This 1-hour live panel discussion covers evidence-based Thyroid Nodule Management Pathway. The panelists, a cross-disciplinary team from across Penn Medicine, will help address critical decision-making points along this patient-centered pathway for the Primary Care Provider. If you’ve ever asked yourself when is the right time to consult with an endocrinologist, we hope that you will participate.
This activity will provide immediate key takeaways to your clinical practice, answering questions such as:
• What is an FNA, how do I educate my patient and who performs it?
• When to refer to a surgeon?
• What does follow-up care look like—including physical exams and imaging?
See Physicians' Profiles:
Kristen Noelle Kobaly, MD profile , Zubair W. Baloch, MD, PhD profile , Patrick Sayre, MD , Jill E. Langer, MD profile , Jessica S. Berman, MD profile , Karthik Rajasekaran, MD, FACS profile Good morning, everyone. I'm gonna go ahead and get started. Um Welcome to the CMI approved webinar by the Endocrine Disease team at the Abraham Cancer Center at Penn Medicine. Today, we're going to focus on the evaluation and management of the commonly encountered thyroid nodule. My name is Kristen Cobolli and I'm an associate professor of endocrinology at Perlman. I'm joined today by five colleagues. Um First Dr Jessica Berman is also an endocrinologist at the Perlman Center and an assistant professor of medicine. Our radiology colleague this morning is Dr Joe Langer is the sex section chief of ultrasound imaging. And Jill was one of the authors on the group that developed the American College of Radiology is Tyrod system for classifying the ultrasound pattern of thyroid nodules, which you'll hear about today. Let me just put this up here. Um Dr Zuber Galoshes, a professor of pathology and laboratory medicine who also joins us and he's one of the authors of the Bethesda system for reporting thyroid psychopathology representing surgery. Today is Dr Karthik Roger Saccharin, an E N T surgeon who's focusing on head and neck oncology, also microvascular reconstructive surgery and an assistant professor at Pennsylvania Hospital. And lastly, we're joined by Dr Patrick Sehr from the division of Internal Medicine Doctor, shares an assistant professor of Internal medicine and also an associate program director for the Internal Medicine Residency program at hub. Our partnership today illustrates the multidisciplinary collaboration that's required for patient care in this area and evaluating thyroid nodules. Our goal this morning is to review an approach to thyroid nodules, both patient centered and evidence based And I'm gonna walk you through our learning objectives for the program. So first we plan to apply evidence based evaluation for patients with thyroid nodules. We're gonna illustrate the association of Sana graphic imaging with cancer risk and its application to FDA decision making. And third, we plan to describe the Bethesda system classification for reporting thyroid nodule FN results and the indications for molecular testing. And this slide just shows are relevant financial disclosures for the presentation. This webinar is live and it will be conducted as a panel discussion. If at any time during the webinar, you have questions, please submit them using the Q A um and send them to all participants will be trying to answer these as we go and will also allow to um breaks between this section for about five minutes each to answer questions. Um The session today is being recorded and link future listening will also provide a PDF of key slides and instructions for obtaining credits will be forthcoming in an email um within a week of this meeting. All right. So that we have the logistics over. Let's go ahead and get started. Um I'm gonna start with Patrick so often thyroid nodules are discovered as incidental findings on imaging ordered for um you know, unrelated purposes such as a ct of the chest, er and ex C T and occasionally these can also be found on physical exam as a primary care doctor. Can you just talk us through some of the most important questions that arise when you're working up a patient with a thyroid nodule? Yeah, thanks Kristen. So I mean, as you point out, thyroid nodules are so often incidentally discovered. And so it is rare that I've asked the patient any questions related to that or done any evaluation of the thyroid? Um And so the questions that most often arise for me are, you know, one, what other questions I need to ask the patient if any in order to make advancement decision, you know, to like what laboratory testing is needed to work up a non dual. Um Maybe what the most important imaging is to order. And you know, once I do have all of that data, how do I decide when a biopsy is needed and what I need to refer patients to endocrinology? They're great questions. Um we do have an algorithm that's developed that shows our evidence-based practice pathway. We develop this in 2020 to help with the management of thyroid nodules, Jessica, would you be able to walk us through these questions and this algorithm at a high level? Sure, thanks Kristin. Hi, everyone. Um so as you, many of you probably know firsthand thyroid nodules are exceedingly common. So we get a lot of these consults. Um And similarly, just like Patrick said, the first kind of branch point um when I see a patient um is looking at the ultrasound, of course, but then also getting a TSH and looking at what TSH is. Um So we whatever you do find a thyroid nodule um over sound, which really is the best modality to fully image the nodule and risk stratify, which we'll get into later. But the next important step is to get a TSH to decide what our next steps and work up will be so low TSH. Um And on the algorithm, you can see we define that is less than or equal to 0.3 um requires a little more work up because it could be that the nodule is functioning. Um So the first thing to do is we get a TSH, if it is low, we do a functional scan. So a radioactive iodine uptake in scan or technetium scan. Um and then if it's not low and the TSS is normal, um we decide kind of what our next step is based on the patient's history. So there are a few things to keep in mind that put somebody at a higher risk of thyroid cancer. Um generally, that includes radiation to the head or neck before the age of 18. This is generally childhood cancer survivors. Um Also, they have a strong family history of thyroid cancer. Generally defined as more than three or more first degree relatives with thyroid cancer or if they have a genetic syndrome that has a known predisposition to developing thyroid cancer. So, that includes familial adenoma, this polyp Asus P 10 hematoma syndrome um and the end syndrome. Um and, and so based on that, if they have a high risk, then you probably should be referring those types of patients here to endocrine and we can handle um which of those patients need biopsy, but if they don't have a risk factor, um then using the tie rods criteria, which will go into those, you decide which patients require biopsy. Thank you. Um So I'm gonna turn it over to Jill. Now who's gonna walk us through the most commonly used risk stratification systems for thyroid nodule imaging and she'll share some representative ultrasound images as well. Um And Jill will also hopefully comment on the importance of the lateral lymph node assessment of cervical lymph nodes for our audience. So we'll turn it over to you. Thanks Kristen and good morning, everyone. Okay. Hopefully, everyone can see my slides just fine. Um Certainly someone will let me know if not. So a little bit of a sneak peek of the radiologist approach to assessing cancer risk based on the ultrasound appearance of thyroid nodules. As we've heard already, authority nodules are just so incredibly common and imaging is so sensitive that it turns out that the majority of patients will have thyroid nodules when we look with ultrasound. And now C T and M R I are getting so good, we're going to see them with those modalities as well. Fortunately, the overwhelming majority of thyroid modules are just benign hyper plastic regions of the thyroid or benign tumors, benign adenomas. And they are turning up most commonly as Patrick said in asymptomatic patients. And therefore, we think of these as incidental meaning there were no risk factors, no clinical symptoms. And so we know from several different avenues of medicine that you the care providers do want to know from us. The radiologist, a recommendation about what to do when these nodules turn up. We also know that ultrasound is far and away the best imaging test to determine if there is concern from malignancy. We'll take a look at some examples, but you'll be able to hopefully appreciate that ultrasound can do a very nice job and separating nodules from those that look suspicious for malignancy from the much more common benign appearing nodule. In some instances, we really can't separate because there's an overlap between benign adenomas and some types of thyroid cancers. One thing that I want to bring to your attention is that you may have noticed that on some CT reports. For example, they'll mention that there are small thyroid nodules, there's a size cut off that we don't need to work up every single teeny tiny nodule that's uncovered. Um As long as there's no risk and no additional associated findings. So sometimes but very rarely, there are very obvious features of malignancy. These would be local invasion into the soft tissues around the thyroid or the presence of lymphatic apathy that is suspicious for thyroid cancer. Lymph nodes may have cystic change, calcifications and so forth. These would be changes that we would see indicative of metastatic thyroid cancer. So here's just an example of an ultrasound. We're looking at the right lobe of the thyroid, we can see there's a nodule outlined there with the red arrow. And when we look just on the other side of the carotid artery, we are identifying an abnormal metastatic lymph node. So right away, we know that we have a high likelihood that there's thyroid cancer. We would go ahead and biopsy both the novel and the lymph node because that would help manage the patient and every neck ultrasound should really look at lateral cervical lymph nodes because as you see in this case, very important to make the diagnosis and provide all the information necessary to take care of the patient with thyroid cancer. Now, the minority of patients are going to present with those obvious features of thyroid cancer. So instead we're gonna have to take a deeper dive into what the nodule looks like. An ultrasound far and away, gives us the best sense of all of the features that we need to evaluate to see if we are concerned for malignancy. We're gonna look at a few of these, but basically, they consist of all solid consistency, the brightness or darkness of the nodule, how dark it is or how high pollock OIC subtle features having to do with the margins. Are they aggressive such as infiltrating or lobby elated? Is there a taller than wide shape that's growing against the grain of the thyroid and some types of calcifications including large coarse ones and true micro calcifications. Here's an example of a nodule that is solid hyperbolic OIC taller than wide. And so already we be suspicious. But for the eagle eyes in the audience out there, we can see that this nodule is actually breaking through the capsule and extending into the local tissue. Only. Ultrasound gives us this type of spatial resolution to pick up this feature, which is very important. Again, some examples of ultrasound looking at the margins of the nodules, these aggressive speculated and jagged borders are very suspicious for cancer and ultrasound will determine them on the bottom left. You can see it and a plastic cancer which is grossly invasive. But again, that's the minority of nodules. Again, we can see borders such as micro or macro lobular borders and notice how all of these modules that I've shown you are solid and hyperbolic OIC. So there are definitely combination of features that go together, also increasing the risk that they're sorry cancer. Rather than just a single feature, we have different types of calcifications that may make us concerned very large central and dystrophy calcifications, sometimes called coarse calcifications or if we have a nodule that not only has peripheral calcifications but has a soft tissue x crescents poking out of it that, that orange arrows showing you. Sometimes we have non specific calcifications such as thin regular eggshell calcification. And also it's very common for benign nodules to have some linear central calcifications due to fibrosis within those particular nah jewels. Now is something called micro calcifications, which is really a pathologic observation under the microscope. These are seen in about 40% of thyroid cancers and we'll hear more about the pathology when they're present on ultrasound. They appear as teeny tiny bright dots most concerning if they occur in solid and hypothetical models. But we want to be careful because there's many other reasons to have bright dots and thyroid nodules. We don't want to call every single one of them a micro calcification At the opposite end of the spectrum. And very commonly we have nodules which you can say right off the bat. We're not concerned about these guys if they're entirely cystic where they have what we call a spongiform appearance, like a sponge that means an aggregation of multiple micro cystic components running through the nodule. Nothing else that flags our attention. So this has a less than 2% risk of cancer. But in many series, really, none of the nodules that had this classic sponge of form appearance were malignant. So our smiley spongebob is a good sign here that we don't have to worry about this most common type of thyroid nodule. Now, something that I sort of alluded to before it can happen is that someone could look at these very innocuous sponge of form nodules and worry about these bright dots. Are they the same things as micro calcifications that we saw in that cancer a moment ago. The answer is no, there's a lot of things that cause bright dots and thyroid nodules and in a sponge of form nodule, it can just be reflection from the little cystic areas or colle oid. We call these academic fosse previously, every dot was called the micro calcification. But now, radiologists are gradually getting better at realizing there are subtle differences. But as in everything in medicine, this is a subtlety and this is a tricky part of ultrasound interpretation. So, really landmark work was done to show there are a variety of academic fosse within nodules. The vast majorities of these are benign and even that punk kind that we worried about before we really only need to worry about them in some nodules, those that are solid and hyperbolic OIC rather than all modules, many nodules are mixed cystic and solid. And as we've already learned, most cancers are solid. So we have a mixed cystic and solid nodule. It's usually benign. But some cancers can have that appearance. Usually we can pick them out of the crowd by other features of the solid component. Solid component may be very front, like have calcifications, have a lot of vascular charity. And as I mentioned before, sometimes we just can't tell there's an overlap between some subtypes of cancers, those with follicular histology, with their benign follicular adenoma counterparts. These appear very similar as solid and bright or dark OIC or hyper cohen naturals. Okay. So after that big introduction, we're ready to tackle tirades. Many of you are familiar with by rods, the system that's been in place for decades to help breast imagers sort of characterize breast breast lesions and come up with a likelihood of malignancy Tyrod stands for the thyroid imaging reporting and data system. So the philosophy when the group met was no nodule left behind, we wanted to give radiologists a good way to describe incidental nodules with very defined terms of glossary or lexicon of terms. And to be able to classify all nodules and to do the we needed to come up with a point system to handle some features which otherwise could not be described as we saw in the algorithm with Jessica. This is tie rods in its full glory, but we're going to take a deeper dive into some of the elements. So you can appreciate what we're doing. The first thing we're gonna do is to go through those five categories that we discussed a moment ago and award points based on the features, the points run from 0 to 3 which within each category. So just some examples for, for composition, you can see cystic zero points all the way up to solid or almost entirely solid as three points. The Eco Judas City is scored from Anna Cohen, which is really no solid component all the way up to very hypoxic OIC which is three points, the shape if it's taller than wider, not taller than wide. And the margin again, ultrasound really excels and identifying some of these subtle margin features with a suspicion of extra thyroid extension having three points, academic fosse again, the preferred term and calcifications are scored in this category, we score all that we say um with again, punk psychogenic Fozzie receiving the most points at three points. So this is really a deal breaker. You have to be really sure that these are the concerning type of punk psychogenic fosse. And far in a way, that's the most common discussion we have in the reading room. Is it the real deal or not? Once we have all of these things assessed, we summer points and that gives us a so called tirades level of suspicion which runs from 1-5. Based on that level on the size of the nodule were able to come up with a recommendation from no further imaging at all required to follow up ultrasound at a prescribed time which we'll discuss in a moment or that nodule meets the criteria for biopsy. Now, how do we come up with these different levels of risk? This was our multi institutional validation study and you can see what we did is we took almost 3400 nodules, applied the points and came up with these natural breaks in the risk category. So tie rods, one is 0.3% risk of cancer and tie rods to is 1.5%. So these are essentially your leave alone lesions in low risk adults, tirades three which is mildly suspicious about a 5% risk tirades, four, moderately about a 10% risk and tie rods five overall, one third of the nodules are risk with the risk becoming higher and higher as the point total goes up. So here's our recommendations for those tirades. One and two nodules, nothing further is recommended in your lowest patients for the other nodules. If they don't quite meet the size criteria for follow up, we don't recommend any follow up if they are under the biopsy threshold, but meet the size criteria for follow up. We recommend follow up at prescribed intervals and we'll put these in the reports for you. The one thing I want to draw your attention to is that for tirades, five are highly suspicious nodules that are under a centimeter. We have a slight modification and that is we feel like these patients should have an endocrine console because the management of these are very idiosyncratic depending on where the nodule is the age of the patient and so forth. One of the strong features about tire ads. It's really one of the few systems that has a fine eight follow up period. If the nodule has followed for five years and it doesn't grow and it doesn't develop any new features, we no longer recommend follow up and we can retrospectively applied it. That is if you're patient had an ultrasound in 2016 and they walk into ultrasound today, we'll turn back the hands of time and say, gee look, this nodule has been already followed for five years. It's okay. It hasn't done anything bad. We're off the hook. The concern was gee this is fairly liberal, not recommending all of those biopsies. Are we missing malignancy? And the answer is fortunately not if you consider recommending a follow up ultrasound or a biopsy. And you compare tirades with the other two major systems out there. The American Thyroid Association and the Korean Radiology Association, actually, we have the benefit of capturing as many cancers by follow up or biopsy. But with far fewer biopsies. Now, when don't we use the tie rods, we heard high risk patients fall into a different group and these are generally managed by um by our endocrine colleagues. Pet positive non jewels have a higher than baseline incidence of cancer. And those are a special category as we heard before, if it's a functioning nodule. But the thing that draws us some confusion sometimes is a nodule that's already been biopsy. We really shouldn't apply. Tirades. Tirades is a system used to determine if we should do a biopsy. Once we have the biopsy result in hand, we do need to think about what the nodule looks like in order to manage it moving further, but we manage it in concert with the cytology result. Here, we use the American Thyroid Association criteria to figure out what to do. This chart is very similar to what we discussed. The 2015 American Thyroid Sina graphic pattern is all that we've already learned. We have our high suspicion features, intermediate, intermediate, intermediate, excuse me, suspicion, low suspicion and very low and benign appearing if it's entirely cystic. And here, if we have a nodule that has that very low suspicion feature, the likelihood that we have a false negative biopsy is so low. In combination with that ultrasound appearance, there's no proven utility and following those nodules. But for the nodules that don't have that appearance, there's a small chance we have a false negative result and we'll follow those patients generally at 1-2 year intervals. If we have a really suspicious nodule and we have a negative result. It may be a reason to repeat the biopsy. We have learned that ultrasound is a better way to tree as nodules in terms of suspicious and non suspicious than growth because benign nodules grow and she's just growing a little bit is not particularly helpful, particularly in cystic nodules, which sometimes in large, just due to the fluid content. And let me just end here with a hashtag not nodules, not everything that we see on an ultrasound is a quote unquote nodule. I'm sure you all have tons of patients that have hashimoto's thyroid itis. And instead of looking at every little spot on the draft back, we try to take a step back and look at these patients that have all of these hippo Coca patchy areas and resist the urge to call them nah jewels quite a different scenario. So hopefully, that was a little bit insight into what the radiologist is looking at when we, when we are analyzing and the mystery behind tire. It's Thank you, Jill. That was great. Um Before we move on to discuss cytology outcomes for biopsy nodules, I'll turn it over to Dr Kells to from endocrine surgery who's moderating the Q and A. Um I don't know if there's any questions actually, but if you can review anything that has been submitted so far, our team can try to help out and answer these. Thanks, Kristen. So there was a question about who does the biopsies at the University of Pennsylvania? And Dr Mandel has put the answer in the Q and A available for everybody to review. Okay, great. Um I think of that in that case, we will hold further questions till the end and please keep them coming, fill those out from the Q and A. We're happy to um answer anything that comes up. Let's summarize where we're at so far then. So we now can understand how imaging is correlated with cancer risk. Um And this has led to several professional societies including the American College of Radiology and the American Thyroid Association recommending um FN a size cutoffs based upon the risk of the imaging. So there is some variability is still mentioned in the middle risk categories that does allow for patient centered decision making. So for example, if I have a young patient who has some personal risk factors for malignancy, I'm gonna be may be more inclined to biopsy those than someone who's elderly. Um and has comorbidities or maybe will be more likely to just keep an eye on, on these nachos with ultrasound, particularly if the risk isn't high. Um Before we move on to interpreting the thyroid biopsy results, though Patrick, did that answer your question? Is there anything else that you think would be beneficial as an internist um to hear about when caring for these patients? Thanks, Kristen, know that. Definitely answer the first part of my question. Thank you. I think that one thing that would be helpful also for us to know, you know, I have definitely found that my patients are sometimes a little nervous or one more information about what to expect with an F and A. Um And I'm wondering, could you share a little bit about what the procedure entails is, whether any particular risks or contraindications we should talk about with the patient. That's a great question. Um Karthik, would you mind walking us through your experience performing FNS? Absolutely. Thank you, Kristen. Um So yeah, I tell all patients just come in, make sure you've actually eaten a good breakfast or lunch. Um It's just contrary to what people think because most people think you have a fast before any procedure. But I find that eating is good because sometimes patients see a needle and then they get lightheaded. Um What happens if you come in with street clothes, you sit in the chair, we first start off with using an ultrasound, take a look at where the nodule is. Um And um then I personally numb the neck up with lidocaine. Um so they feel a pinch and a burn, let that sit for a few minutes. And then we start the procedure. The procedure consists of, I use four needles. Some people use two needles. The needle is 27 gauge. So that's about half the size of what we use for an IV um Or some people even use a 29 gauge. Um and then you make about each needle has about 5-7 or 10 passes. So the whole procedure lasts maybe two minutes in terms of anti coagulation or anything like that. I tell patients they can stay on aspirin, Plavix, Coumadin or any of the drugs that doesn't really bother me. Um I would just say that they, you know, whoever does the procedure, they may have slight variances in their practice pattern, but most of us are pretty comfortable doing it without with the patient being on anti coagulation. And I know this also came up in the chat, but in general, from who does these procedures? Um in general. Yeah. So surgeons, radiologists, endocrinologists and in some places even cite a pathologist to do the procedure. Great. And I'll just add that. I think um anesthesia is pretty variable. Some of us don't use any anesthesia um a lot of the time. Um and I know hop radiology at least. And um myself and our endocrine practice, she's just a topical numbing spray sometimes as well. So um once the needles in the thyroid retail patients, there's no nerve endings, they usually feel a sense of pressure. So the issue is getting that needle through the skin. Um Is that hopeful Patrick? Yeah, definitely. Yeah. Thanks so much. So, I think some to summarize many physicians can perform a biopsy. It really depends on where you practice the pathway to the FAA will vary. Um There's really two major keys to success. So one I think is personal knowledge and skill and ultrasound interpretation where to sort of lineup, the lineup for the procedure, knowing what to biopsy and then access to high quality psychopathology. And at our institution, we have the site, a pathologist on site to actually look at the specimen and help guide as we're going with making sure we have enough material. Unfortunately, after the biopsies performed, the results aren't as straightforward as simply having an answer that's either benign or malignant. Um and about 30% of results are actually going to be classified as indeterminant. So I'm gonna turn it over to the bear to walk us through the different cytology outcomes and additional testing that are available um and further evaluating these nodules. Thank you Christian. Um Do you see my screen? Yes. Okay. Um So thank you for inviting me and give you a perspective from the colleges point of view. And um as we know that the tired fns are classified or read by side a pathologist and diagnosed on a tiered classification scheme. And the most common one that is utilized in the United States is the protest a classification scheme. It has gone to, it's two editions already. It initially was introduced in 2007. And now it's um actually the second one was 2,017 and we just finished the proofs on the third version of it because the things are so fast changing in para pathology. So this is the way I look at. Um definitely this stock is not going to make you the expert side a pathologist. But what we look at as you can see here, um the amount of colle oid that is the product that is produced by follicular cells um based upon the cells that we see in the nuclear 80 ps. And based on this, we have developed paradigms um and teachings that what the benign are the most close to benign Tiger Nadia looks like based upon these features up to what looks like malignant. And as you can see here, the beautiful inter nuclear inclusions that you see in popular carcinoma, as I said, the third edition is on its way. So what I have learned and this is maybe just my opinion um that, you know, everything matters. Um and this includes everything that we have been talking about and I'm gonna kinda little bit focus on morphology, which will also include what happens when the surgery is done. And plus some of the molecular aspects of profiling these pre operatively to really assess and in some cases even decide what type of management that that nodule needs. I am not going to go through it and this will be, you know, jail is online, but this is actually my version of really looking at it and there's a lot of literature on ultrasound and radiology. And um as Jill pointed out, we use tirades and the American Tired Association. But as a side of 1000 some sometimes that can make things confusing. But I basically use these cartoon type stuff to really realize when Christian or Dr Mandel or Dr Langer are talking about on site what the na do looks like. Now, this was the 2017 version. And I think this is not just a diagnostic categories. To me, this is really a big step up and classifying carter nodules on a tiered classification scheme. And this really presented the practice of psychology. So it's not everything is black and white, benign and malignant. Even some clinicians want the pathologist to give that diagnosis, but there's a whole group in the middle which you can see here, which is indeterminate. We cannot tell this is benign. In most cases, we can say this is a typical or this is definitely a neo plasm, but we cannot say this is a benign like an adenoma carcinoma. And definitely the most common malignancy with being diagnosed based on nuclear speeches of a cell is tap Larry thyroid carcinoma, which is the most common tumor that you see in thyroid. And now this is my version of just putting it all together. And this is what Jill talked about. The benign nodule has that spongiform appearance. And I just want to quickly just point out that that spongiform appearance on histology really relates to these macro follicles, which are these larger follicles filled with Colin Lloyd. And based upon this, the cytology shows those benign features as compared to something which is chronic lymphocytic parad itis. And I have been in instances where it has been read as very atypical features, but you can see the amount of the cells and the lymphocytes and the vascular charity gives rise to this really vascular or heterogeneous appearance. And based upon seeing lymphocytes and some of the cells aside, a pathologist at least can guide and say this looks benign and they favor a chronic lymphocytic parad itis similarly popular thyroid carcinoma. It's a slam dunk because most of the time the radiologist reads it as basically it looks very high suspicion, auto malignant audio and showed these beautiful cinema bodies which give rise to these academic foresight. This is the most common tumor of the thyroid. And looking at the psychology of these inter nuclear inclusions and inter nuclear groups, we can really say that this looks like a popular thyroid carcinoma and majority of the cases. Now, these are the inter indeterminate nodules. Even on radiology, they sit in that middle groupings and these can be add enormous or carcinomas. We do see a very monotonous population of follicular cells and this kind of triggers to whether this is an atypical aspect, definitely not benign and definitely not malignant in most of the cases. And here are what I just want to point it out. And I learned from this chill that this is really distinct nodules that show up on ultrasound. And this is an adenoma. You can see that it's really from the surrounding thyroid. It has a beautiful capsule and that gives rise to its being distinct nodule which has a halo around it. And now when we look at the and this, I have learned a little bit more being on site and naturally talking to my colleagues in this multidisciplinary teams. And this isn't actually an arc ascetic nodule, which used to be called as heartful cell in the past. And these tumors can appear different on ultrasound and looking at that population of an ascetic cells, we can say this is an empathetic neo plasm or on Pacifica lesion and put it in the atypical category again, cannot definitely say this is a carcinoma versus benign. Now, what is happening after 2017 when the classification was on its second edition, what we really learned that when we look at the malignant neo plasm of the thyroid, even the molecular profiling is not so clear cut. Definitely, you have your popular thyroid carcinomas will show the most common mutation will be the better half the 600 E mutation. Then you have these follicular pattern tumors. And there was a big overlap between the benign audience that we call adenomas, minimally invasive carcinomas and high risk carcinomas So there was a lot of overlap and most of these are rest uh tumors, they have rest uncle gene mutations. So we begin to call these as rest like tumors and then be rough like tumors which are popularly thyroid carcinoma. As you go down this uh this stream, you can see that the poorly differentiated and a plastic and what I want you to just get from this, that there is a layering of these molecular events that happened which cause aggressive tumors. So taking this, there are molecular tests that can help FN a specimen For the triage these tumors. And this is my kind of version of taking the clinical data looking at the risk of recurrence, which is the 80 classification it really fits in with what we see on histology. So you have really low risk neo plasm, which includes the follicular pattern, intermediate risk and then high risk which will include the poorly differentiated on high grade follicular carcinomas or even in a plastic carcinomas. Now, when we're looking at the molecular task, I'm kind of a person who really breaks down everything and I hope it kind of makes sense. So when we talk about gene expression profiling is the measurement of the activity that we're looking at the thousands of genes at once and it creates a global picture of cellular function. Now, you will see the term as copy number alterations, which are actually somatic changes within the tumor, not in the genome. And that results changes in the chromosome structures that can be either gain or loss of copies of D N A. And then mutations are specific genetic events which happens into the gene. I'm kind of my favorite is single nucleotide variations. And you will see that because I think this is the backbone of all the molecular assays that we used. And these are genetic alterations of one single base occurring specific cells. And they can manifest as the involving the same gene or even at the diff usable elements involving other genes. And these are the strong promoters and enhancers. So you will see this. So when you take this data that we talked about the terminologies, I'm just listing the three tests which are commonly used. And I'm naturally not a proponent of one or another. At this point, you can see basically all of them use. Then you take the SNB or single nucleotide variations, they're really looking at different aspects and they basically do the same thing and they have the same sensitivity and the specificity, the one test does use micro colonies which I think are helpful, but you know, it has to be really understood and at a deeper level. So let's break it down the benign call rate. What is the benign call rate of A S A? And you're taking more of focusing on that enter terminate categories. As you can see the benign call rate actually is the same for these three essays that are utilized in there. And you can see that this is actually a our study that we published, which actually showed that the benign call rate for those intermittent indeterminant nodules that were called as the test of three are atypical, was much higher than the ones which were called as the test of four. So the test and psychology and radiology really work together very well. This is also further breaking it down when you look at the risk of malignancy with the suspicious pattern on radiology or risk of malignancy with the benign pattern. The benign call rate actually stays the same. There's not much of a change and in the in these essays. So all these essays, whatever you utilize are good. I think what a side of pathologist has to learn that how that works with their diagnosis and the coalition to really interpret it, how that is going to affect the management. I think this is where the multidisciplinary pattern comes. I'm just gonna show you very quick examples. This was an audible which was a dominant model. It looked suspicious pattern on ultrasound. The biopsy was done and this was called a suspicious for papillary thyroid carcinoma. And just there with me to just show you because there is these beautiful chromosome clearing and inter nuclear groups, no inclusions. And this was labeled as suspicious for papillary thyroid carcinoma and it came out to have an unrest mutations. And as you can see, this is an encapsulated thyroid nodule here which has nuclear features of carcinoma. It is follicular pattern noninvasive. So this is that new entity which is nifty, which used to be the encapsulated follicular variant in the past. Similarly, another nodule which has this follicular growth pattern was called as a test of four. When it was submitted for molecular analysis, it had unrest mutation. But again, I want to point out to you there was a layering of third promoter mutations on the top that puts it into a higher risk category. Most of the Nadia looked like noninvasive follicular pattern, tumor and has nuclear features of papery cancer. But I do want to find out to you, there was areas of necrosis and poorly differentiated transformation. So cytology, layering of molecular with those in the in the background of ultrasound features can really guide what we will be expecting. So I just want to point out that this, when we're looking at thyroid athletic classification scheme, we cannot just think of us. We really also have to think about the global terms because the patients do go back and forth and you know this. But what I want to point out that all these categories which are most likely indeterminant categories kind of have a different risks of malignancies when we compare us versus other countries or Asia, the big change that you are going to see as also clinicians and surgeons and even the radiologist is how the tire oid tumors are classified. So this is the new classification scheme from W H O which will be, which will be coming in and the later part of the year and these tumors are basically have will have different terminologies and different um audition based upon also molecular profiling. We are designing these tumors. So this is going to even affect the psychologic interpretation. Also the third version of the test that classification is going to be more simplified. We are not going to use two terms, everything will have won a term that we're gonna use. So if you will not see flush or you will not see suspicious for follicular neo plasm, we are also including the periodic population in it is going to be an updated risk of malignancies. And also we are putting in notes how to classify these A US specimens. And it's going to really imagine with the the new W H O classification scheme and different images. So this is the classification scheme that you're going to see in the third edition. Um Here are the categories, these are the refined risk of malignancy and averages and definitely newer recommendations because we have also radiologists who have written, who have been involved. This is also has changed because we now have these tumors that are recalling low risk neo plasm such as Nick P and this also are the risk of malignancy for this is going to change because now we have since 2016 more cases of next piece that we are looking at and this is again, the pediatric thyroid nodules, which will be included in this. So as I said, everything matters. Um and you know, being on site which is available in some institutions, not all of them. Um It's, it's a two way stream I learned from my radiology and clinical colleagues and then putting it together what I see on psychology. And if a molecular test is performed, I think it really correlates to what we see on excision. So this is my last slide. So the third edition of the test is coming. But I think as I said, everything matters and it's not just one factor which is more important than others. So I think that thyroid nodule management has to be personalized and it's, it's that dialogue between the clinicians that really helps us put together the best foot forward for the patient. So thank you so much. Great. Thank you for that wonderful lecture. Um I know for our next Jessica, I was gonna have you follow up and walk us through the follow up of patients who have benign cytology. I know Dr Langer talked about this a little bit, but I think it's probably worth reiterating because this is such a um sort of evolving area as far as what we do next. Yeah, sure. So, um so generally, um when we get a biopsy results from a thyroid nodule that is benign um in a high quality um with an experienced side of pathologists like we have here at Penn, we generally think that these benign results have about less than a 3% false negative rate, which is pretty good. So, um in those patients that we get a benign nodule, um you know, we obviously worry, you know what, what if this is one of those nodules that were missing at cancer? So the question is after we have the benign result, how do we kind of monitor and follow these nodules? Um And so we alluded to this earlier um in this program that we used to think that if a nodule through that most concerning for cancer, but I think it's Jill said benign nodules also grow. So we don't just use side or growth as an indicator for something kind of bad happening or if it's a missed cancer. Um So if the nodule itself, we look, we actually look back at the original ultrasound and what it looks like an ultrasound to help guide us. So if the nodule has a low risk ultrasound appearance, so with Iran's two or three, we generally don't need to follow some of those nodules. Um But on the other hand, if a nodule has a benign cytology but has a very high risk appearance, so generally tirades four or five, we do follow them. Um And, and so depending on the literature that you look at the nodules that have a higher risk appearance on ultrasound, that have a benign cytology are generally thought to have a higher false negative rate, maybe 10 to 15%. And so we, the 80 guidelines actually recommend repeating the FN A generally within 6 to 12 months in a high risk nodule in my practice. And in our practice and the endocrine division, we generally will repeat the F N A if the tr four or five nodules grow significantly or if they have a change in ultrasound characteristics, so that they become um they become, they develop a regular borders. Or if they develop classifications for some reason, we would then decide to repeat the biopsy based on those features. Great. And I would add that I, you know, if, if you do in fact, repeat a biopsy of a novel. So let's say a tr four solid in hippo cove nodule and you get benign cytology. The second time, the risk of a malignancy at that point is so low that the American Thyroid Association recommends no ongoing surveillance. So, you know, again, sometimes these patients have one nodule, sometimes there's many that we're following. So it's a little bit nuanced and when we can stop. But to benign biopsy, results of a single nodule is completely reassuring. So, um great um Patrick, so turning it back to you. Hopefully, we're helping you as an internist, manage these patients a little bit better. Are there any other questions that you think are still burning that would be helpful in um following these nodules? No, this has been really great. And actually I think that additional um info that Jessica gave about what to do about folks who have, you know, been in psychology. But concerning features was helpful. I think something that's still outstanding for me is you know, what to do. So when I should actually really be thinking about referring to a surgeon, you know, particularly thinking about some of these intermediate cytology results we heard about. And so when, when should I be thinking about referring to a surgeon? Yeah. So um there's a few different scenarios, one would be malignancy. So if the needle biopsy demonstrates a malignancy, then we would plan for lebec to me if the nodules small or low risk um really to obviate the need for thyroid hormone. Um Sometimes we offer a total thyroidectomy if it's high risk or very big nodule, usually over four centimeters. Um Another scenario is when you have an indeterminant site cytology. Um and the molecular texting is also um not conclusive in such a scenario, we would offer a lumpectomy. Um And then two other scenarios are, if you have obstructive symptoms where or compressive symptoms, where patients say that they feel like they're being choked or they lie down, they feel pressure. Um That's a scenario. And then, or if you have such a large nodule that's cosmetically displeasing. Uh And such a scenario would remove, um, either the half the thyroid or the whole, depending on how, what's actually involved You mentioned about a lumpectomy and needing legal fire oxy. Do you routinely prescribed both I rock scene for patients who are discharged from the hospital after they've had a partial thyroidectomy. That's a great question. I tell patients, um, that I do not, I tell them during their counseling that 80% of the time, Um, they will not need thyroid medication for the rest of their life. 20% of the time, even with half a load, they may need thyroid medication and their, um, either primary care physician or the endocrinologist, um, will monitor their blood work. Yeah, that's great. That's been a real paradigm shift for everyone with even the smallest of thyroid cancers used to have a total thyroidectomy. And, you know, this patients don't always love having to take a daily pill for the rest of their life and it's really beneficial. Um, some things that would predict needing thyroid hormone patrick, if we're thinking about this, like if we know they have hashimoto's T P O antibodies, their TSH is already upper limit of normal. I will counsel those patients that even with the low back to me, they might be at an increased risk of needing to take thyroid hormone. But, um, yeah, that's a really, really great point. I think that, um, these smaller surgeries have had a lot of benefit to patients. On our end, they can make them monitoring a little more trickier, but that's for a different, different topic. Um um if they do have a thyroid cancer. But um great. So I think um first of all, thank you to all of our panelists for providing such a great overview today um of the evaluation and management of thyroid nodules. I don't, I'm gonna turn it back over to Rachel though. It doesn't look at the Q and A has been terribly active. Do we have any additional questions from our audience? Kristen? I think it was a very comprehensive panel. So I don't see anything in the Q and A. It's possible people may have questions, they want to save two later and so they can certainly email um any of the panelists myself or Susan. Um And we'd be happy to get back to them a new question just popped up. Oh, it's a wonderful um congratulatory statement from one of our audience members. Alright. Well, I think we'll wrap up a little early then and give everybody a few minutes of their day. Um So that's going to conclude our webinar this morning. I want to thank my colleagues for joining me today, especially. Thank you to the Abraham Cancer Center for organizing all of this webinar and um to all of you, thank you for making time this morning to join us. And um we really appreciate your participation.