Dr. Kendal Williams (Host): Welcome everyone to the Penn Primary Care podcast. I'm your host, Dr. Kendal Williams. Thyroid nodules. So when I came out of hospitalist Medicine back to Primary Care, thyroid nodules seemed to be everywhere I was getting them on CAT scan reports. I inherited a lot of patients for whom thyroid nodule followup was appropriate and necessary. So, I was having to do that work. I was also following patients who had had thyroid cancer in the past and needed to have levels checked of thyroglobulin or TSH and so forth. And so, all of a sudden I'm managing all these thyroid nodules and I felt completely unprepared for it. So, I have been actually trying to get this podcast together for about two years. And finally, we were able to get Dr. Kristen Kobaly to come and talk to us about how we should think about thyroid nodules and thyroid cancer in general. Dr. Kobaly is an Associate Professor of Endocrinology at Penn with an expertise and a focus on thyroid disease. And Kristen, thank you so much.

Dr. Kristen Kobaly: You're so welcome. It's really a pleasure to be here tonight and I am looking forward to talking to you about one of my favorite topics, hopefully demystify things.

Host: Demystifying is going to be good, because this workup is actually a little bit confusing, and just everything about it has confusing elements, and I find it confusing, and I think I have a better handle on it now, but I still have questions. So, first off, I think we should say, just up front that thyroid nodules are really common. When I started prep for this podcast, I learned that 60% of patients have thyroid nodules. So, it's actually the fact that I felt like I was swimming in thyroid nodules was not unusual. This is a very common thing, right?

Dr. Kristen Kobaly: Absolutely. And, you know, it's something that while it's very common and the majority of thyroid nodules are going to be benign, patients have very high levels of anxiety about this topic and, when they're diagnosed, a lot of fear and concern. So, I think, in many cases, reassurance right off the bat is appropriate, and we can talk more about that.

Host: So before we get into the workup of a thyroid nodule, let's talk about the nodules themselves in terms of, you know, when should we worry that something's benign versus malignant. But also, let's talk about thyroid cancer, because that's ultimately what everybody's concerned about and what you're trying to detect early and treat. Let's just start with nodules generally. Benign nodules are pretty common, right? And of those, only a certain percentage, a smaller percentage, are going to be cancerous, right?

Dr. Kristen Kobaly: So, the majority are going to be benign, so less than 5% of nodules actually end up being thyroid cancer. We see a lot of other types of nodules that form in the thyroid. So, remember the thyroid has this proteinaceous material called colloid that's present and that can form cysts. So, those are very common. You can also have just nodules filled with colloid. And then, we'll see patients who have autoimmune thyroid diseases, so things like Hashimoto's can develop focal areas of thyroid nodules or thyroiditis and areas of inflammation. And then, about 10-15% of nodules are actually going to be true neoplasms. So, they may not be malignant, but they are tumors in the thyroid that we have to further delineate if they're benign or cancer.

Host: You'll have a lot of patients that will have, you know, we talked about multinodular goiter, which is common in older folks. But in the case of what we're talking about, we're really talking about a dominant nodule, usually that would be greater than a centimeter, I think, is the cutoff for when you need to be concerned. Is that right, Kristen?

Dr. Kristen Kobaly: Yeah, I mean, we'll talk about ultrasound features and a lot of what we worry about is more how the nodule appears than its size per se, although really small things we try not to worry about too much, because papillary thyroid cancers, which are the most common, are so indolent that we don't like to be biopsying most things that are under a centimeter. So, we usually will leave those alone. But yeah, I think, you know, in terms of nodules, patients may have one nodule, they may have multiple. It's really looking at each individual nodule's ultrasound features to decide if any look concerning for malignancy. And we've gotten really good at using ultrasound to figure out which nodules are suspicious. And so, those are the ones we typically we'll be biopsying.

Host: So, let's talk about what we're concerned about. Let's talk about thyroid cancer. The most common is papillary, which is also, I think, the more indolent form.

Dr. Kristen Kobaly: It is. So, papillary cancer is going to be 70-80% of the cancers that we find in the thyroid. These are cancers that arise in the follicular cells of the thyroid. So if you think back to med school, these are cells where thyroid hormone is formed. And this isn't really a surgical disease for the most part. So, patients who have papillary thyroid cancer generally have their thyroid removed. And there are patients who will have local regional lymph node metastases. So, we worry about the lymph nodes as well. But this is a cancer with a really excellent prognosis, has a five-year survival rate of over 98% and the majority of patients do really well. So, we think about thyroid cancer, that's going be the biggest thing we see.

The next most common are follicular and oncocytic cancers. Those are another 10-15%, and those are also formed in the follicular cells. These are tumors that have either transcapsular invasion or vascular invasion, but don't have nuclear features of papillary cancer on histology and these worry me a little more. Unlike papillaries, which tend to spread to lymph nodes in the neck, these types of cancers are more able to spread hematogenously. So, some can be really low risk, but if you see vascular invasion, those become more problematic. So, these are cancers of a little more concern and that's the majority.

Now, we see medullary thyroid cancer, that's about 2%. And those arrive in the parafollicular or C cells of the thyroid, and these can be a little bit more aggressive. They secrete calcitonin, which we can use in a tumor marker, and we think a lot about familial cancers with these. About 25% are familial. And they can be part of the multiple endocrine neoplasia type 2.

And then, we have anaplastic thyroid cancer. This is really rare, but this is our bad actor. This is not something we want to see and, you know, I've been doing biopsies over 10 years now and haven't biopsied an anaplastic thyroid cancer. These rarely are going to present as a incidental thyroid nodule, but patients will come in with, you know, rapidly growing neck mass. They may have troubles with hoarseness, trouble swallowing. These are pretty aggressive tumors that are generally managed by Oncology.

And then, very rarely, we'll see mets from other things, so lung cancer, breast cancer, renal cell carcinoma actually can metastasize, and then we have some thyroid lymphomas as well.

Host: Yeah. That was surprising to me. I haven't seen metastasis to the thyroid gland, but I guess it's a very highly vascular organ, I think.

Dr. Kristen Kobaly: Yeah. Yes.

Host: And so, it's possible like the adrenal gland is highly vascular that you can get metastasis there. But those are folks obviously, they aren't generally presenting with a thyroid nodule and metastatic disease, although I suppose you might see that from time to time, right?

Dr. Kristen Kobaly: Yeah. Over the years, occasionally, we'll biopsy something and be very surprised. And typically, we have cytopathologists on site, which I'll talk about later. But if they're suspicious for that, they'll often look back to the patient's original surgical diagnosis if they already have, like, let's say a lung cancer, for example, and compare the tissue. But that's, again, extremely uncommon.

Host: It's interesting you said about the anaplastic, because that's what I worry about in these thyroid nodules, but you just made the point that those actually don't usually present as sort of asymptomatic thyroid nodules. Those are usually growing so quickly that they present with symptoms.

Dr. Kristen Kobaly: Exactly.

Host: Okay. So, let's talk about the thyroid nodule once you become aware of it. I do thyroid exams on patients and I've picked up a nodule from time to time. Now, we should just say that the guidelines do not necessarily recommend routine screening of these nodules. And I guess that's because of a combination of things, their relatively indolent nature and the risk of sort of over-diagnosis and over-workup. I think about this similarly to the way we think about low-grade prostate cancer in some ways, you know, as being sort of you could really do harm if you overtreat it. But any thoughts on sort of screening?

Dr. Kristen Kobaly: I use that analogy a lot, thinking about prostate cancer. We've really seen a very significant increase in the incidence of papillary thyroid cancers. And in spite of that, there's really no corresponding increase in patients who have bad outcomes or death from thyroid cancer. And so, it kind of leads to this concern for over-diagnosis. And as so many nodules are picked up incidentally on imaging, we really are trying to avoid like diagnosing every single papillary cancer that a patient might have. And so, think just because of how indolent it is.

So to your point, you know, if they're small, we don't necessarily want to jump to intervene on a lot of these, which is why I think about prostate cancer. And really, I think that our professional societies really have been trying to be more judicious in terms of what we biopsy. So if you look at thyroid nodule guidelines over time, the nodules we biopsy, the sizes keep increasing. So, something maybe we used to biopsy at any size was then a centimeter, now a centimeter and a half and so forth. So, it's definitely something that we're trying to be cautious about over-diagnosis.

And as far as screening, the U.S. Preventative Service Task Force, which will always look and make recommendations actually recommends against thyroid cancer screening in asymptomatic adults. Now, obviously, there's certain family histories where that might be different, such as multiple endocrine neoplasia type 2, but that those are rare patients.

Host: Before we go into the workup, actually, I want to go back on a couple of issues. Kristen, we didn't talk so much about the epidemiology of papillary and follicular and oncocytic, which are the sort of the three most common. But, you know, these are often young people, and young women in particular, right?

Dr. Kristen Kobaly: So, thyroid cancer is common with advancing age, but we certainly see it in patients of all ages and plenty of reproductive age women will have thyroid cancer, which can be problematic when we're thinking about things like radioactive iodine therapy. It's less common in children, but we see it in children as well. So, it can really occur at any age.

Host: Yeah, I think I have three people in my life. My wife's friends who have actually been diagnosed with thyroid cancer, they've all done very well. But, you know, they're in their 30s. And so, I read recently that it was a 3:1 female-to-male ratio, so that's more common. Then, I want to go back to medullary thyroid cancer, and we were going to talk about this later. But now that we're talking about it, because it's come up recently with GLPs with the GLP drugs, you know, Ozempic, Wegovy, and so forth, and the increased risk of that specific cancer, and that's my understanding, that it's that specific cancer, the medullary cancer of the thyroid that's been associated with GLPs and only in, I believe, preclinical studies, but maybe you can talk about that.

Dr. Kristen Kobaly: Yeah, I mean, this is a really important question, because I think I get emails and questions about this like every single week. So basically, in studies of rodents who received GLP-1 receptor agonists, they were found to have C cell hyperplasia in the thyroid gland. And C cells are the cells that can arise into medullary thyroid cancer.

So as a result of this, the FDA has a recommendation that it's contraindicated to give GLP-1 receptor agonists in any patient who has either a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia type 2. And so, a lot of emphasis has been placed on this recently and there's been a lot of concern about do these patients need a screening ultrasound? Short answer is no, that's not recommended. Should they have all their nodules be biopsied before they start these drugs. And so, there's been a couple interesting studies recently that have looked at this. So, one was a meta-analysis done by an author named Liu in 2022 in a journal called Frontiers of Endocrinology. They actually looked at 35 randomized controlled trials and found that these drugs did not increase or decrease the risk of thyroid cancer nodules.

Another large study by Pasternak was published in BMJ earlier this year in April of 2024, and it was a large Scandinavian cohort study, and they didn't see any increased risk of thyroid cancer over a followup of 3.9 years, which isn't the longest followup, but still no signal there. So, I was just at the American Thyroid Association meeting recently, which is our professional home. And I hate to give up upcoming guidelines, but one of the things they addressed is that there are some new guidelines being published and they're going to recommend that they should not screen patients with thyroid ultrasound or calcitonin. It is safe to use these drugs in patients who have a history of thyroid nodules, regardless of whether or not they've been biopsied. So, hopefully, that will clear up some of the confusion and concern surrounding that. But certainly, if someone has medullary thyroid cancer, then they should not be on those agents.

Host: Or a history of MEN. You would just address that, right? That even in the MEN cohort, you don't have to--

Dr. Kristen Kobaly: Yeah, and 2A and 2B. Yeah. And those are very high lifetime risk of medullary cancers.

Host: Okay. So, let's talk about how to work one up when we know it exists, or we inherit one from one of our colleagues, a patient who has had a history of them and we're evaluating them. Ultrasound's a wonderful tool. and the thyroid is superficial and so can be seen very well with a linear probe gets the entire depth. I assume maybe you're even doing these in your office ultrasounds, or at least you're very comfortable interpreting the images when you see them, right?

Dr. Kristen Kobaly: Yeah, I do both. So, I definitely do ultrasounds in the clinic or on consult service. Um, We actually have some nice ultrasound probes that we'll plug into our iPhones when we're in the hospital. So, those are pretty cool. But yeah, we do bedside ultrasound and then certainly get formal ultrasounds with Radiology. And people and patients will ask, "Well, why would you give me an ultrasound? Why not a CT scan, an MRI, a PET?" And really, we have to emphasize that that is by far the superior method to imaging the thyroid and, as you mentioned, the gland is really superficial. And so, we can characterize the nodules very accurately with ultrasound. We also need with anyone who's getting a thyroid ultrasound, there should be a lateral lymph node assessment as well. So as we talked about papillary cancers and other thyroid cancers can spread to lymph nodes, and we do want to make sure that the lymph nodes don't look like they have metastatic disease and, disregard a small nodule. And so, that should be part of any ultrasound. So, any patient with a known or suspected nodule should have that.

It's interesting about 15% of the time when people think they've palpated a nodule, the ultrasound actually won't show one. So, we're not great at feeling nodules, although there may be some asymmetry in the gland. And then even when we feel one, there's often others there that we can't feel. So, ultrasound's where we start. But we need a TSH level as well, and that's something that gets missed a lot. Patients will be sent for a biopsy. And that's important because rarely, but some patients will have functional thyroid nodules, so "hot nodules", if you will, that make too much thyroid hormone. And so, we like to get a TSH. And if it's low, which suggests the patient's hyperthyroid, then actually, regardless of what the nodules look like, the first step would be a nuclear medicine uptake and scan and that's where we give I-123. And we look to see where the thyroid is forming thyroid hormone. And if a thyroid nodule's functional, we really don't need to biopsy it because the risk of cancer is so low. But most patients don't need those scans. It's just when the TSH is low.

Host: So, ultrasound and TSH for starters. And then, when we get these ultrasound reports back, they're divided into different categories based on the features of the nodules that are seen, right? And it looks like from what I was reading that all the guidelines and there are different categorization systems, but they all sort of rely on the same features, if you will, of the nodule. And so, maybe we could go over those.

Dr. Kristen Kobaly: Yeah, this is going to be the area where I really wish we had some visual aids, but that's okay. For those listening, I guess if you want to use your internet browser and look up the American College of Radiology's TI-RADS system, that could be helpful to see some pictures. But basically, we use ultrasound patterns to help figure out what we're worried about in the nodule.

So, the first type of nodule we might see is just a cyst. It's a pure cyst. There's nothing else going on. We love fluid and nodules. Cystic fluid is a benign finding, and a pure cyst is no risk of cancer essentially, and you can leave those alone. So, that one's easy.

We also have nodules that are called spongiform nodules. If you can envision like a typical kitchen sponge on an ultrasound, that's sort of how they look. You'll see these microcystic spaces that aggregate. They should be at least half of the nodule. And these are usually nodules that are isoechoic to the thyroid. So, what does that mean? So when we look at the thyroid, we're looking at the echogenicity of the nodule as compared to the surrounding thyroid. So if the echotexture is the same, that's--

Host: The same shade of gray.

Dr. Kristen Kobaly: Same shade of gray, exactly. So, those are spongiform nodules and those are another like very low risk cancer, less than 3% risk of malignancy, generally classified as benign and we tend not to biopsy those. So yeah, those are pretty straightforward. And then, there's other variations of mixed cystic and solid nodules. And again, we like fluids. So, mixed cystic solid nodules are generally benign and reassuring. Although you do have to look carefully at the features of the solid part. So, we do sometimes see cystic papillary thyroid cancers where you might see a cyst and, kind of off to the side, there's a solid component that has some worrisome features, maybe irregular borders or microcalcifications within that solid part that would give you pause and think that could be a cystic papillary. We might want to biopsy that.

But when we're really thinking about worrisome features, we're worried more about, first of all, solid nodules, so nodules without any fluid become more concerning. And that's where that echogenicity really plays a role. So, we look to see if they're brighter than the surrounding thyroid, which is hyperechoic, if they're the same shade of gray, isoechoic to the surrounding thyroid, or if they're darker, right? So hypoechoic. And the ones that are iso or hyperechoic, we will biopsy those at a certain size threshold. But in general, the risk of cancer is about 5-10% percent, so still quite low. Most papillary cancers are going to be solid and they're going to be darker than the surrounding thyroid, so hypoechoic. And so when we see that pattern, those are nodules we start to worry about a little bit more. But most solid and hyperechoic nodules are still benign. So, only about 10-20% of those end up being papillary cancers. Well, we're going to biopsy those at a smaller size and some of these other things I've talked about, but that's not quite as concerning. But there are features within solid and hyperechoic nodules that start to get really suspicious. So, calcifications can be concerning, especially when they're small punctate. We typically are using the term punctate echogenic foci these days. If the borders are irregular, that's very concerning. When you're looking in the transverse view of the nodules taller than wide, that's a suspicious feature as well.

And then, sometimes we can actually see a nodule just growing outside of the border of the extrathyroidal extension as problematic and very suspicious. So, those types of nodules that have multiple concerning features have a risk of cancer well over 50%, and those we're going to biopsy at the smallest size thresholds. But we do look at the lymph nodes because if the lymph nodes have features of thyroid cancer, then we have a lower threshold to biopsy the nodules regardless of how they look.

Host: I think more and more providers are familiar with ultrasound language now, because we're just doing a lot more bedside point-of-care ultrasound. I have a question actually about the hypoechoic. I thought cysts were relatively hypoechoic as well, but maybe I have that wrong.

Dr. Kristen Kobaly: They're actually considered anechoic, so they are just completely black. And so, it's hard to explain without having a picture in front of me, but you really can tell the difference of like some darker texture versus just a lack of anything there. A radiologist can probably put that much better than I just did, but...

Host: No, no, that makes a lot of sense. So, it's just a really dark, like completely black sky. Whereas, you know, you're going to get a little bit of a lighter shade of gray, if you will. So based on those features, you mentioned the TIE-rads or Ti-RADS, I don't actually know how to pronounce it, system, but that will put people in low intermediate and high risk, right?

Dr. Kristen Kobaly: It does. So, we have several risk stratification systems that are used. And an endocrinologists will often use the American Thyroid Association sonographic pattern system. And then, the American College of Radiology has their system, which is the thyroid imaging and reporting system or TI-RADS. They have a similar system for breast imaging called BI-RADS and sort of how this evolved.

And you know, at the end of the day, these systems are very similar. The size thresholds of biopsies differ quite a bit. And I think as part of these new guidelines that the American Thyroid Association is coming out with, those should align more. But there's sort of different ways to getting at the same thing, and they perform fairly similarly. So, our radiologists use ACR TI-RADS, and that's what we're very comfortable using in talking to patients and other clinicians. But they're both really good systems to help figure out what to biopsy. The ATA is more of a pictorial atlas versus TI-RADS. So, what TI-RADS does, they actually have five categories. So, they look first at the composition of the nodule. So, is it cystic, spongiform, mixed cystic-solid, or solid? And we've talked about all of those, right? And you get a point. So if it's a completely solid nodule, you get two points. If it's a cyst, you don't get any, right? Then, they look at the echogenicity. So, our anechoic or cysts don't get any points. Hypoechoic will get two points, right? So, isoechoic, hyperechoic get a point. It just depends. As the risk goes up, you get more points. Then, they look for that shape. Is the nodule wider than tall or taller than wide? Taller than wide gets a point. They look at the margins of the nodule. Are they smooth? Are they irregularly marginated or lobulated? Or is there even extrathyroidal extension? Those things get more points as you go up. And then, they look at echogenic foci or calcifications. And if they see like a coarse calcification, that gives you a point. Those aren't as concerning peripheral or rim calcifications, think of like an eggshell around the nodule, that can get two points. And then, these punctate echogenic foci are worth three points.

And so at the end, you have these five different categories. You add up all the points. It seems complicated. But as you get good at looking through ultrasound, you can do this very quickly. And then, your nodule gets assigned to a TI-RADS score between TI-RADS 1, which is benign, to TI-RADS 5, highly suspicious. And the nice thing about TI-RADS is based on sort of where the nodule falls, if it's something that doesn't need biopsied, there's really clear criteria for should it be followed and, if so, for how many years and at what interval. That's really nice.

What they're currently doing for TI-RADS 3 is you biopsy over two and a half centimeters. Those are the mildly suspicious nodules. For TI-RADS, which are moderately suspicious. You biopsy at one and a half centimeters, and then for the highly suspicious tyres five. You biopsy over a centimeter. And what's interesting is that none of these systems in the ATA is very similar recommend biopsying nodules under a centimeter unless there's other concerning features.

Host: And so, your low risk ones are the TI-RADS 1 and the TI-RADS 2. What's the difference between the TI-RADS 1 and 2 in terms of practical management, I guess?

Dr. Kristen Kobaly: Very little. They actually neither recommend a biopsy or any surveillance. I guess, we could argue why there's a little bit of a difference there in terms of how they're being categorized, but...

Host: yeah. So you, may follow those up. I didn't memorize these guidelines, but you just follow the report. But they may recommend just to check on it in a year or so, or do they just say nothing to do?

Dr. Kristen Kobaly: Nothing to do. TI-RADS 3, 4, and 5 end up being followed.

Host: And so, let's talk about biopsies. So, you're getting TI-RADS 3, 4 and 5. Those are the ones that need to be biopsied. I know you can do these biopsies in your office. We generally have to ask somebody who's trained in them to-- I'm out at Radnor, so we send them to Radiology and they biopsy them under ultrasound. Can you just take us through that process real quick? What's involved in a biopsy?

Dr. Kristen Kobaly: Absolutely. So, these are fine-needle aspirations, and they're done by a lot of different groups. So, Radiology, as you mentioned, does those. Endocrinologists will do them. Ear, Nose, and Throat surgeons, sometimes endocrine surgeons. And so, depending on who's doing them, they can be in the office or in a Radiology suite. And it's nice to have them done in Radiology where the images are stored. And so, I think there is sometimes a lot of help to be able to go back and say what exactly did they do 10 years ago and have those images? So, some of us in Endocrine do biopsy and Radiology. So, I actually do my biopsies in the pulmonary radiology practice with their sonographers.

But basically, the patient comes in. There's no specific restrictions before the biopsy. They can eat and drink, just kind of live their life until they get there. First, we obviously consent them and then the patient will lie down there on their back. We put a pillow usually behind the shoulder blade and then have them really like stick their neck so that it's hyperextended. I often use the analogy to patients that it's kind of like the shampoo sink at the hair salon. So, that's sort of the position that we have people in. Occasionally, people, especially older patients, don't tolerate that well, that's the optimal position, we can get by in other ways if we need to.

And then, one of our ultrasonographers uses the ultrasound to locate the nodule. And these are really small needles. So, 27 gauge needles, which is smaller than what's used to even do a blood draw. So, there's a lot of variability as far as anesthesia. It's very rare to use lidocaine. That's probably more uncomfortable than the procedure itself. But patients definitely get nervous with the idea of doing procedures like this without any kind of anesthesia, although there's definitely providers that do that. So, a lot of us will use a topical numbing agent, and that just helps to dull the skin before you enter the needle, dull the feeling of the needle going through the skin. But the thyroid gland itself really doesn't have any nerve endings, so people generally feel like a sense of pressure when the needle's in the thyroid gland.

It's pretty well tolerated, I would say. There's some exceptions to that, but generally people do quite well with it. So, we start off doing two needle sticks. They're each about 10 seconds long, so it's fairly quick. And then, we have cytopathologists that are on site, and it's really helpful to have on site cytopathology, first of all, because they're there to ensure adequacy of the specimen. They look under, they make slides and look right away. They also can tell if it looks like a nodule might be indeterminate and you need to do a molecular test or they know on site that it's thyroid cancer. You can have that conversation with the patient face to face instead of having to call them later. But they will look at the sample and often ask for two more needle sticks. So, we typically don't do more than four and the results can take a few days.

Host: Wow, that's really interesting. I didn't realize that you really can sort of separate the extremes at least, benign and malignant, that quickly. And 27 gauge, that's pretty fine. That's a pretty small needle.

Dr. Kristen Kobaly: Yeah. It's called an aspiration, but we don't really like pull on the needle. Basically, pull it back to about 1 cc, the syringe, put the needle on it, just move the needle up and down. It's capillary action. We'll often tell patients it's like moving a straw through Jell-O and that's how we get our sample.

Host: So once you get that result, now we have another classification system we have to go over. We talked about the TI-RADS, which is the ultrasound results classification system. But now, we have a Bethesda classification system based on the pathology on the sample, right?

Dr. Kristen Kobaly: We do. And this is the result that you're going to get back, which really confuses, I think, some primary care practitioners because this, again, is very nuanced. And so, people get these results and don't necessarily understand what to even tell the patient what they mean.

So, we'll go through these, and there's six results. Each result comes with an implied malignancy risk though. And before I dive into that, I just want to explain that these malignancy risks that I'm going to share with you also include an entity that used to be considered cancer that now isn't cancer. So, let me tell you about this.

So back in 2016, there was a type of papillary thyroid cancer, a follicular variant. These are completely encapsulated tumors without any capsular or vascular invasion, very low risk of malignant potential. And so, the pathology community got together, and said we are giving a lot of, you know, anxiety to people who have a cancer diagnosis for something that's really indolent, even more than like just your average papillary cancer. So, they reclassify these into something called a non-invasive follicular thyroid neoplasm with papillary-like nuclear features, which is very hard to say, but it's NIFTP. That's what we call them. And so, those are still considered in these malignancy risks. And they are really a pre-malignant lesion because if you didn't take them out, you might develop a vascular capsular invasion.

And so, they definitely need surgery. So, that's just something to kind of know that some of these are actually going to be like pre-cancerous lesions. So, the results of Bethesda, back to that. So the first potential result, which no one ever wants to get when you're doing a biopsy, is non-diagnostic or unsatisfactory. Happens from time to time. You know, when we have ultrasound and we're watching our needle on the screen and we have the pathologist there say we're not getting any cells, like, what's going on there? Sometimes it's just the nature of the nodule. They can be like an old fibrotic nodule. There's just nothing to get out. Sometimes they're heavily calcified and it's really hard to get the material. But the risk of cancer is quoted to be 5-10% in that. So, if we have a nodule like that, we may repeat the FNA, is what we usually do on another day and hope for a better result. But that's always frustrating for a provider and the patient.

The next classification is benign, so that's Bethesda 2 and, you know, self-explanatory. But the risk of cancer is still a risk of cancer. You can have a false negative. So, 0-3% risk of cancer is what's quoted, and there is some data that at higher volume centers like Penn, it's probably more like less than 1.5%. So, these patients don't need surgery unless they have something else going on that's causing problems where that would need to come out like symptoms from the nodule. But we usually still do surveillance for these patients.

The next category is Bethesda 3. This is atypia of undetermined significance. And this reminds me a lot of sort of Pap smear cytology and kind of some of these indeterminate things, but these AUS has a risk of cancer about 10-30%, and these ones are tough. You can just repeat the biopsy. And about half the time, you'll get a benign result. So, that's certainly a possibility. But patients don't love to have to come back and have a biopsy again on another day. And so, we'll often do a molecular test in these patients. And then if they continue to-- like, let's say you repeat the biopsy and you have the same result, like lobectomy is also an option for these, but I don't think that's very common.

So Bethesda 4, these start to be trickier. These are called follicular neoplasms. The risk of cancer is 25-40%. These are true neoplasms. And so, really to tell if they're benign or malignant definitively would require surgical resection. And the pathologist will look at the entire tumor for capsular or vascular invasion, which is a carcinoma. Otherwise, they're benign. But patients, of course, don't want to have diagnostic surgery. So, most of these patients will get a molecular test to help sort this out.

Then, we have our Bethesda 5, suspicious for malignancy and that has a risk of cancer in the 50 to 75%. All of those patients need to have surgery, the extent of that may vary. And then Bethesda 6 is malignant, and this has a 97-99% risk of cancer. It's usually a true cancer and that requires surgery. Although I will say, and this is probably beyond the scope of this podcast, that we are doing sometimes active surveillance for small papillary cancers.

Host: So, Bethesda 3 and 4, the sort of undetermined significance levels, these are the folks that are getting molecular testing. Now, at Penn, I think that's known as ThyroSeq, thyroid sequencing, I assume that's what it stands for, that's just the company or the particular one that we're using globally, it's molecular testing, right? So, what's happening there? You're trying to better figure out who needs to have that nodule removed, right?

Dr. Kristen Kobaly: Exactly. So, this sort of started, and if you think about these follicular neoplasms, that there was no way to know whether they're benign or cancer without a surgical diagnosis. So, lots of patients going and having half probably or even all of their thyroid removed for a benign nodule. And so, that's not optimal. And so, molecular testing really is supposed to be used to rule out cancer. That's the idea, is for indeterminate nodules to try to, rule out the cancers, and then you have surgery on the others. So, we use it to risk stratify people for surgery or observation. And there's lots of available commercial tests. There's ThyroSeq, which we use, as you mentioned. Afirma is another test, ThyGeNEXT, ThyraMIR, those are three that have multicenter validation studies. And there's some nuances to each of them.

But in general, what you do for these, they are an actual needle stick. So, it's one or two biopsy passes with the needle and then into a special tube that gets sent out. What ThyroSeq does is they actually use next generation sequencing, and they look at DNA and RNA of actually 112 thyroid-related genes. And they'll come back and give you a result. Usually, it's either positive or negative. So, the negative predictive value, if you have a negative ThyroSeq is 97%. And so, it's very helpful to rule out cancer. The positive predictive values, these tests aren't as good. So, they really shouldn't be sent on a nodule that's not indeterminate. The positive predictive value of ThyroSeq is about 67%, but you'll get details, which is what I like about the ThyroSeq in particular is they'll actually tell you what mutations they found. So, they may say, for example, that you have a BRAF V600E mutation, that's a common mutation in papillary thyroid cancer. And so, that may have a risk of cancer of about 99%, or there might be a mutation has a much smaller risk of malignancy. And so, if there's a risk of cancer, we usually do go on and recommend that the patient have surgery. But we can use the specifics of that mutation to help figure out how much surgery they need. Do they need all of their thyroid removed? And they also will comment on these results about if it's cancer, like, is it likely to be aggressive or low risk, intermediate risk, so that can be helpful as well. And then, interestingly, it can also pick up signatures with like an intrathyroidal parathyroid gland or some things you might not be suspecting. So, that can be helpful too. And then, the other tests are relatively similar, there's some nuances, but...

Host: So, I've done all of the process we've talked about so far in primary care, in working up a thyroid nodule. I've sent people for biopsies, I've gotten results back, I've had ThyroSeq done on those results. And then, I've gotten those results back and I'm like, "Okay, now what do I do? " And so, that's the step where I think my realm ends, clearly, and your realm begins. Everything that we've talked about so far is clearly within your realm and we can refer people earlier, I'm sure. But I just wanted to point out, I've done up to that point, on my own, and I think other colleagues have as well.

So then, the question is, you clarified, you know, who needs to go to surgery, and let me just ask about referring to a surgeon, because we have ENT surgeons who do this, we have oncologic surgeons who do this work, right? So, who operates on thyroid nodules is, I guess, my question, and who should be doing it?

Dr. Kristen Kobaly: Both of those groups, so ENT surgeons and Oncology or Endocrine Surgery are very happy to do this. I think that the key is to choose a high-volume thyroid surgeon. And most surgeons, by the way, are at least the high-volume thyroid surgeons that I work with are very, very well versed on all the things we're talking about today. And, so if, you know, a patient was sent, they'd be very comfortable making the recommendations for what they need to have done. But I think one of the tricky parts in these patients who have these specific needs, like having indeterminate nodules or even a papillary cancer, is what surgery are you recommending to the patient? Because we used to take any patient who had any size thyroid cancer and remove the entire thyroid.

And so, back around 2016, I believe the American Thyroid Association came out with guidelines that said it's actually okay to do a lobectomy in smaller low-risk papillary cancers. And the benefit of that is to preserve thyroid function. So, when I think about referring a patient for surgery and how much of their thyroid to take out, there's a lot of different things I think about. So, like, you know, if it's a potential benign tumor or a low risk cancer, I'll often send for a lobectomy. But sometimes those patients have a more concerning cancer than you realize. So, their small papillary cancer ends up having vascular invasion, and that's problematic. They're going to need to have the other half of their thyroid removed. So if someone's older and they may not handle two surgeries, well, maybe they should get the whole thing removed the first time around. If they're already taking levothyroxine, there's probably no good reason to not take out the entire gland. Someone who has lots of different nodules or maybe a large benign nodule that's potentially causing symptoms, that can be a reason to just take out the whole thyroid. And then, patient preferences actually are just a really big factor here in kind of making these decisions. And this is something we in Endocrinology certainly talk to the patients about a lot, but also discussions that the surgeons generally have as well.

Host: Before we talk more about thyroid cancer and the follow up of thyroid cancer, I just want to go down the path and not forget about the nodules that ThyroSeq says are low likelihood of cancer, I suppose, and didn't look at one of these reports before when prepping for this podcast. But I suppose within there, there's some guidance about followup as well, right?

Dr. Kristen Kobaly: Yeah, as we talked about, TI-RADS will tell you what to do for non-biopsy nodules. And just really quickly, because I forgot to say this earlier, and I think it's really important is that all of these risk stratification systems, by the way, are for the average risk patient. So if you have someone with like multiple first-degree relatives with papillary cancer or family history of multiple endocrine neoplasia or something like that, you might biopsy some of these at smaller sizes.

But let's say that we biopsy a nodule and it's benign, like, does it need to be followed with ultrasound? And there's different guidelines for that. And the ones that are coming out are going to be revised more to look at how worried we were about the nodule in the first place. But a benign nodule that's solid is usually followed at least for several years to make sure there's no change or interval suspicious features that might warrant repeating the biopsy because we did talk about how that benign still has about a 3% risk of cancer.

But let's say we biopsy one of those TI-RADS 5 nodules, so really suspicious nodule with benign cytology. We would do an ultrasound, again, probably within six to 12 months. And actually, the guidelines in that case, if it's still in that same like high risk criteria, would be to repeat the biopsy because the ultrasound features are worrisome enough that you'd want to really do that biopsy again. So, that's one thing.

For the nodules that have benign molecular testing, we don't have any good guidelines and probably not great data on how to follow those, because these tests are not terribly new at this point, but not something that we have 20 years of data either. So, what I think most of us do when someone has a nodule, let's say that's a neoplasm with a benign molecular test is do ultrasound surveillance, probably for at least five years, maybe more, maybe less, depending on how the nodule looks. And we'd always consider a repeat biopsy if the features are changing or even, in that case, surgical resection. So, I have had patients that had a nodule that looked very worrisome that had benign molecular testing that I've sent to surgery just because I was not convinced because the ultrasound was that suspicious. So, there are some nuances that I think it can be helpful having Endocrinology involved. But again, since most of these nodules will not be quite so complicated, we don't need to see every patient, although we're certainly happy to help.

Host: Of course, at Penn, we have the e-consult feature, and I assume we can do an e-consult for a thyroid nodule that we're trying to figure out the appropriate followup, right?

Dr. Kristen Kobaly: Yes, absolutely. We get those a lot.

Host: Yeah, because oftentimes we don't have to have somebody see you. All the data is there. We just need some guidance on what exactly to do.

Dr. Kristen Kobaly: It's a great use for an e-consult actually.

Host: Yeah, I agree. And these things come up a lot in primary care. So, let's talk about thyroid cancer. You know, obviously, you hope to get it localized, in which case, surgical resection is appropriate, but there's some follow up as well on that. Let's talk about that. What else do you do to treat a thyroid cancer?

Dr. Kristen Kobaly: Yeah. So, I guess we'll kind of limit this to differentiated thyroid cancer, which would be like papillary follicular and oncocytic cancers. So basically, after the surgery, let's assume the patient has their entire thyroid removed. We can do two things. So, we can measure serum thyroglobulin, which is a tumor marker. And then, in most patients, we use thyroid ultrasound to monitor for recurrence. And the first really big decision point after the surgery, we'll look at the surgical pathology and say, "What is the risk here?" And how concerned are we for this cancer being problematic in the future and using that information. We'll then say, "Does this patient need to have radioactive iodine?" And so, radioactive iodine is given fairly judiciously. But if we have a patient who has like a confined papillary cancer, no lymph node involvement that they don't need to have that treatment. But certainly, if someone has a tumor that is having extrathyroidal extension and multiple lymph nodes involved or vascular invasion or more high risk features, they should have radioactive iodine.

And that's done for a couple of different reasons. So, we will do it at a low dose, which is called remnant ablation. And that's really just to destroy any residual thyroid tissue in the neck so that we can get rid of anything that makes thyroglobulin that isn't cancer to make our tumor marker more sensitive. And then, some patients have more suspicious cancer, but we'll give adjuvant therapy. So, those are higher doses of radioactive iodine, which are really designed to try to target any residual cancer cells that might be left behind. And if patients have metastatic disease, we might actually give even higher dose called dosimetry, which is where nuclear medicine calculates the maximal tolerated dose, and we get very large doses. But in most patients, you're having surgery, you may or may not have radioactive iodine.

And then, you're having monitoring with neck ultrasound and thyroglobulin levels. Now, if the thyroglobulin is high and the neck ultrasound is negative, then those are more advanced patients that need to have other imaging. Certainly, if someone has a lot of vascular invasion, we'll do imaging to look for distant metastases, depending on what the thyroglobulin is. And then, in patients who have very severe metastatic thyroid cancer, some of those patients will need to go on to see Oncology for other systemic therapies.

Host: There are patients in which you would do superphysiologic doses of levothyroxine in order suppress the TSH. Who do you do that in?

Dr. Kristen Kobaly: Yeah. So basically, the idea of that is that this is only for papillary and follicular carcinomas and oncocytic carcinomas because medullaries aren't responsive to TSH. But the idea is that TSH is a growth factor for thyroid cancer and so we want to keep that value low to prevent cancer cells from growing. So, we'll do that in patients often in the first year of follow up while we're looking to see if there's any signs of disease, although in a really low risk papillary we won't. But if someone maybe has some antithyroglobulin antibodies or indeterminate thyroglobulin, maybe some nonspecific ultrasound features that probably aren't cancer where we're not sure, we might keep the TSH 0.1 to 0.5. Now if someone has papillary cancer that's involving multiple lymph nodes, that we aren't ready to go back in and have another surgery yet, for example, we'll actually try to suppress the TSH to be less than 0. 1. But the patient needs to be able to tolerate that. So if they're older or they have AFib or something, we might be a little more cautious in that.

Host: And that's not necessarily forever, right?

Dr. Kristen Kobaly: No.

Host: That'd just be for the period. So, just a quick question on thyroglobulin. It can be used as a tumor marker for papillary, follicular, oncocytic, not medullary, right? Is that a true statement? But all those others, you can, right?

Dr. Kristen Kobaly: Yes. And then medullary, we typically will follow calcitonin levels.

Host: So, what point can these folks who have had thyroid cancer, who have been followed by you, be transitioned back to primary care? Because I have a few patients that, you know, my endocrinologist said I don't need to see her anymore. And at what point are you making that decision?

Dr. Kristen Kobaly: That's a very complicated question that is also being addressed a little bit more in the upcoming thyroid cancer guidelines. I think that if someone has a low risk papillary cancer with no sonographic evidence of disease or biochemical evidence of disease and they've been followed for 10 years, it's sort of where we're starting to discharge back to primary care. But stay tuned, I'm hoping we'll have some more to know. That's always challenging.

Host: And do we continue to do thyroglobulin levels yearly in those folks, or once they're sort of transitioned back, can we stop that?

Dr. Kristen Kobaly: Yeah. So, I think that the plans are to hopefully stop that at about 10 years, and that's something that isn't a finalized recommendation yet, so I shouldn't maybe go on the record saying that. But typically, when we're ready to discharge the patient, the idea is that probably doesn't need to be done anymore.

 If you were to order it for someone, it's just important to make sure that you're ordering the tumor marker because patients who are hypothyroid will have antithyroglobulin antibodies, and labs are very good at doing that test instead of the actual thyroglobulin. So when you do a thyroglobulin, you always get an anti-thyroglobulin antibody with it because that can affect your thyroglobulin measurement. So, you should get two results. If you just get the thyroglobulin antibody, that's not the correct test. And that's one reason we worry about sending patients away to have that done because it gets mistaken even by the lab just putting in the wrong order sometimes.

Host: Well, Kristen, and this has been excellent in an area that I think many of us find confusing, and I just want to kind of ask you any last thoughts to talk to the primary care audience that come to mind in terms of things you want us to know.

Dr. Kristen Kobaly: yeah, one thing I forgot to mention is that there are a lot of nodules picked up on PET scans. So, we have patients in Oncology who are getting PET scans done and we'll see FDG-avid thyroid nodules. Those, we still get the ultrasound. We might have a little bit higher threshold to biopsy those though, but about a third of them will be malignant. So, that's something that you might see in your practice.

The other thing I see a lot on ultrasound are findings of thyroiditis, which means inflammation in the thyroid. And that can be from various causes, most commonly probably Hashimoto's thyroiditis, could be grave disease can look like that, and even like a subacute thyroiditis. So, that's something that I think if a patient has as a finding you're seeing on ultrasound, it certainly should warrant thyroid function testing. Perhaps TPO antibodies to see if there's a risk for hypothyroidism, and then maybe checking a TSH, at least annually, if not sooner, if clinically indicated.

Host: I considered trying to bring in treatment of thyroid disease generally into this podcast, but I'm glad I didn't because it really took almost a full hour for us to go through thyroid nodules. Kristen, thank you so much for coming on. This has really been helpful. I think it helps us get in our minds much better the algorithm of workup of what we're supposed to be doing when we think through these. So, thank you so much again.

Dr. Kristen Kobaly: You're so welcome. It was my pleasure. And I hope that people find this informative.

Host: I'm sure they will. Thank you everyone again for joining the Penn Primary Care Podcast. Please come back next time.

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