It's an honor and pleasure to be with you today. My goal here in this session will be to speak about elevated risk breast lesions but from the perspective of pathology. So we'll be speaking about a few things. Number one, we'd like to gain an understanding of what exactly constitutes a high risk lesion. Next we'll talk about the histologic challenges of diagnosing these lesions. And we'll also review the pathology literature for management considerations for these lesions. Just to begin, I have no disclosures. So when we talk about risk, we need to first define what is meant by risk. And when you think about risk, there's really sort of two independent tracks to consider. The first is whether or not there's an elevated risk for the lesion as a predictor of the future of invasive carcinoma. So we're talking about a risk in the future, meaning if a person has lesion X, patient has lesion X, does this increase their relative risk to develop invasive carcinoma in either breast at a later time? And you can look at that risk as a relative risk, which would be a risk relative to baseline. And you can also look at that risk as an absolute risk over lifetime. And so, for example, the way that we categorize this in pathology is that when we have these lesions, we classify them broadly into different types of changes or diseases. So for example, you have some things which are called nonproliferative changes. An example of a nonproliferative change would be something like cystic change or fibrosis or maybe some mild epithelial hyperplasia, apocrine metoplasia. These types of things are called nonproliferative changes, are subclassified as nonproliferative. And these really don't increase the risk. And so the patient remains with a baseline risk and a 3% risk over lifetime of developing invasive carcinoma in either breast. However, you can develop proliferative disease. And proliferative disease here would indicate some sort of proliferation of either the acini in the lobule or the degree of epithelium within the acini of the lobule. So for example, an example here might be a florid hyperplasia or sclerosing adenosis or papillomatosis, all of which would be proliferative diseases. These increase the risk slightly, maybe 1.5 to 2 times, which would then also increase the absolute risk over the lifetime as well. Then you come to the next category, which are proliferative diseases with atypia. And basically here you're thinking about things like atypical ductal hyperplasia and atypical lobular hyperplasia, so ADH and ALH. And the atypia in the name gives away the fact that it's classified here. And these would increase the risk by four to five times off baseline, giving you about a 15 to 17% lifetime risk. And finally, you come to carcinoma in situ, which can be seen as a risk lesion as well, particularly in the case of lobular carcinoma in situ, which we're going to talk about in a few moments. And here the risk does increase significantly, eight to 10 times over baseline, giving you a lifetime risk of 25 to 30%. So this is how we see sort of this one basket of risk. And then the second basket of risk would be if lesion X is determined or discovered on biopsy, what is the risk that there's something more sinister left behind? So for example, let's say that there's ADH on a biopsy. What is the risk of DCIS being present in the breast, which is then going to drive us to perhaps, based on that biopsy, do an excision to ensure that nothing more sinister is present? So just to start off, we really need to understand that there's two baskets of risk, two types of risk that we need to consider. And those are all going to sort of come into play in a concert in order to eventually determine how to best serve the patient. So in this discussion, we're going to talk about, I think I've got five, or sorry, seven lesions listed here, which are elevated risk from one dimension or another. And these include flat epithelial atypia, complex sclerosing lesions, ADH and ALH, LCIS, or lobular carcinoma in situ. And then we're going to end with a discussion of fibroepithelial lesions and papillary lesions. So to start off, let's talk about five of these sort of in sequence, FEA, complex sclerosing lesion, ADH, ALH, and LCIS. The first point to make here is that all of these arise from a similar compartment, which is the terminal ductal lobular unit, or the TDLU. And the TDLU is thought to have a stem cell. And this stem cell can eventually pick up the series of genetic hits, which is then going to result in one of these subtypes of lesions. So we're going to walk through each of these lesions one by one, but we're really here focused on the TDLU. So the first of these lesions is flat epithelial atypia. This is the earliest recognizable clonal lesion of the TDLU. Now histologically, the way that we make this determination on the slide, is we're looking for dilated acini and cysts. And usually these are going to be lined, or I guess characteristically, these are going to be lined by cells with mild atypia. And of course, calcifications will also be, will often be seen as well. Just to hammer home this point, I sort of put here in contrast two images. On the left, you have the normal TDLU, and of course the TDLU is the terminal duct, which opens into this lobular unit. And these lobular units are going to contain all of these little circles, or grape-like acini. Now you can see normally the TD and the OU, all of the acini and all of the ducts, they're not cystic, and the cells are fairly monotonous. Now you can't see that at this power, but that's how the cells will look. What happens in flat epithelial atypia is that this TDLU becomes cystic. You get these dilated cystic ducts, and you also can have dilation of the acini. And the lining changes into a monotypic, hypochromatic, flat layer of cells. Now a couple of points that I want to make here, because the terminology can be a little bit confusing. Flat indicates that we don't see architecture. What that means is that we don't see the architectural patterns of DCIS. That's why we call it flat. And the atypia here, what this means is that we see a monotypic population of cells suggesting monoclonality. The cells, by definition, are going to be low grade. So although the term atypia is used, what we intend here is not cellular atypia, but rather the monotony that's suggestive of the lowest degree of clonality. So I just want to make that clear, because that atypia term can sometimes throw us off. Now this is considered a nonproliferative change. Remember that I said that nonproliferative changes include things like cystic change, fibrosis, mild hyperplasia. These types of things which really don't increase the baseline risk. And so this is considered sort of the ultimate extreme of a nonproliferative change. And so the studies essentially show that there's no increased future risk of carcinoma in either breast with this change. But the problem here, and what creates a diagnostic challenge, is that this lesion often is associated with other risk lesions. For example, you can often see lobular neoplasia, such as ALH or LCIS, in association with FEA. And you can also see ADH in association with FEA, or tubular carcinoma in association with FEA. So this is something that we need to carefully exclude, and it's part of the diagnostic dilemma that the pathologists will work through. We also have to exclude higher-grade nuclear features. Now if I see something flat, normally when you see something flat, you're automatically thinking about flat epithelial atypia. And the nuclei then need to confirm it by being low-grade. But if, for example, they're high-grade, that changes the entire discussion. That automatically nails the diagnosis of DCIS. High-grade nuclei should not be seen in flat epithelial atypia. And sometimes I might see intermediate-grade nuclei, in which case I wouldn't necessarily – or I would still call it flat epithelial atypia, but I might put in a little comment saying that I see nuclear features that are a little beyond what is normal for FEA. It's important to exclude all of these things that I just discussed, because with RADPATH correlation and FEA alone, there's a very low rate of upgrade on excision. In fact, there was a recent study which showed a review of about 73 cases with a 7% upgrade to IDC or DCIS. When there was an upgrade, a couple points need to be made. First of all, there was, I think, one upgrade. Upgrade was either to invasive ductal carcinoma, low-grade, tubular type, ERPR positive, sentinel lymph nodes were negative in all cases. So generally, if there is an upgrade, it's to a very low endolink carcinoma. All of them, by the way, were T1A. And if it was DCIS, it was low-grade. But one important point to make here is that if all the calcs were removed, if there was good RADPATH correlation and all the calcs were removed, none of the cases were upgraded. So it really is important to have good RADPATH correlation. And in our practice, we don't act upon FEA. The next lesion is a complex sclerosing lesion. And the reason I chose the second is because this is sort of the extremity of what we call a proliferative change. Now, proliferative change basically means that you've got a change or a disease. We would call it proliferative disease. And typical features would be like sclerosing adenosis, epithelial hyperplasia, cysts, and papillomas. All of these independently constitute proliferative disease. Sort of the amalgamation of all of that in one lesion is called a complex sclerosing lesion. And the additional feature that's seen here is that you're going to get distorted fibroelastic stroma along with all of the changes that I just described. When the ducts and lobules radiate from the central nidus of sclerosis, that's commonly then going to be termed a radial scar. So underneath the rubric of complex sclerosing lesion is included radial scar. Just to highlight this distinction, I've again shown you normal against a complex sclerosing lesion on the right. And you'll see here, this is the normal TDLU, whereas here you've got this sclerotic background shown by this pink or light white. Along with the cystic change, you've got hyperplasia in the spaces. You've got perhaps some papilloma formation, some sclerosing adenosis. All of this put together would constitute a complex sclerosing lesion. So again, this is a proliferative disease. Proliferative diseases generally have a slightly increased risk of future carcinoma about two times above baseline. And this is especially true in females greater than 50 and if the lesions are larger, for example, greater than a centimeter. The diagnostic challenge here always is to exclude atypia and invasion. And of course, that's essential because that would be an upgrade. And recent studies suggest that observation may be considered with good RADPATH correlation here as well. In fact, in a prospective study of 100 patients, a third which were excised and two thirds which were observed, only about 10% of the cases were upgraded. But the 10% upgrade rate actually is, in all cases of that upgrade, there was actually discordance between RADPATH correlation and all of them were BI-RADS 4B or greater. So again, with good RADPATH correlation, you can safely observe these lesions in again a subset of cases. The next lesion is atypical ductal hyperplasia. So now we're moving our way up the rubric and we're talking about proliferative disease with atypia. This is a clonal proliferation of low-grade cells with some features of DCIS but not completely meeting the criteria diagnostically for DCIS. The cells often contain a loss of 16q and 17p, both of which are molecular abnormalities seen in DCIS. And so essentially, you can think of this as sort of like the very earliest precursor to low-grade DCIS. The problem diagnostically is that this lacks the extent and or size of low-grade DCIS. And so that's what holds us back from actually making that diagnosis. Again, this is proliferative disease with atypia. And so there is an increased future risk about four to five times above baseline. The diagnostic challenge here is to ensure that we're not dealing with UDH and to also ensure that we don't have high-grade nuclear features. Again, as a reminder, high-grade nuclear features automatically equals DCIS. You're not going to be debating between ADH and DCIS if high-grade nuclear features are present. Excision is recommended here because the upgrade risk ranges from studies. But it's about probably 15% to 20%. And that upgrade risk exists even if all the calcs have been removed. So in this case, excision would be recommended to ensure nothing sinister was left behind in the breast. Atypical lobular hyperplasia is similar to ADH in some ways and different in others. Histologically, it's a neoplastic proliferation of small, discohesive cells which fill the minority of acini. Now, notice that I've italicized the word minority here because it's this minority versus majority that differentiates between ALH and LCIS. Essentially, this is a spectrum. And we use the distension of the acini and the extent of that distension in order to categorize ALH versus LCIS. Almost all ALH is almost always incidental. There is an increased future risk of carcinoma. This falls under atypical proliferations. However, excision is not recommended due to the extremely low upgrade rate with RATPATH correlation. And I'll talk more about this when we discuss LCIS in a moment. So when you think about LCIS, it's the exact same process. Again, this is a spectrum. However, in this case, instead of distending, let's say, a minority or less than 50%, imagine all these acini, so each of these little circles, was distended by the same cells that are present in this acinus here. So this would then allow for a diagnosis of lobular carcinoma in situ. And this is usually an incidental finding as well. As you're aware, LCIS is often multi-centric and commonly bilateral. And in its classic form, it's actually a marker for future risk. So about 8% to 10% above baseline. Recent studies suggest low upstage rate of LCIS. In fact, in a most recent or prospective study, only two of 79 cases were upgraded to cancer. But in each of those cases, in the first case, it was upgraded to tubular carcinoma, but tubular carcinoma was actually present on the biopsy. And in the second case, lobular neoplasia was not even present in central review on the original biopsy. So less than 2% is the upstage rate of LCIS. In our practice, we don't excise LCIS with good RATPATH correlation. The diagnostic challenges here, however, are to exclude things that are going to suggest a more sinister proliferation. For example, if there's necrosis, which normally should not be seen in LCIS, pleomorphism, which normally should not be seen in classic LCIS, florid growth, which normally should not be seen in classic LCIS, the thought here is that these are more aggressive lesions and hence would require excision to ensure nothing is present in the breast adjacent to the biopsy site. Moving along, the last two lesions we're going to discuss. The first is fibroepithelial lesions. Just as a reminder, fibroepithelial lesions are essentially lesions that arise from the intralobular stroma. Remember that in the breast surrounding the acini or the lobule, you have intralobular stroma and outside of the lobule, you have interlobular stroma. So it's this intralobular stroma that actually expands in a fibroepithelial lesion. So this is a neoplastic proliferation of that stroma. And then of course, the epithelium is just going along for the ride, but it ranges depending on the extent of the stromal proliferation and the degree of atypia from fibroadenoma to phalloides. Fibroadenomas are generally associated with slightly increased future risk, about 1.5 to 2 times. It may be higher if there's some complex features. For example, one of the complex features can be cysts, usually greater than three millimeters, or the presence of papillary apocrine metaplasia, as shown in this image here, where you can see this papillary proliferation lined by these pink cells. And so this could suggest a slightly increased risk, slightly, again, not necessarily significant. And here, observation is reasonable with a fibroadenoma. Interestingly, even in the case of ADH, one of the interesting features of fibroadenomas that are involved by LCIS, DCIS, or ADH is that those lesions tend to be confined to the fibroadenoma itself. And so some authors actually suggest that if you have a small ADH within a fibroadenoma, that further excision may not even be warranted, given that finding. Now the diagnostic challenge here, always, is to exclude something more sinister, such as a phalloides. And so in order to determine a phalloides, we look at the stroma. And so we're looking at the degree of cellularity of the stroma, along with other features, such as atypia, mitotic activity, necrosis, these types of features. And if present on a biopsy, we often are sort of left on the fence, because we can't really nail down the diagnosis as to whether it's a phalloides and even what subtype of phalloides, whether that be benign, borderline, or malignant. And so you're often left with a diagnosis that reads something like fibroepithelial lesion with increased stromal cellularity, which is basically just an indicator that we need to see more in order to classify this. And so it's usually the final classification is going to be deferred to resection. And the last of the lesions that I'm going to discuss today is large duct papilloma. Large duct papillomas, they arise from the larger ducts, the lactiferous or the major ducts of the ductal system. And essentially, a papilloma, which is benign, is a neoplastic proliferation of epithelium that lines fibrovascular cores. So notice here, this pink represents a fibrovascular core, and you've got this epithelium, which is lining the surface of it. So that allows us to see that there's a papillary proliferation. Now in a true papilloma, the future risk is very low, and there's also an extremely low risk of upgrade to DCIS on excision, less than 2%. I'm not going to go into the details of the study here, given the limits of time, but essentially, a papilloma on biopsy usually is not going to be associated with anything more sinister near the biopsy site. The diagnostic challenge is to exclude other papillary lesions. So as we're looking at papillomas, we're always trying to exclude the presence of ADH or DCIS, we're also trying to exclude the possibility of papillary DCIS, which would essentially mean that the entire papillary proliferation represents DCIS, or other things such as encapsulated or solid papillary carcinomas. Now the way that we do that is based on sort of mapping out the myoepithelium and the clonality of the cells present within the lesion. And so on this very last slide, what I'm trying to show here is just some of the techniques that we use to do that. Notice here that this is a papilloma, you've got your fibrovascular proliferation lined by epithelium, but you've got this expansile epithelial proliferation. And so the presence of extra cells is always going to raise the possibility of hyperplasia versus neoplasia. So here, morphologically, this appears to be hyperplasia, or UDH, and we can confirm that by doing what's called a 5-6 keratin stain, which helps to show the spectrum of epithelial cells and also will support the monoclonality of this hyperplastic proliferation. So this would be an example of a papilloma with UDH. On the other hand, on the bottom here, we also have a papillary lesion. Notice the fibrovascular core lined by epithelium. It again has an expansile epithelial proliferation, however this expansile epithelial proliferation has some appearances that are suggesting clonality, in which case we would be making a diagnosis of DCIS. So we can use the 5-14 stain here to show the negativity or the lack of 5-14 as a cytoperitin filament, and this then allows us to prove the monoclonality of the proliferation, allowing for a diagnosis of DCIS. So in conclusion, we talked about a series of lesions, and we also spoke about how to define risk. And so essentially there's two types of risk we want to consider. The first is the risk for future carcinoma, which can lend to certain chemoprevention and other types of recommendations on how frequently to screen, perhaps. And then also an elevated risk of upgrade on excision, which is always going to be dependent on red path correlation, especially in the more recent studies. So thank you very much. So I'm going to talk to you about the management of these high-risk lesions from a European perspective. And when we're talking about high-risk lesions, often what I find is that there is confusion. A lot of people think of high-risk lesions and equate that to BI-RADS 3, and they're very distinct. So as Dr. Sattar beautifully described, high-risk lesions are defined histologically as lesions of uncertain malignant potential when we look at the UK classification, whereas BI-RADS 3 is an intermediate category in the breast imaging reporting and data system. So if you have a BI-RADS 3, it's probably benign with a risk of malignancy from 0% to less than 2%. So BI-RADS 3 does not equate to a high-risk lesion. So in my presentation, I'm going to talk about the importance of developing guidelines. I'm going to talk about the key difference between the UK and the international consensus guidelines. I'm going to talk about why these high-risk lesions are important from a radiological perspective. And then I have the pleasure of being able to present data from the English National Breast Screening Program. So when the Marmot review was published around 2012, this was looking at whether breast screening saves lives, because you'll be aware that the UK breast screening program was getting a lot of criticism. Fortunately, the report said that breast screening does save lives, but there was a lot of focus on over-diagnosis. And when we talked about over-diagnosis, suddenly our surgical colleagues were blaming us for over-diagnosing cancers, lesions, and saying that we were resulting in over-treatments. Fortunately, the narrative changed and the pressure moved on to the surgeons, because we realized that over-diagnosis was inevitable. We cannot, on a mammogram, decide if the calcifications are benign, high-risk, or DCIS. And therefore, what we had control of was over-treatment. And so following the Marmot review, it was recognized within the National Breast Screening Program that these high-risk lesions probably fell into the category of over-treatment. So what could we do to minimize that? So we set up this multidisciplinary working group, where we had two radiologists, of which I was one, with three pathologists and three surgeons. And at that time, we did a comprehensive review of all the literature involving these high-risk lesions, and we developed pathways for managing each individual high-risk lesion. But when you develop guidelines, it's really important that your objectives are clear, because that will determine the success of your guidelines. So our objectives when we developed the UK guidelines were, one, to stop women from going for surgery, benign surgery, unnecessarily, because most of these cases ended up staying benign. And the second one was that we wanted to identify the cancer preoperatively. So we know that these lesions do get upgraded to DCIS and invasive cancer, but if we can diagnose them preoperatively, then what that means is that the lady will only have one operation, which is a therapeutic operation. So those were our clear objectives. So when we developed the guidelines, they were endorsed and adopted by the National Breast Screening Program, and they became an appendix to our assessment guidance document in 2016. And in the UK, we have a national screening program, and when women are recalled because of a mammographic abnormality, we call that second-stage screening. That's still part of the screening program. And then our guidelines were published in 2018. So when we developed our guidelines, definitions are really important, because if you're not clear, then people will misinterpret your guidelines. So we made sure that we used the term vacuum-assisted biopsy and defined it, and vacuum-assisted excision and defined it, because when you look at the literature, people use this terminology interchangeably, which creates confusion. So for the purposes of our guidelines, vacuum-assisted biopsy is where you are replacing your conventional 14-gauge core biopsy with vacuum to make a diagnosis. So you're aiming to take minimal tissue. And in the UK, most of our stereotactic biopsies have moved to vacuum-assisted biopsy rather than 14-gauge, but all our ultrasound-guided core biopsies are still 14-gauge. Diagnostic vacuum-assisted excision is where we are using vacuum to replace the surgical diagnostic biopsy. So here we're aiming to take plentiful tissue. And if the lesion is small, we will excise it in its entirety. But if we have a larger lesion, then what we will have is representative sampling. Now what you have to remember is in the UK, when a lady goes for a surgical diagnostic biopsy, the surgeon has to take less than 20 grams of tissue. Now that, again, is a patient-centred KPI because you shouldn't be excising lots of breast tissue for benign lesions. So when we are doing diagnostic vacuum-assisted excision, we're aiming to obtain representative sampling and replace the surgical diagnostic biopsy. Vacuum assisted excision is a significant biopsy. You will end up with more complications such as bruising and hematoma. So it's really, really important that you recognize this and that your team are skilled and recognize that you're doing an important biopsy with higher rate of complications. We will always perform a mammogram post vacuum excision unless the patient has had moderate bleeding and then we will defer the mammogram to when they attend clinic. The reason that we're doing the mammogram is to see has the lesion been excised in its entirety and is the marker clip in a good position and these are two important points. So the traditional pathway for managing these high-risk lesions were that if you did a core biopsy you got a high-risk lesion you needed more tissue and that was traditionally surgery. So all high-risk lesions were managed with surgery. Now within the UK what we're saying is that yes if you have a high-risk lesion and core biopsy yes we need more tissue sampling but we will do this with vacuum assisted excision. Now the UK guidelines say that we can do that for all lesions except papillomas with atypia, fibroepithelial lesions and then your spindle and stromal cell lesions and the reason for that was our pathologists. They wanted these lesions excised whole rather than piecemeal with vacuum assisted biopsy. Now the international consensus guidelines agree with what we've said in the UK except for the management of atypical ductal hyperplasia. So this is just an example of one of our pathways that we use for our high-risk lesions and what you'll note is that multidisciplinary discussion is really important. We're saying if you have a core biopsy and you have a high-risk lesion we would discuss that at the multidisciplinary meeting. We would then go on to do vacuum assisted excision if appropriate and we would rediscuss those findings at the multidisciplinary meeting because we want to look at the pathology but also look at their risk as an individual and then decide on the type of surveillance or whether we've upgraded to cancer that they need to go for a therapeutic operation. Now the reason that we've always said traditionally you need further sampling is because we've got a field change in the breast. So when you do your initial core biopsy we know that there will be under sampling. So I tend to get a bit nervous when people say well we've got five millimeter cluster of calcifications, we did a core biopsy, we got ADH, we can just do active surveillance because for me that field change hasn't been adequately sampled. So we would always recommend further sampling and even if the calcifications have been removed we would go on and do a vacuum assisted excision because you may miss the co-existent DCIS. So why is there a difference between the UK guidelines and the international consensus guidelines? Well it centers around what are your objectives. So as we said in the UK we wanted to identify cancer pre-operatively and we wanted to stop women from having surgery, benign surgery unnecessarily. Whereas in the international consensus guidelines they had stated that your upgrade rate should not exceed 5% for invasive cancer and 10% for DCIS. So if that was the case then you had to do surgery. Now ADH is the most contentious of all the high-risk lesions but by definition it's intraductal epithelial proliferation showing the features of low-grade DCIS but in less than two duct spaces or less than two millimeters in diameter. So just remember that. So when you look at the guidance that's out there the National Cancer Comprehensive Network they say if you have ADH and core biopsy you should do surgery. The American Society of Breast Surgeons again they say if you have ADH and core biopsy you must do surgery except if you have small volume ADH which has been completely excised by the core needle biopsy and imaging and pathology is concordant then you may do observation. The American Rheumatogen Society again have a flowchart which says that if you have ADH and additional atypia you must do surgery but if your ADH has arisen from calcifications on a mammogram and is small volume then you could do active surveillance but if not then you need to do surgery and if your ADH was diagnosed on an ultrasound or MRI then you must do surgery. You know that in the UK we recommend vacuum assisted excision and the German Society also recommends surgical excision. So there's an added complexity that if you have a high-risk lesion and core biopsy the lesions excised on mammography then in America and in Europe they're saying that you may could just do surveillance rather than doing further sampling. But what I put to you is ADH is not DCIS and we at an international level we are trying to minimize overtreatment of low-grade DCIS. We have four trials with Dolores, Lord, Comet and Loretta and in all these trials they're talking about active surveillance for low-grade DCIS with or without endocrine therapy and yet for ADH which is not low-grade DCIS which isn't even a cancer we're recommending surgery. So we're overtreating ADH and we're happy to minimize overtreatment of low-grade DCIS. So the reason that these lesions are important is this was a meta-analysis looking at the traditional management of these high-risk lesions with surgery. So not vacuum assisted excision surgery and they showed the upgrade rate was 17% and when you look at this table you can see that the upgrade rate was high for ADH, papillomas with atypia and radial scars with atypia and it exceeds the 5% and 10% and that's why the international consensus guidelines recommend surgery. So now I'm going to present some data from the English National Breast Screening Program. So we endorsed these guidelines and implemented them in 2016 and we wanted to look at the impact in terms of management of these patients. So this is a study population from the 1st of April 2018 to the end of March 2019 and this data was extracted at a national level from the breast screening information system and we split the lesions into high-risk lesions with atypia and high-risk lesions without atypia. So during this one year as the National Breast Screening Program, we had just over 2.2 million women attend for screening and just under 85,000 were referred for second stage screening because they had a mammographic abnormality and just over 40,000 had a core biopsy of which 3,355 were high-risk lesions. So we had a high-risk rate of just under 9%. We diagnosed 556 cancers so we had an upgrade rate of just under 17% which fits with the literature and not surprisingly our upgrade rate was higher for high-risk lesions with atypia than those without. But the introduction of our guidelines have resulted in just under 74% of B3 lesions with atypia and just over 65% of B3 lesions with no atypia being managed with vacuum-assisted excision alone. So they've avoided surgical biopsy altogether. The data highlights that these high-risk lesions do need further sampling to make sure that you identify the co-existing cancer but majority of these lesions will still remain benign and therefore treating them with vacuum-assisted excision is appropriate. So in summary, the objectives of our guidelines have been met. We've reduced the number of women going for a benign surgical biopsy and we've improved the pre-operative diagnosis of cancer in this high-risk group. We know that now that we're collecting national data, this will help us refine our pathway and support research in this area. But we have created a patient-centered pathway that allows them to avoid unnecessary surgery while still identifying the cancers pre-operatively. So thank you very much. Thank you for attending this session. I'm going to talk to you about the American view. We're going to ask some important questions when we talk about the management of high-risk lesions such as what are included in that category. And then what is the scope or burden of diagnosing these high-risk lesions in the United States? And of course, what's the impact on our patients? And what are our standards? Dr. Sharma just provided a wonderful summary of European and UK standards. What are they in the United States? And then what is changing as we evolve towards greater understanding of these lesions? And so the challenge, I think, in the United States is that we don't have a national health system. Now there are of course advantages and disadvantages to having an organized national health service. But we really operate in a patchwork of private and public standalone imaging centers, hospital systems, as well as academic medical centers throughout the United States. And so we have quite a heterogeneity of how patients interface with our health care system as well as their breast health. What we do have in the United States are a few organizations that provide us with some guidance. But even among those, we don't necessarily have consensus. The United States is not necessarily known lately for its internal consensus. But for example, the U.S. Preventive Services Task Force recommends different screening guidelines than the American Cancer Society and the American College of Radiology. But what we can turn to for guidance with respect to this particular problem is the American College of Radiology BioRx Atlas provides us with a pretty solid document to work with, as well as we have the Food and Drug Administration's Mammography Quality Standards Act. Now that act was signed into law in 1992. This is a graph of the overall death rates from breast cancer since SEER, the Surveillance Epidemiology and End Results Registry published those data in 1930 to now. And you can see that the death rates for breast cancer were very, very consistent until that time when the Mammography Quality Standards Act was signed into law. And this was designed specifically to provide us with a uniform process for and quality metrics for mammography. And since that time, the mortality rate from breast cancer has decreased fairly steadily by 43%. And the law actually specifically states that the radiologist is responsible for program quality and patient management after biopsy. So when we are looking for a guidance document, this is, and it's legal, passed by Congress, this is one of those. Our facilities must collect data on the outcomes of all breast biopsies, correlate with pathology, and repeat biopsies and track complications. We also have to then, of course, manage these patients, whether that includes additional biopsy or additional imaging or referral to a surgeon for excision. Those are all of our responsibilities based on the MQSA. And determining concordance, as Dr. Sharma and Dr. Sutter have described, is critical to this process. And that is also heterogeneous with the United States. For example, at my institution, every time the pathologist is ready to sign off the results from a biopsy, he or she calls me. If I'm sitting in the read room, get a random phone call, hey, this is your pathologist, I have biopsy correlation for your patient, I pull up the images, the pathologist tells me what they're seeing under the microscope, and we have a discussion about whether or not it's concordant. Not everybody does that. And we decide by the end of the phone call whether or not we're sending the patient on for surgery, or she can return in a year, or she needs to return in six months, whatever needs to be done. And reviewing those images, determining if all the calcifications have been excised or not, for example, if the sampling is accurate, is critical to this process. And so, with that in mind from the MQSA, then we can also look to BI-RADS for guidance, which requires us to do our audit. And that means that we have to track all exams, including all biopsies, to determine if they were true positive or false positive. Now, a word about the atlas regarding true positive or false positive is specifically for the detection of breast cancer, which is why, in the true positive column, you only see malignant breast cancers. In the false positive column, you will also find malignancies, but these are not breasts, right? So a diagnosis of lymphoma in the breast, for the purposes of the audit, is a false positive. But we also have classically benign findings, which we're not discussing today, but then what we are determining as high risk, which are also actually benign. And in the BI-RADS fifth edition, these are the histologies that are listed as quote-unquote high risk in the false positive or benign column. And what I can tell you is that the data, since the fifth edition was originally revised in 2013, have continued to evolve, of course, and what we are now moving towards is moving papillomas out of the high risk category and into the benign category. Again, these are still considered false positives and all considered benign for the atlas, but when these discussions about what we should be managing as additional risks come up, these are being moved. And we are also considering moving or changing the name because we have now, I think, discussed amongst us today at least three different definitions of what consists of high risk, whether it's a lifetime risk, an immediate risk, or also a B3 lesion, right? Which is different from a B3 lesion. So, and we want to emphasize that these are technically benign. Now, you'll see that there are a couple on this list that I'm going to ask you a question later as to whether or not you think they should be in the benign category. Shhh, pleomorphic LCIS, Florida LCIS. Okay? So, now let's talk about the scope of the burden of this in the United States. So, roughly, we can estimate that approximately 30% of our biopsies are going to be true positives and 70% are going to be false positives, and that varies a little bit from practice to practice, of course. But for the sake of estimates, let's say that that is an average. Now, in the United States, we have, and these are straight from SEER, estimated 287,000 new cases of invasive breast cancer and 51,000 cases of DCIS. And so, together, that's 339,000 cases of malignant breast cancer in the United States. And I didn't, these are all approximations, but those are the data that are coming from SEER for this calendar year. And so, what that means is that we also have over a million biopsies in this country every year. And the vast majority of those are benign, of course. There are some malignant non-breast cancers, but we probably diagnose over 100,000 patients a year in the United States with a high-risk histology. It's a lot. And I think from the perspective that Dr. Sharma is saying, I would fully agree that we want to do everything that we can for patients to diagnose breast cancer and nothing that we don't need to do. We need to constantly balance those two things. So, that leads us, of course, to discussions about whether or not we need to send patients for surgery. So, let's talk about that. And I'm going to gloss over this because, actually, this has been summarized very well by my colleagues here. There's long-term risk, of course, and for lobular neoplasia, for example, it's four times relative risk and accumulative incidence of breast cancer approaching 30% at 25 years for other atypical ductal hyperplasias as well, as Dr. Sutter suggested. And what that has led to in this country also are these guidelines published in the JACR as a summary of the American College of Radiology, which includes patients who are post-menopausal with breast cancer or have been diagnosed with ADH or LCIS at any time in their lives. Basically, this qualifies them as lifetime risk that is into that area of threshold of 20% or above where we also recommend, for example, annual MRI as a supplemental screening tool. And so, this also then fits into our current evolution into capturing those patients so that they can be plugged into the system and get the additional supplemental screenings that they need. And I will tell you, so my institution, and I think that many institutions are at different points along this evolution, we capture demographics at the time of the mammogram. We do a family history questionnaire. But unless you ask it every year, you might miss new or different updates. We have an automated breast density system, but it's not included in our risk model. We have limited openings with nurse practitioners and genetic counselors for high-risk discussions for these patients who are either newly diagnosed with a high-risk lesion or cancer. What we want or what we strive for, I think, is to be able to capture all patients who are high-risk by detailed family history questionnaires and automated model and a functional high-risk clinic that has openings relatively in short terms to talk to any patient who meets this threshold, along with a separate reminder system for those patients who meet that threshold. So the other thing that we have discussed is short-term risk. The patient currently has a higher-than-average risk of undiagnosed DCIS or invasive cancer at the site of the biopsy. And I think in the United States, it's fairly consistent that ADH is sent for surgical excision. Or when we do our correlation with the pathologist, either over the phone or through medical records, the vast majority of us say ADH recommends surgical excision, which is different from recommend surgical consultation or recommend discussion of the options of surgical excision versus imaging follow-up. And so ALH is very different in this regard. So at my institution, we are certainly recommending that patients have a lifetime risk assessment when they're diagnosed with these, and the ADHs are sent for surgical excision. But ALH is different. So we did an internal review of both our experience and a literature search for the data. And what we discovered or what we find is that the actual upgrade, the immediate upgrade of lobular neoplasia to DCIS or invasive malignancy is very low. So less than 2% actually is that same threshold for which we would call something a B3, a BI-RADS 3, not a B3, and allow patients to return in six months for imaging. And it's also actually lower than just the average risk of cancer for women. I believe it's 65 or 60 to 65 in our country. At that point, the lifetime, the average annual risk of being diagnosed with cancer hits 2%. And so with that level of or at that threshold, we looked for studies that were sufficiently powered with exclusion of non-classical DCIS and other lesions as well as adequate RADPATH concordance. And there are very few of these that exist. Dr. Sauer has also already cited Nicholas and colleagues. And these two studies that meet those rigorous standards show that there's a less than 1% risk of upgrade for lobular neoplasia when all those criteria are met, right? No other high-risk lesion and excellent RADPATH concordance. And then we also refer to the American Society of Breast Surgeons, as Dr. Sharma did earlier, to find that they have also recognized this, that when the core biopsy of lobular neoplasia is made and there are no other lesions and it's concordant, the upgrade rates are very low. And so they no longer recommend routine excision. So on the same page of us as well as the Europeans is don't do surgery if you don't need to. Let's really think more cautiously about what we're asking and what we're doing. Now, this also makes a caveat that there are non-classical LCIS variants that we have to treat differently. And so at our institution, what this meant was we needed to get together with every stakeholder in this process. So that meant that we had meetings with radiologists and the pathologists and the surgeons, as well as our APPs who frequently receive patients to discuss their high-risk histology and what it means for them and what their options are, as well as medical oncology sometimes actually gets involved to prescribe chemopreventive agents or risk-reducing agents. So it's really a team effort to make sure that your system is on the same page. And, again, since in the United States it's very much a patchwork of health care providers, this is incredibly important. And so this is the new pathway that we came up with. So it's the management of patients with lobular neoplasia. And I'll just make it clear that pleomorphic LCIS and florid LCIS are not here, but if the routed path is discordant, stick with surgical excision. If there's additional high-risk histology, stick with surgical excision. If they have cancer, they go for the entire oncology management. But if it's concordant and it's lobular neoplasia alone, then they are invited for a discussion of the option of excision versus imaging surveillance. And the imaging surveillance is then in the same vein as our typical two-year follow-up for biurets 3, again, that 2 percent threshold, where if it was calcifications discovered on a mammogram, then they would have a mammogram every 6, 12, and 24 months. If it's stable, then they're back to annual screening. And, of course, they are also at the same time referred for the discussion about their lifetime risk based on the elevated risk that we've mentioned. So to summarize, our patients with ADH or lobular neoplasia are at this increased risk, which we've now said a few different times, and should get plugged in for potential supplemental screening. Those with benign and concordant lobular neoplasia really have a very low risk of immediate upgrade and could be followed. And so what this means is when I look at this, and this is the sneak preview of the upcoming BI-RADS chapter, the question becomes, should lobular neoplasia, ALH, and LCIS still be in this category? I don't have an answer for you. I'm actually curious to your opinion. I am actually very curious to what you think about that. And then also I'm also very curious about your management of pleomorphic LCIS and fluoride LCIS and not if it should be moved to benign, but does that still stay in this high-risk category? So that's my summary for the American experience. And, again, I thank you for inviting me to share that with you.

high-risk breast lesions

pathology

management strategies

diagnosis

proliferative diseases

European guidelines

surgical excision

multidisciplinary discussions

conservative surgical approach