I think we're all on here nice and early so we'll go ahead and begin. So, good morning and welcome to our cmi this morning which is sponsored by the endocrine disease team at the Abraham Cancer center at Penn Medicine stay we're going to focus on the evaluation and management of the commonly encountered thyroid nodule. My name is Kristin Cavallari and you pull our presenters up here. Um and I'm an assistant professor of medicine and endocrine at the Pearlman Center um for advanced medicine and I'm joined today by four colleagues. First, Dr Matthew Sauder is an endocrinologist practicing at Penn medicine Lancaster General Health. Our radiology colleague is Dr Jill Langer, the section chief of ultrasound imaging. In addition Jill was on the rating group that drafted the american College of Radiology is Tyrod system to classify the ultrasound imaging of thyroid modules and we'll hear all about that today from her. Our 3rd colleague is Dr. Jalal Jalali of Psycho Pathology. Jalal is an assistant professor of clinical pathology and laboratory medicine. Finally, we're joined by doctor Jeffery Jagger from the division of internal medicine. Dr Jaeger is a professor of internal medicine at Penn medicine University city and he's the lead physician there. Our partnership here today illustrates the multidisciplinary collaboration that is essential to patient care in this area. I'm just going to review our learning objectives for this morning. Um First our goal is to apply evidence based evaluation for patients with thyroid modules. We want to illustrate the association of Sana graphic imaging with Cancer risk and its application to fine needle aspiration or FN, a decision making. And lastly we want to describe the Bethesda cytology classification for reporting thyroid nodule FN results and the indications for molecular testing. We have no financial relevant financial disclosures. Our webinar is live and will be conducted today as a panel discussion. If at any time you have questions, please submit them to the chat box and send to all we have carved out five minutes for questions at the end of both Jill and Jill ALS presentations and then at the end of time allows our session is being recorded and will link will be available for future listening. We will also provide a pdf of any relevant slides um instructions for obtaining credits. You will get an email from penn cmi to go ahead and do this and you will not be able to claim credit until you receive this email. All right. So we're going to go ahead and begin. My first question is for Jeff, let's get started. So Jeff. Often thyroid nodules are discovered incidentally as findings on imaging ordered for another diagnosis, such as a chest ct or a neck ct. And they're also occasionally found by physical exam as a primary care doctor. Can you tell us where the most important questions that arise when you're working up these patients. Thanks Kristen and thanks for inviting me to be on this panel. It's an honor and a pleasure to be here this morning. Um I think that as a primary care doctor as you know and as the audience knows, we certainly get an awful lot of uh imaging discovering these modules and it's most often incidental. I would say that first and foremost what we want to know is what labs that uh you specialists I think we should order and what specific imaging we should get if it's anything other than a routine thyroid ultrasound per counseling I think would be most helpful to have some sense of the likelihood of anything serious being found on these incidentally found modules. And we also want to know how to counsel patients about what to expect if the ultrasound that I'm getting ready to order shows anything concerning. I think that um quite frequently patients urgently want a consultation and I'm comfortable managing most of uh this algorithm myself. So it would really help to have a good idea of what criteria you will be using to determine your recommendations and importantly would be good to have some sense Of when to refer to you an endocrine or two. My colleagues in surgery, thank you for those great questions. Um the slide that's on the screen right now is an algorithm that was developed in 2020 20. Rather this is our evidence based practice pathway for the management of patients with thyroid nodule matt. If you can help to answer Jeff's questions and walk us through the work up in. This algorithm is at a high level. That would be a great way to start morning kristen. Thanks so much for the invitation. Um I'll just walk through the algorithm here and I'll start at the top and really point out that this is a symptomatic thyroid nodule. So if someone has a big mass that's causing compression symptoms, uh this is not necessarily algorithm for you. And in the second line down talks about severe comorbidities or life expectancy less than two years. Again, this is an acknowledgement that really sick people get a lot of cross sectional imaging and if their life expectancy is less than two years, they're asymptomatic nodule is probably not priority number one certainly is not priority number one. And the big things with with the nodule, our thyroid ultrasound and TSH. Right? So those are two essentials to obtain once you find the na jules. And the reason the TSH is so important is that if you have a functioning nodule and the TSH is less than 0.3, um We need to make sure that there is not a functioning nodule. So we really do need The I-123 or technicians can, depending what center that you use. Um because you don't want to biopsy a hot nodule because it gets uh confusing. Often times get uh indeterminate pathology. So if the TSH is normal, then you follow down and you get the ultrasound. Uh And the ultrasound, which Jill will describe at length about how to interpret the ultrasound, but a few things that I should mention that should raise your level of concern and would warrant. And endocrine consult are some of the risk factors listed here. So if you have an F. D. G. Avid nodule on pet, which is pretty common, uh the answer can get fairly nuanced. And those things we think probably should be referred because there's some you know F. D. G. Na jules, F. D. G. Positive modules are higher risk but that the whole gland uh F. D. G. Abbott that can make the hashimoto's and so it gets nuanced. Uh Certainly if there's a family history of thyroid cancer and greater than three first degree relatives that would warrant a referral. Same with XRT to head her neck in a patient who had that less than uh their 18th birthday hereditary cancer syndromes should also raise the concern and would warrant referral as well as organ transplants and patients who've had biopsied modules in the past. Uh Also we think should be referred to endocrine. If um if none of those things exist then we go down to the ultrasound pathway and then our pathway sort of branches from there. Great, thank you. All right, well Jill langer is now going to walk us through some of the most common ultrasound findings that we see in thyroid nodule and the risk stratification systems that are used to determine which modules to biopsy. Um Jill, if you can also comment on the ultrasound, examine the importance of assessing the cervical lymph nodes. That would be helpful for our audience as well. Now turn it over to you. Great, thank you so much. And uh a pleasure to be here. Just go ahead and get my my slides teed up back up here for a second. Perfect. Alright, so just as christian mentioned, I'm going to give you the radiologist perspective of how we evaluate thyroid modules with, with an eye towards what makes us concerned that they may be a cancer. And as we just heard from my colleagues here, the most common way the thyroid nodules are now detected is what we call. Incidentally they're just popping up because they're on an imaging exam in a patient who otherwise has no risk factors and no symptom Atala ji. And the good news is the overwhelming majority are benign and this is something that comes up very commonly in all of radiology that when we discover lesions are clinical colleagues do want evidence, evidence based guidelines about how to best handle these incidental findings. So, one question that came up is what is a thyroid nodule and it turns out that's a that's a pretty good question. That's a little bit mystifying. The iconographic definition is it's just an area of the thyroid that looks different from the background, per income up The good news is that the vast majority of these are benign and in fact they're not tumors, they're just dis plastic or hyper plastic, disorganized areas of the thyroid. Um and as we've heard before, these modules are incredibly common. As a matter of fact to fit over 50% of adults will have modules if we look with ultrasound and as many as 67% of seniors historically of modules that come to biopsy. Again, the overwhelming majority are benign and we can have tumors. Those tumors may be benign adenoma or maybe a thyroid cancer. Again, these are the minority of lesions we will find. So we know sonography is far and away the best imaging exam to evaluate the likelihood of malignancy. And we know there are sina graphic features which will look at, which we call suspicious features which have a high prediction for malignancy and the risk of cancer increases when multiple of these suspicious features are present in a nodule. This increases the specificity but lowers the sensitivity at the opposite end of the spectrum. We know there are appearances that are highly correlated with benign modules and then we know that there are no jewels that are indeterminate from the perspective of sonography, meaning they neither have features that we can put them in the box that we think they're well ignorant nor the box that we think they are highly likely to be benign and they may require a biopsy to figure it out. But again, the overwhelming majority are still benign. So what are the features that tell us something is a cancer, as you would imagine if we can see local invasion. That for sure, it tells us we have a cancer. But identification of abnormal cervical lymph nodes, often not palpable lymph nodes is very important. We're going to look for cystic change, calcification around the shape and so forth. So it is mandatory that whomever does an ultrasound examination of the neck, they should always be on the lookout for abnormal lymph nodes because that senses the diagnosis that we're dealing with the cancer. And here's an example of the nodule in the thyroid pointed to with this with the red arrow and looking into the lateral compartment of the neck on the other side of the carotid artery, we see there's a metastatic lymph node. So this tells us we are dealing with a cancer that is metastatic to the lateral compartment of the neck. Now, there are a number of ultrasound features other than local invasion and lengthen apathy which do predict malignancy. And we'll just briefly have a look at some of these hypo echoed ethnicity or how dark the nodule is definitely tracks with the risk of malignancy and the darker it is, the higher the risk we talk about mark, typo exogenous city, which means as dark as the strap muscles pointed out with this orange arrow, the borders of the thyroid nodule? Very important, speculated jagged borders, highly predictive of the cancer. And I'm showing you for for examples, notice how they are all solid dark hyperbolic OIC and each and every one of these has aggressive margins. La belated margins are also concerning for malignancy. Whether there are large lobular ations or small lobular ations taller than wide shape is a finding that came right from the breast ultrasound imaging. And that means when we look at the transfers view of a thyroid nodule, it's growing more front to back than it is side to side this we see most commonly in very small cancers, but it tells us it's an aggressive growth pattern and this is something that should be obvious. We're not going to take this down to the millimeter. It should be visible from across the room calcifications. There are certain types of calcifications that are very suspicious. Large. Destro thick or coarse calcifications and particularly peripherally interrupted calcifications, an example of which with the orange arrow showing you actually soft tissue growing through the calcifications. Very suspicious eggshell or complete peripheral calcifications, somewhat suspicious. But very commonly we're going to see central linear calcifications which are non specific. This is an important concept and that is of the difference between micro calcifications and something called punked eight academic both sides. True micro calcifications represent Simona bodies, which is part of the histology of papillary thyroid cancer and are present in up to 40 An ultrasound. They look like very, very faint little dots that have no ultrasound artifact of acoustic shadowing and their president up to 40% of papillary thyroid cancers. But again, most papillary thyroid cancers of solid dark and have other suspicious features in combination with these tiny punted academic those at the opposite end of the spectrum. There are features that are highly predictive of being benign, such as entirely cystic or nearly entirely cystic composition and something called spongiform where the nodule looks like a sponge. These are almost always hyper plastic modules. So something that comes up very commonly is when someone looks at an ultrasound and they see some bright dots. They worry that these could be micro calcifications. But as it turns out, the vast majority of these bright dots are not punk kid academic focus. I they are non specific academic facility, including this example of linear academic facilities. This is just the sound bouncing around in the cystic spaces of this nodule. And this is a very common pitfall and stenography where people um unnecessarily raised concern for malignancy based on the finding of these non specific breakdown. And then, as we mentioned before, there are not jewels that are solid and bright on ultrasound and these this is a non specific finding that carries a risk of malignancy of about 10%. But many of these modules are benign adenomas and of the cancers as we'll hear a lot about later. This appearance correlates with some cancers that have a less aggressive course and therefore molecular testing is key. So historically guidelines have been developed by endocrine societies to sort of sort out this level of risk. The American Thyroid Association evolved over time from originally recommending biopsy of all nodule is greater than centimeter to incorporating ultrasound into risk assessment in the current day. And this is the current 88 guidelines that are published and this now should be very familiar to you from high suspicion on the top row, going over all of the features that we just reviewed all the way down to very low suspicion and benign appearing when a nodule is entirely cystic. What's different about american thyroid Association guidelines as compared with what the radiologists use is that these guidelines take into account patient related factors. They tell you what to do with both high and low risk patients. The american thyroid Association guideline tells you what to do for na jewels that have a previous biopsies. So you know the results and the management is therefore driven by the ultrasound appearance and they also um we'll tell you how to follow modules also based on ultrasound appearance as well. The problem is that many nah jewels are not classifiable by that atlas approach and there's no defined follow up period. So in response to this radiologist wanted a mechanism to deal with these very common incidental modules and the goal was to be able to standardize reports and describe an award a point system for every nodule that we say the interpretation though. However, as we mentioned before is very operator to Melinda and the way this works in its full glory here is we have five categories that we assess the composition. Exogenous city shape margin and the presence or absence of these epidemic costa. Each of these findings is awarded points and I'll just very quickly show you the scope of this composition. From zero points to two points based on level of suspicion, echoed ethnicity from cystic to very hyperbolic OIC with graduated increased points shape taller than wide. Yes or no aggressive margins yes or no. And if there's possible extra thyroid extension that gets points, if there's definite extra thyroid extension it's just called a cancer. And then these academic focus. I again highlighting the difference between non suspicious which gets zero points and true Punkt eight academic fosse which get three points the most challenging I think. Thing for radiologists to sort through once the points are totaled. We then assign a level of suspicion and recommend biopsy at certain thresholds which I'm showing you or follow up ultrasound or no. Follow up imaging. If the nodule either has a very innocuous appearance or is relatively small in size in low risk patients, imaging goes for five years and if the nodule stable, no further follow up is recommended. We think about the american thyroid association guidelines and a cr tire. It's there's a lot of similarities I've given you the risk of malignancy here based on each of the categories and you can see there's somewhat similar with the tire adds a slightly lower risk. You'll note that the tie rods five risk is not 100%. It's only up to sort of a mid range depending on the point scale. The difference here also lies in that if we identify abnormal lymph nodes or definite extra thyroid extension, it's just called a malignancy. It's not called tyrus. The differences are important as well. As we talked about before, tirades really only applies to incidental modules and low risk results. As matt was saying this is not applicable to pet positive na jules patients with genetic risk. Biggest difference is for the size threshold in in recommending F. N. A. With the size threshold being higher in a cr tyrants. And what this does is I'll show you in a minute is it limits the number of biopsies that are performed and puts these patients into a follow up group. Also there's that defined follow up period of five years which the current 80 a um is lacking. So when we compare sort of the sensitivity, if we look at biopsy of all modules of all sides, there is a statistically significant difference between a cr tirades recommending less biopsies as compared with american thyroid association guidelines but if we look at it from the perspective of biopsy or follow up, you can see them that a cr tire ads in fact does recommend follow up of more nah jewels And when we talk about biopsy or follow up of all malignancies greater than one cm. There's no statistical difference and the way that a cr tire ads in terms of yield of malignancy that is catching all of the malignancies, it has the same rate to slightly increased rate of detecting malignancies but recommends far fewer biopsies as compared with american thyroid association or the korean guidelines which is a guideline used around the world. So in summary, a sierra tirades is designed to detect most biologically significant cancers specifically in low risk adults. That is your incidental module without any clinical confound er It recommends fewer biopsies than other stratification systems with similar cancer rates. It does not apply to high risk patients or patients that have had a previous biopsy. The american thyroid Association guidelines are used to manage that and most importantly, Tyrod is designed to be adapted after re evaluation of these points and that's an ongoing process. With a number of papers coming out in the literature. Re examining whether the points that were derived for these different modules are appropriate or indeed adjustment. So hopefully that gives you a little view behind the scenes for how the radiologist is trying to tackle this problem of the very common thyroid nodule, the vast majority of which are benign with a plan that accounts for and detects most cancers without unnecessarily exposing large groups of patients to unnecessary testing? Thank you Jill for that. Excellent overview. Before we move on to talk about psychology outcomes, I want to open a few minutes session for questions so please go ahead and submit questions to the chat box. Um And Rachel Kells from endocrine surgery will lead us through the questions that have been submitted at the moment. We have no questions. I think everybody is still having their first morning coffee. All right. We'll have plenty of time at the end then to address questions. Um I think we will move forward but just to summarize so right now what we've learned is that imaging is correlated with cancer risk and we can use ultrasound features to help decide what modules to biopsy. Um And because of the several professional associations have provided recommendations for FN. A cutoffs based upon risk. And these cutoffs again are the same for the highest cancer risk here one cm. Um As well as the lowest risk where F. N. A. Is not necessary and there's some variability in the middle categories. So we can allow this, use this to allow for patients and our decision making. Um So you're a young person who has higher risk factors for thyroid cancer. You may go ahead and use a lower size cut off an older patient with comorbidities. You may use a higher size criteria or surveillance alone. Um Before we move on to a talking about interpreting thyroid biopsy results. Chef, do you have any other questions that would be beneficial for an internist who is caring for these patients? Thank you Kristen. Um I have a question for matt matt. It's really frequently the cases I'm sure my primary care colleagues in the audience will agree that the incidental finding of an asymptomatic nodule makes patients very nervous. Too many patients, any nodule or lesion that they read on their report is potentially cancerous and needs further evaluation. By definition. This is especially true for the patients who have tirades one or two lesions who are told they don't need any further imaging or my patients with tirades 34 or five lesions who are told that despite the language in the report and the scary appearance, they don't need to biopsy possibly because of size. I don't want to refer all of these patients to you for counseling. So how would you advise those of us in primary care uh to counsel these patients so as to reassure them that this evidence based protocol will not result in a bad outcome. Yeah. Thanks Jeff. I think that's an excellent question and I think is really the uh the biggest um Struggle we deal with in clinical medicine because you have the patients. Um some patients want to be very proactive with their health and they don't like um ambiguity. Right? They want to know with 100% certainty that this is not something to worry about. And so I feel like I spent a lot of my day trying to um uh, convinced them that nothing needs to be done unlike my diabetic population where I'm trying to convince them to do things. So, you know, my usual uh, pattern of, I usually try to talk a little bit about the natural history. I say, you know, kind of like Jill said number one na jewels are super common. Number to 90% of them are benign. Uh, number three, ultrasound truly is a powerful tool. Right? And I think the evidence based saying that we're not going to, you know, ignore aggressive na jules. I think we can feel confident in the ultrasound tool. I tell them, you know, there is some risk of marching down a more aggressive path and right. And so I always try to bring that up and then I say, observing is doing something right? So it's not that, you know, you know, if we say, hey, it's tyrants four, we're just gonna watch it. That's not what we are doing something there. Um, and I think usually when people understand the natural history and that, hey, we're, we're not seeing any aggressive features. We're not seeing it extending out of the, of the thyroid. Most people are willing to, you know, take a more conservative path. I do think there are gonna be some patients who, uh, no matter what you tell them are gonna still be scared and I want to say as endocrinologists were okay seeing, you know, some of them probably not all of them. But yeah, because you know, I do think, you know, not every not everyone, but you know, I think as a technologist and I do the benefit of being able to look through the ultrasound and scan through the images and say, hey, you know the reason they're calling this as not suspicious because hey you don't have these calcifications, it's not going outside the thyroid bed. So again, feel free to send them if if if you're unable to convince them, thanks Kristen. Did you want to address the questions in the chat before I ask my next question or you want me to go on to my next question? Let's go ahead and keep moving. And then we can I think the questions at the end of my other question that I wrote down was when my patients wanted more information about F. N. A. Can you share a little about how the procedure works and if there's any contraindications. Yeah. Now also a good question. And so I always say, hey well you're gonna it's gonna be similar to the ultrasound that you just had. Uh And so it's a small needle, about a 27 gauge needle, there's no special preps or no anesthesia. Can you walk into the procedure? They may give you local, they Probably will give you local anesthetic, but no systemic anesthesia. Uh and then you're going to have a series of needle sticks which will be 2-4, 2 to 4. Sometimes a little bit more needle sticks and uh will be uh there's some discomfort but not a lot of pain. Um We then talk about, you know, if they're on oral anticoagulants, usually, you know, some of the newer ones we might hold for 24 hours, Coumadin or platelet inhibitors and aspirins, we usually don't stop. So usually it's a very safe procedure and they can walk home after the procedure. Great. And matt, who does this procedure? Yeah. So I think it's uh I think a lot of people do it and and our institutions, our radiologists do it but some endocrinologists do it. Some surgeons do it. So I think it's whoever who feels comfortable doing the procedures. Thanks. So I think many physicians can perform an Fn a depending on where you practice, that's going to vary a little bit. Um And really the key to a good thyroid biopsy is knowledge and skill and ultrasound and then access to high quality site a pathology. So we'll shift to that area. So let's say we perform the biopsy and the samples adequate. So enough material has been removed. Unfortunately, it's not as simple as getting back an answer of either benign or cancer. Um and about 30% of results will actually be classified as indeterminant. So to take us through these cytology results in molecular testing, I'm going to turn it over to jalal. Thanks kristen. It's an honor to be here. Uh Let me share my screen. So um so what we use for diagnosing uh side of pathology after the decision was made to uh biopsy and audio is what we call the Bethesda system for reporting thyroid side of pathology which was uh have been in uh used in the United States and worldwide as well for more than a decade. And now it's in its second edition. And as you can see here, basically the Bethesda system for reporting thyroid sort of pathology has six diagnostic categories ranging from nine diagnostic all the way to malignant. And uh I'm gonna go and take you through those different diagnostic categories. So for the non diagnostic or unsatisfactory psychology, what it means that it's basically an inadequate specimen. And For an adequate specimen we need to see six groups of well visualized follicular cells with 10 cells in each group. And as you can see here, there are a lot of reasons for um a cytology specimen for not to be adequate, which is kind of can be due to the novel itself or the technique that was used. So some of the techniques can be uh related to the needle size that was used. That's why we always use Really small gauge needles, preferably 27 gauge uh cystic nodules. Usually you want to target the solid component of the nodule when when you target a legion classification sometimes or fibrosis can make an ideal difficult to aspirate and also previous japanese because of hemorrhage. Um so the advantage of psychology is that we can be with you on site when we come and examine these nodules. So you can see here that when we are present on site, we use what we call the diff Quik stain, which is a rapid stain that allows us to visualize the cells immediately and make sure that we have an adequate specimens. So that's our main job when we're on site is to determine whether the specimen is adequate, but not only that we can actually tell you whether or not, we think the nodule will be benign, likely or malignant, but a lot of times we end up in an indeterminate category. And having the advantage of cytology on site, if we think the model may end up being indeterminant is that well allow the patient to go through another past while well while the patient is there for potential use of molecular testing, which will not be sent until we look at the entire specimen, including the pap stains, which are alcohol, fixed slides and uh those stains take a longer time to perform. But as you can see here, they give us a better visualization of the chroma team and better uh kind of uh nuclear features of popularity, thyroid carcinoma, which I'll go over in a few seconds. So as mentioned before, most of the thyroid nodules are going to end up being benign, Even those that undergo fine needle aspiration. And those are pretty straightforward and easy for us by psychology to identify these nodules tend to have a lot of watery colloids and follicular cells tend to be really small, smaller than red blood cells and they're really nicely spread out through that colloids And that will, depending on the literature you read, it's about maybe 70% of nodules that end up being aspirated. End up being in this benign category. Um On the other extreme end of the spectrum is the malignant category or because the category six which can be most commonly popularity thyroid carcinoma but can be other carcinomas. So, here's an example of popularity thyroid carcinoma. With this really nice popularly And whirling of the novels, the the follicular cells are quite large that larger than the red blood cells and you can appreciate here the really nice chroma team clearing with the delicate groups as well as the interim nuclear inclusions. So, about 10-15% of nodules will end up. And the category of malignant Hello over uh more recently, about five years ago. Uh an entity kind of on a paradigm shift happened in in uh pathology and a lot of what used to be called encapsulated follicular variant of popularity, thyroid carcinoma is now being called noninvasive follicular thyroid new plasm with fabulously like nuclear features, which is an indolent nia plasm. And uh although it's a surgical disease, it's unlikely to produce any harm for the patient and unlikely to produce any metastasis. So what does that mean for us uh in pathology and side of pathology? Well, fortunately, uh it did not affect the benign and the malignant category, which till this day are the majority diagnostic categories that are used in sight of pathology. But it did have an impact on the indeterminant category ranging from a U. S. Flus particular neo plasm and suspicious for malignancy. And you can see here that before nifty and after an FP that where the majority of the risk of malignancy shift happened. Uh so what do we do when an audio falls into this indeterminant category? Ah As you know, uh psychology can have a wide range of spectrum and there's a lot of reasons why an ideal may fall into an indeterminate category. Uh the things that we look for are kind of the amount of colloidal follicular cells and the nuclear a tilapia. And as you can see here in the spectrum, a lot of reasons why something may fall in the mid range. And this is a this is a really nice diagram that shows why something that may fall in this uh this middle in determined category that was developed by dr Zuber evolution, my mentor and as you can see here, it could be due to the amount of colloids. It can be less collide, it could be due to the popularity of the region. Or it could be because of some 80 P A. That is in the follicular cells but not enough to push it all the way to malignant. Uh It also may be due to the fact that cytology alone cannot tell uh follicular adenoma from follicular carcinoma. Because as you remember, follicular carcinoma is a diagnosis that is based on architecture and it needs in Beijing into the capsule or in Beijing through vessels. And we don't have that architecture in psychology. So let's say that something falls into an indeterminant category. And a decision was made to pursue molecular testing. The main advantage of molecular testing is to try and decide for those indeterminant because the categories and try to determine whether a nodule is benign or has a low probability of malignancy and a high probability of malignancy or an indeterminant probability of malignancy. Now there are a lot of molecular tests out there in the market but the most common are the thoracic virgin three. Uh The afirma gene sequencing classifier and the thigh jean next and time era which is kind of uh 22 hybrid tests with kind of A two step based test as you can see here. The advantage of these molecular testing mainly falls into the really high negative predictive value. So these are really good rule out tests. So when when something comes back as negative uh the uh the clinician as well as the patient can be reassured that the probability of malignancy is really low. Uh as these uh molecular tests are also kind of advancing uh they are getting better and better in identifying the higher risk for a probability of malignancy, especially if driver mutations or mutations that are defining for uh malignancy were identified. However, sometimes nodules will fall into this indeterminate um or intermediate risk of malignancy and uh but they will uh Kind of justify surgery because the risk of malignancy usually falls into the range of 50-70%. So here's an example of not you that uh was uh called uh Bethesda category four by F. N. A. A. Follicular nia plasm. You can see here that's quite cellular, it's forming really uh small follicles with overlapping, very monotonous population of cells. And it was called Bethesda Category four or follicular new plasm molecular testing was done on this nodule and undress and a third promoter mutation were identified. So it got excised. And when the audio got excited, you can see here that it's quite encapsulated, not deal with nuclear features of popularity, thyroid carcinoma. So it is a background of follicular variant papillary thyroid carcinoma. But because of the third promoter mutation may have more aggressive, more aggressive uh weakness here. So if you're on, if you're not on mute, can you please mute yourself? I can see some um here's some background noise. Thank you. So the third promote our mutation indicates some aggressiveness in the nodules. And uh and you can see here that there was a focus of poorly differentiated carcinoma in this uh particular variant at PTC. So that's the advantage of uh finding these uh beforehand by identifying this mutation before surgery. So that surgeons sometimes can uh determine the extent of the surgery before going in. Um Here's an example of this report uh where the probability of malignancy is shown on top with an interpretation and the findings at the bottom. And I'm happy to take any questions if there are any or at the end. Thank you. General great discussion. I want to take a minute and talk about modules with benign cytology. So, a benign cytology result, as we just saw as with an experienced pathologist is really reassuring with the risk of cancer under 3%. So how do we follow novels that have been biopsied and decide what to do and make sure we're not in one of those circumstances where we've missed a cancer Um has Jill showed us there are certain ultrasound features that are very suspicious for cancer. These are our tr five na jules and the american thyroid Association guidelines recommend that if you have a nodule that really has imaging features highly suggestive of a cancer that you actually repeat the biopsy within 6 to 12 months of the original F. N. A. To make sure that you're not missing a malignancy. Um For other na jules. However, it used to be that if the nodule grew and this is one of the questions in the chat. We would think about um repeating a biopsy. And the problem with this approach is that benign nodule absolutely grow as do malignant modules. Um And studies have shown over time that nodule growth is really not an appropriate discriminator to decide when to re biopsy and nodule. So if the nodule has a low ultrasound appearance or tr two tr three, um Typically we wouldn't do further ultrasound exams And what we're doing with tr four nodules if they grow is thinking about repeating a biopsy and then certainly any nodule that's being followed that develops an additional suspicious ultrasound features? Would be a reason to repeat an Fn. A. Those would be things like irregular borders. Grace, I'm going to turn this back over to Rachel to feel any additional questions from the audience? I know a lot of them have been answered through the chat feature. Um But you can go ahead and let us know other questions. Yes. So I think a great job on fielding the question about nodule growth that was a big one. And then did you comment explicitly on what is the risk of malignancy and a thyroid nodule when there's a suppressed TSH. Um And then Joel perhaps you can just comment a little bit about differentiating between papillary and follicular carcinoma and what we can tell from a biopsy on cytology regarding the presence or absence of follicular carcinoma. Great matt. Do you want to feel the question of low TSH? Sure I can. Yeah. So I can address that. You know, it's very low if the TSH is suppressed and it's truly a hot nodule. Now, sometimes on the the it's a little bit of a judgment call on the uptake in scan and if it's not it's not absolutely a hot nodule. Get a little bit concerned. I will say. I mean it's not zero though. So there is. And so there's a Tr five. My personal I usually biopsy tr five even you have hot nodule chris O'donnell, that's your approach as well. But I think functional modules are very rarely malignant but you can't have functional thyroid cancers. And so if a nodule as math is really highly suspicious on ultrasound. It's still important that it's biopsied. And that's definitely a conversation that needs to happen with the site, a pathologist. So they're aware that this may be a functional nodule july. I don't know if you have anything else to add. Sure. So uh regarding functional nodules uh as matt mentioned initially in the in the talk a lot of times. Those would fall into an indeterminant category when definite it's the reason for that is because a lot of them have this papillary hyperplasia. And they have they can tend to be really cellular. And sometimes because these cells are really active. They can display some nuclear a tip here. So that's kind of why uh the pathologist discourage and uh also clinicians discouraged deafening these not tools. Um going back to the question of identifying papillary carcinoma versus follicular carcinoma. That's a great question. Uh Psychology is really great and identifying papillary thyroid carcinoma. And the reason for that is because papillary thyroid carcinoma carcinoma that is defined by the nuclear uh features which we can really identify by psychology. However follicular carcinoma is mainly defined by in Beijing. And because we do not have that architecture when we do fine needle aspirations, we can tell that it's a new plasm but we cannot tell if it's an adenoma versus carcinoma. Another one uh that we can identify by cytology is medullary thyroid carcinoma. A lot of times those will display specific nuclear features which we call salt and pepper, chromatic neuroendocrine type chrome a team. And the cells will also look different. Um But fortunately most of the times what we're dealing with is papillary thyroid carcinoma, which psychology is really good in identifying. That's also very helpful. And we actually have another question that I think would be good to discuss publicly. What are the recommendations for na jewels that are less than a centimeter with highly suspicious characteristics on ultrasound that's for me. So uh Tyrod follow up kicks in at 0.5 cm for tirades five. Remember this is in the absence of overt features of malignancy. So this is in the absence of um capsule er invasion linkedin apathy and and in low risk patients. Um In our practice we do put into the report um all Tyrod five na jules regardless of size. And um I personally dictate that tyrants does not recommend follow up um but it is not unreasonable to obtain a follow up in particular. I would add this to a younger patient. A male patient in that say an 85 year old patient with significant comorbidities. I would probably just leave it as it is a little bit of adding uh you know A. T. A. And you know, comorbidities in versus an incidental finding there is actually a fairly high background of small papillary thyroid carcinomas in july you can speak to this but if you were to look with very careful Surgical pathology, you can find these micro carcinomas in as many as 30% of patients having thyroid surgery for other causes. So we don't wanna sort of over diagnosed and over treated by dipping into a to a bucket of incidentally nonaggressive papillary thyroid carcinomas um against the background in that a very small minority of these do have the potential to be biologically active and significant in that particular patient's lifetime. I think the other key here is to remember that these small thyroid cancers are typically very indolent lesions and we have good data to support active surveillance for those and I think it's often just a matter of shared decision making and getting the patient to understand that this is not putting them at any risk provided they follow up. So this is one of those cases. We're probably seeing someone in endocrinology is definitely necessary if they have a suspicious nodule that's really small. And kristen I just want to echo that because I think it's important to recall that active surveillance is not do nothing. Um, I think there's a lot of confusion in the patient. We're all done. So framing it to the patient that we're going to do active surveillance and you're going to see a specialist for this problem is often I think very relieving to them because they don't feel like they're doing nothing. Yeah, that's great. Um I think in the interest of time, I'm going to turn it back over to Jeff to see. There are other questions that would be helpful to you following these patients in primary care. Um, what else can we tell you today? Well, certainly mindful of what's been said about the risks of over treatment and the importance of counseling patients about observation being um, definitely part of the treatment plan and not quote unquote doing nothing. Um this is sort of an answer, but I just love to have matt outlined clearly the criteria for referral to surgery when when do um, those of us in primary care or you folks in endocrine point people towards Rachel or other surgeons. Yeah. Thanks Jeff. Um, well, I think um, certainly obvious malignancy needs to go to surgery as provided. It's greater than, you know, the one centimeter that was just discussed about. And then I think the indeterminate cytology ones, especially if they have a non reassuring molecular test. Um, you know, oftentimes, well, we will send those uh, as well. Again, um, uh, just emphasize that has, you have to have this conversation with the patient. Right. And so, you know, uh, and as we talked about some patients just, you know, do not like any ambiguity. And so you have to work through that a lot. But again, indeterminant modules where the molecular test is non reassuring. I'll usually send their uh, certainly, you know, outside of the cancer world, we have obstructive symptoms of compression symptoms, which we haven't really talked about. A lot of people with large nodule that's pressing on their trachea, pressing on the esophagus. Now, that can be a little bit tricky because a lot of people say, hey, I feel something in my throat that's not compression symptoms so that you have to be pretty specific what you mean by compressive because, you know, people will commonly mention that. Um, and you know, those are really the things, you know, I guess uhh people sometimes say, hey, this thing is really, really bothering me as though it's cosmetically disfiguring or something like that. Yeah, I mean that's also an individual conversation with the patient. I again I'm I'm usually trying to discourage people from doing doing surgery though. So we have two other questions that were submitted in advance. I'm just going to bring those up. Um So one was just pen have R. F. A. R. Ethanol ablation for thyroid nodule is and so um the current answer is not currently um ultrasound guided ethanol ablation or radio frequency ablation or techniques that we can use to reduce the volume of psychologically benign large cystic modules that cause patients symptoms. Um And there are specialized centers that perform these in the main side effect that can occur is some pain. Another question that I want to raise before we finish here today um is for Jill and this is a scenario that's become increasingly common is what to do about F. D. G. Uptake in the thyroid nodule and pet performed for an unrelated diagnosis. I know we've talked about this a little bit but you can you just tell us what your approach is to these modules. Yeah. So um so generally speaking, if you have focal update, which happens in about 1-4% of all pet scans, the risk of cancer as a group in those modules is somewhere between 25 and 35%. That risk actually can be stratified by ultrasound appearance. That is that many of these modules look like a tire it's five or or a PTC and certainly as you would imagine, the vast majority of those turn out to be a fiery cancer. There are pet positive modules which have a very innocuous ultrasound appearance and the risk of cancer in those is quite low. So the very first step is to figure out the comorbidities as we heard before. It would not make sense to do an aggressive work up of a nodule without invasion or lymphoid and apathy. And a patient who's in the midst of dealing with uh you know, an aggressive malignancy. And unfortunately, we do get a fairer number of patients that are referred for thyroid F. N. A. When they're immuno suppressed or something like that. You know, they're sent to the hospital probably more risky to send them to the hospital for the F in a that they would become ill than it is to just wait until they have recovered from their primary malignancy. You want to be careful what we see a lot of patients where there is diffuse thyroid uptake and this can be related to a diffuse thyroid process. Um and particularly in patients who are having immunotherapy, we now see a lot of uh thyroid disease related to immunotherapy which can cause diffuse uptake as well as other things. For example, hashimoto's thyroid itis with which matt mentioned before. So diffuse uptake is an entirely different category. So it's a very individualized approach. And my advice is to wait and let the patient recover if they're being in the middle of a pet scan for a advanced malignancy because even if it is to be a PTC, it's, it's not going to be their primary health concern. Great. Thank you. Um, I don't see any more questions in the chat and we're heading towards the top of the hour. So I think that will conclude our webinar for this morning. Um, I relate to appreciate all of my colleagues for joining me today. Thank you to the Abra Abraham Abramson Cancer Center staff for organization and especially thanks to everyone who joined us today. We hope that this was beneficial and that you learned something new and we appreciate your time. Thank you.