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Okay. Thank you all for staying with us. So we're not going to move on to the second part of this evening where we're joined by Doctor Lisa Johnson, also from the Pathological Society and she's going to be taking us through key concepts in breast disease and with a focus on commonly examined topics within MRCS. Um So thank you Lisa for joining us today. No problem. Thanks for having me. Okay. Can you see that now? Perfect. Yeah. Okay, great. Thank you. So, we're just gonna be running through some rest pathology today. Um I'll try and keep it quite short. I've had to look through as many past exam questions and papers as I could and I've tried to include what I think is um the topics that come up again and again and hopefully relevant. Um I didn't put questions into my talk, but I do have a list of questions. If anybody wants them, I can send out what I've got uh separately afterwards if anybody's interested. Okay. So we'll make a start. So just a quick overview what we're going to go through today. So basically, why, why are we talking about breast pathology? Today. Um then going on to recapping some anatomy and basic astrology, breast screening and triple assessment, then common encountered breast pathology um with a focus on things that I've seen coming up. And um past paper questions, this tends to be actually quite a lot of benign things and, and then sort of federal studies and genetics just to end on high. So a few breast cancer statistics to start with, um there's more than 55,000 people diagnosed breast cancer in the UK each year. Um Of those, about 390 I think it is our, our men. So, um it's only about 1% of male cancers and not in the top 20 but for women, um it's about 30% of all new cancers um and 15% of all new cancers overall um combined um and the lifetime risk um for a female getting breast cancer in the UK is currently one in eight. Uh common benign conditions can mimic breast cancer. Um And over 90% of symptomatically presenting breast lesions are benign. Only about 5% of breast lumps are cancer um that are symptomatic. That is, and approximately 45% of breast cancers are symptomatic and the remaining detected by screening. So we start with a little bit of a revision on anatomy. So um there's 6 to 10 sort of major ducks um extend from the nipple and those branch um further into minor ducts and then terminate in um the terminal duct lobular units. So you have eternal duck surrounded um by small Osanai um forming a lobule. Um And there's stroma both within the lobules and between lobules. And then the majority of the breast tissues actually formed by the surrounding adipose tissue. Um And this is what it looks like histologically. So, and if you look at the image on the left hand side, that's probably the uh best one to start with. We've got down in the left hand corner, a large duct and then you can see up towards the top of that left hand image. Um There are several La Buell's with surrounding stroma and then you can see some fat at the very top of the picture, some of the edibles tissue just at the edge. Um Then on the right hand side, the top image shows you some nice lobule surrounded by stroma um with um some ducts. So these are the sort of terminal duct lobular units. Um And then the bottom in that showed you the intralobular stroma um surrounding um the Osanai. And you've got a basement membrane which is that pink um sort of structure encircling the Osanai, which is important when you're looking at um in situ or invasive disease. Um And then you've got a layer, a double layered epithelium. So you've got the inner Luminal cells next to the secretions and then surrounding myoepithelial cells which are more compact and have sort of cytoplasmic clearing. So we'll move on to talk a little bit about breast screening. Um So women aged 50 to 70 invited every three years. Um You can still attend three yearly after the age of 70 currently at request. Um And this is importantly because 24% of new breast cancer cases are diagnosed in women who are 75 or over. And I think there's currently work in progress looking at extending the screening program. Um So the basis of the breast screening is mammography. Um and then on the clinical review, if they're abnormal findings, and this could be either mass or only 5% of mammograms are abnormality is detected. And so um then go on two triple assessment and mammography does increase. It's sensitive page. Yes, her a lesion detector there will be cancer over the age of 50. This increases 25%. So you can see why starting the screening program at age 50 is currently indicated. So if mammography detects an abnormality, we move on to triple assessment. Um So that's a combination of clinical examination. Um and these are all rated. Um there's three components, there's the clinical examination which is ready P score. Um So you get a P one kind of members palpations, although it's kind of impression um is normal P two benign P three intermediate, but likely benign P four suspicious for malignancy and P five is malignant. Um then if you move onto imaging um this is either mammography or ultrasound and usually ultrasound for women on the age of 35 over the age of 35 straight to um mammography. And that has similar scoring or identical scoring to the P system. So you got em for mammography and you for ultrasound from normal to, to malignant and then pathology. Um We use either core biopsies or fine needle aspiration cytology. Um And that has A B one or C one to be five C five classification as well, although it's very slightly different. Oh good. So B one is normal breast tissue but um on a biopsy, we would call this not diagnostic because actually we are looking at a biopsy taken of a mass or calcifications or a lesion. If we don't see anything, then we're not really calling that benign. We're calling it non diagnostic because we haven't sampled whatever the lesion is that the clinicians think they have and be too is are benign and then be three lesion of uncertain malignant potential, similar but not quite the same. Um as A P three M three U three which is similar, but they're calling it likely likely benign and be four suspicious and B five malignant same. Um but be five is further subdivided into carcinoma in situ be five A or invasive carcinoma. B five B uh cytology similar except see one is inadequate. We haven't actually got enough cells to tell what, what is um there. What isn't? So we can't comment on that. So we call it inadequate and the rest is all the same. So, apart from um screening detected lesion's or other common presentations of breast disease, uh self detected lump or just a generalized nodularity or lumpiness to the breast pain, nipple discharge, skin changes, either the nipple or the breast skin including rash, scale or crusting, dimpling or puckering of the skin can also be a change in shape or size of the breast or the nipple, including nipple inversion. Um We'll go through some of these in a bit more detail. Nope. Uh um I thought this was quite a good diagram because it kind of highlights how all the different components of the normal breast can give rise to either benign or malignant conditions. So it's kind of showing you on the left hand side, the normal structure, the breast with the normal lobules and Osanai. And then um in the middle, you've got your benign conditions like intraductal papillomas, like epithelial hyperplasia and fibroadenomas. Um And then the stomal component, you can get a hemangioma and then um over on the right hand side, um we've got the malignant side although followed, these will come in to come onto that in a minute, but that can have a range from benign suitor malignant. Um And then you got D C I S invasive carcinoma and the stoma component and angiosarcoma. So it's just a nice sort of diagram to illustrate how the different components of the breast can give rise to different types of lesion's. We're going to start by looking at some benign breast lesions. So these will be mass performing lesion's. Um First, we're gonna look at fibroadenoma. So this has an age range roughly from 15 to 35 so openly young women. Um It's usually a small round to avoid mobile um lump that's far more rubbery and texture. And this was called the breast mouse because on palpation, it kind of um moves um and it's not tethered. Um they're usually small, so 12, about 2.5 centimeters and grow quite slowly. Um They can change shape or size or, or disappear. Um particularly after menopause, I think they can um disappear and on imaging, they'll be well circumscribed, either hyper or eyes were quick on ultrasound. Um Not usually concerning if we look at apology. Um This lesion has got two components. Um It's bi phasic, it's got connective tissue which is usually a spindle cell stroma. Um and then a bilayer epithelium, uh epithelium can show some hyperplasia or metaplasia as could be seen elsewhere as part of benign changes in the breast. Um but um it shouldn't have um any malignant components. Um Older lesions can have calcification um and these can show up on screening as sort of indeterminate um areas of calcification which might lead um to being biopsied. Um Sometimes they're difficult to distinguish with loads on a core biopsy. Um, because as we'll see, in a minute, they can have quite similar, um, structure and they might look similar. Um, so sometimes they need to be excised to tell. Um, usually because they're benign, narrow excision or even just sort of shelling out, they sometimes just sort of pop out, um, is sufficient and there's not usually further surgery needed if it just, um, shelled out like that, uh it's over. So the image on the left just shows a macro picture of a fibroadenoma. It looks like this one has really been shelled out. You can see on the left hand side of, of this image that it's um quite, quite a loculated sort of creamed pinkish um cut surface and it's got these sort of slip like spaces in it. Um It doesn't look concerning because it's quite um well demarcated. Um and it doesn't look like it's got a pushing or infiltrative border. Um And if you look on the right hand side, you've got two images of different patterns you can have um just showing the um stromal component surrounding the epithelium and in a fibroadenoma, the stroma component and the epithelial component should both be well represented and sort of they grow at equal rates. So you've not got an overgrowth of stroma in comparison to the epithelium. It's all sort of looks still in roughly in proportion um to the normal breast tissue unless it's important when we do want to talk next about maladies because that's a bit different. Nope. So floaties tumor has a slightly older age range. It's usually sort of 40 to 50 years, um, kind of perimenopausal age range. Um These do range from benign through to malignant and the benign ones tend to occur at a younger age, although all can be represented different ages. Um, they're pretty rare, they constitute only 1% of breast tumor's and um usually present as a firm mobile breast mass there, often fast growing and usually they're larger than fibroadenomas. Um Although obviously you can get large fibroadenomas and small uh maladies, but they tend to be larger up to about 20 centimeters. Um They are oval or loculated on imaging and look hypoech quick on ultrasound and then if we look at Oh really? Uh huh. Yeah. A by layered. Uh and that isn't it is. Yeah. Uh strong muscle, the stroma um is the part in the lesion that's proliferating more quickly and it's growing the epithelial component. Um So regionally component in the fluids. Um and it gives a sort of characteristic leaf like architecture is, it's called um I think uh Fellegi means leaf like in Greek. Um but it's really the, the stroma that's making it have that appearance because it's outgrowing and sort of compressing the epithelium. Um They are divided in tim benign, borderline and malignant based on changes in the stromal compartment. So, um things like mitosis and other elements and sort of pleomorphic stroma, um local excision with clear margins um is usual management. Um narrow margins can be sufficient for benign lesions. Um kind of similar to um fibroadenoma, but good margin is required for the malignant cases. There is up to 30% risk of local recurrence um with malignant lesion's and a 9% risk of distant metastases. However, axillary clearance isn't indicated in these lesion's because even with um distant, distantly metastatic lesion's, um usually there's not any nodal disease, they don't really spread through the lymphatic. They kind of act similar to um other stomal lesion's likes are comas and they're more likely to spread um by blood um or local um invasion here. So, on the left hand side, you can see a mac scopic picture. This is a benign fluids and it's got quite a well circumscribed edge and one of the features of the malignant ones is that the margin starts to become a lot more infiltrative. Um And this one's quite sort of loculated. It's not hugely dissimilar to the fibroadenoma that we saw a slightly less regular architecture. Um On the right hand side, this is kind of what is classically described as the leaf like architecture. So you can see stroma surrounding the sort of elongated um sort of narrow epithelial channels and sort of compressing um compressing that so the larger sort of lobules of stroma are outgrowing the epithelium here. So I have, my computer is reluctant to move on the slides. Here we go. Um So next, we're gonna have a little look at fibrocystic change. This is usually, well, this is benign as well. And it's a secondary response of the breast tissue to hormonal fluctuations. It's common founding over 30% of premenopausal women. So it's usually um I mean, it can be found um through all the age ranges, but it is like predominantly in younger women. Um and usually presents as a generalized modularity that should be nodular retty, not modularity or lumpiness. Um So it can present women can present um themselves having noticed um a nodularity of lumpiness to their breath or it can be picked up on um screening it's multifocal often and bilateral, but you can get solitary cysts as well. Um Small sister seen on ultrasound is not usually a mass on imaging hugely dense breast tissue, but you can have calcifications or architectural distortion as a result of these um sort of cysts and other changes. Sure. Yeah, that's it. So here's a couple of images or fibrocystic change you can see up on the top right there. It's not as well defined um as some of the other lesions we've seen, but they're centrally, there's an area of um sort of cream fibrosis and there's a few little cystic areas around. Um and the image on the bottom, right, we'll discuss in a second. So, fibrocystic changes, sort of an umbrella term use describe common benign breast conditions, either one part of it in isolation or in combination. Um So, essentially excess estrogen leads to proliferation of the epithelium um in the terminal duct lobular units. And this causes stromal fibrosis which kind of struck ducts and Assani, which causes cysts to form. And you also get evolution changes. Um and sometimes a cyst rupture causing inflammatory reaction leading to sort of more fibrosis. So it's all response to hormones and increase or turn over, but it's completely benign changes. Um There's not any abnormality of the epithelium. Um although you can get sort of some hyperplasia and metaplasia, um you won't be getting any dysplasia in it. So you get a combination of a cream metaplasia, usually cyst formation adenosis, which is high plastic proliferation leading to enlarged La buell's with an increased number of glands. It's just big looking lobules. Um and you can get mild epithelial or storm or hyperplasia as well. Um And this image on the right, the lower right shows sort of cystically dilated ducts and they've got some benign calcifications, microcalcifications within their. So that might be a reason that ends up getting um biopsied if you see calcifications and investigating. So just a quick run through of some other potentially mass forming lesion's. Um fat necrosis is usually painless, um forming a palpable mass either or skin thickening or some, some retraction. Um on mammography can look like a density or you can have calcifications within it. Um Usually about half of the cases will have history of trauma or surgery. Um And I haven't got a picture of this but um looking at it down the microscope, you see hemorrhage and liquid active fat necrosis with neutrophils and macrophages in the early stages. This will be followed by fiber blasts, um which will lead to sort of fibrosis and scar tissue. You have giant cells come in calcification um and they'll be hemosiderin deposition. Um So this is important because this can be one of the mimics of cancer. Um And quite often will be biopsied because it might have calcifications and it might be a dense looking mass. Um So it has to be investigated, but usually on biopsy, we can tell it's just fat necrosis. And as I say, like 50% of people have a history of trauma. A lot of people won't remember having any history of trauma, which should be another reason. Um If you don't have a history, you might need to look further into it. Um Lymphocytic mastopathy, I've seen a question about this um come up. Um It's also called closing limb Pacific lobby litis. Um This can be single or multiple hard palpable masses. Um On mammography, they look dense. Um And when we look at down the microscope, we see dense storm containing a trophic ducts and lobules with a prominent cough of lymphocytes surrounding the a trophic ducks. Um and the question I've seen come up, I think about this was related to its association with type one diabetes. So, um it's associated with diabetes and also autoimmune thyroid disease. Um, thought to have an ottoman basis. Um, but it's benign as it's fat necrosis. And again, it's something that can be a cancer mimic because it's got hard palpable masses um and might be detected on democracy. Um And then lastly here, radial scars. Um these are usually incidental um and they show up as a stellate or that should be speculate autocorrect is fix that for me, a speculate mass um on ultrasound, not an ultrasound and mammography. Um And when we look down the microscope, we see central scarring and then surrounding proliferating glandular tissue radiating outwards from the central scar. And that's what causes really the specula, it stellate appearance um which is concerning on mammography has appearance similar to cancer, but it is benign. Um itself, it's not malignant, but it does increase a person's risk of having a malignancy. Um not that it will transform to become malignant, but just it's an association. And if you've got a radial scar, you're an increased chance of having pregnancy. Okay. Um So another benign breast lesion that can be associated with the mass or discharge is docked Act Asia. This has an age range sort of typically from 40 to 70. It's usually perry or post menopausal women, um usually presents as a palpable period. Area, older mass can feel wormlike or do we? Um And it's quite often associated with a thick white discharge. There might be some skin retraction which might be concerning. Um and it can be difficult to distinguish and D C I S radiologically because you can get this ductal pattern of calcifications forming, which can be quite concerning. Um and it looks like um down the microscope, so involves the large extra lobular ducks. So it's not the small ducks. Um Down near the Osanai, it's um the larger ducts and these become dilated and filled with secretions. Um and duck locked rupture then leads to parodontal inflammation and fibrosis. Um You get foamy macrophages, which on the picture here, on the right hand side, you can see there are a couple of ducks around that are quite dilated and then sort of centrally semi to the left hand side, there's a large um ductal space that's been filled by foamy macrophages, which is actually um sort of going into the wall. Um So they're within the lumen of the doctor and also in the wall and that's kind of what we always see with that. Um So that can be concerning from either the mass point of view or um from having nipple discharge, another breast lesion that can cause discharge as an introductory papilloma. So, these are common about 5% of all benign breast lesion's. Um And our senior women of all ages, not particularly associated with any age but not really um present in males. Um They usually present as either a serious or serious angriness nipple discharge, um can also present as a retro retro Lyall mass if they're quite large. Um not usually that large, um they can be an incidental finding if they're more peripheral um these, so here we've got a Mac stopped image on the top, right, a little bit difficult maybe to see, but at the top of the image there's a sort of nodule um with a smooth outline. Um that's the introductory papilloma and you can see nicely down on the bottom, right. There's a duck there with a little um production elated lesion extending into the lumen. So they usually well circumscribed and polypoid um like the one we see here and the present in a cystically dilated duct um due to the proliferation of benign epithelial cells. Um it's got a nice fiber vascular cores and hasn't attacked my epithelial layer. They can be solitary and central arising from the large lactose free stocks. Um And these will be the ones that are more likely to produce a discharge um and be um felt if they're in the peripheral ducts uh near the nipple. Um They can also be peripheral and multiple involving a terminal duct liberal unit, but these ones are much less likely um to be felt or produce any discharge and usually be incidentally detected. They're completely benign. Um Yeah, there's not any consensus on their management unless they happen to be involved by epithelial atypia when they should be excised. Um, but for the benign intraductal papillomas, um I've, well, I've experiences they're generally are excised, but there's not really a consensus on whether that's necessary or not. Um, so I'm just going to run through a list of causes of discharge because I've seen this come up in quite a few questions and there's different types of discharge, different causes. So I'm just gonna put a little list out that and make things a little bit easier. So glad to be a milky discharge can be either normal um or related to elevated prolactin levels due to maturity, adenoma due to hypothyroidism or other endocrine and of history syndromes. Um can also be caused by medications including the oral contraceptive pill, tricyclic antidepressants and methyldopa amongst others. Actually. Um If there are thick secretions, oh, that should say doctor Tasia, um Autocorrect again. Um If the discretions are thick as we've already talked about, this could be a doctor to Asia um present discharge. Um This is most likely abscess. So, mastitis and uh lactating women usually occurs during the first month of breastfeeding. Um get cracks and fissures in the nipple. This let's bacteria get in um usually staph aureus, which can lead to abscess formation if not resolved. Um less commonly strip um species going to also um Kozmus itis. Um but this more like more often leads to a cellulitis than abscess formation. Abscess is also seen in squamous metaplasia of lactose free stocks. And this is usually um seen in smokers and um essentially smoking um affect the squamous epithelium causing um keratin plugging of ducks. And this leads to dilatation and rupture of the ducks and yeah, lock ducks um can lead to abscess formation that way as well. Um Bloody serious or serious sanguine is discharge, have already covered a couple of these um large doc papillomas as we've already discussed um cysts um such a scene in fibrocystic change, pregnancy. Um you can get a bloody discharging pregnancy just to the due to the rapid growth in remodeling the breast tissue. Um and bloody discharge can also be seen in malignancy. This is usually D C I S. Um The prevalence of this increases with age. So if you have a bloody discharge in a woman under the age of 60 is only a 7% chance that there is underlying carcinoma there. Um If the woman is over 60 and just got bloody discharge that increases to 30%. So um increasing concern there, um then we're going to move on to militant breast lesion's. I've not covered these in as much detail regarding the individual lesion's um because I've saved a bit of time to go through some of the hormone receptors and genetics as well rather than focusing on different types of militant lesion's. So um carcinoma in situ first of all. So this is where um you have neoplastic cells, but they're confined by that pink basement membrane that we saw earlier on. So, um in the normal breast, you have the basement membrane surrounding um the nice double layered epithelium. Um So, carcinoma in situ, you've got neoplastic cells filling, the space is um within the Osanai or the ducts, but they're not penetrating beyond the basement membrane. So they don't break through, they're not invasive. Um They don't have ability to metastasize at this point. The risk of progression to invasive carcinoma is about 1% per year. So it's important to get these out. But um usually we'll talk about excision a second. Um There are two main types, there's doctor carcinoma in situ which is usually screening, detected either calcifications most commonly or can be fibrosis. Um You get low intermediate and high grade D C I S. Um Mastectomy is usually curative for these, whether without radiotherapy and hormone therapy as well. Um Lobular carcinoma in situ, that's usually an incidental finding. Um uh usual type LCS is not as concerning, but there are pleomorphic types um as well, which are more concerning um up to 40% will be bilateral and it does increase the patient's risk of developing breast cancer and either breast. So having LCIS in one breast actually increases your chance of developing breast cancer in that breast war in the other one. So I just got a couple of pictures here. Um This first one shows D C I S. Um Well, this first set of images shows dcs sorry. Um So the image a top left um this is um um an image just showing the little calcifications that follow along a duct. Um I don't know if you can appreciate above the wire there. There's actually and below as well as little lines of calcification, little um hyper echoic dots um or hyperdense sorry dots like extending out um almost a sort of a radial pattern there. Um The um panel be top right um contains high grade um Cammy does type D C I s. So it's got the central um necrosis there. Um But it's still surrounded by stroma and you can see that it's not um invading, there's no sort of infiltrative edges there and you can use um even his chemistry and myoepithelial markers to show that the basement membrane there is still intact. Um Bottom left panel C is showing um uh sort of cribriform type D C I s with central calcification. So those would show up like the images in a um And then you've got micropapillary D C I S in the panel D on the bottom, right, which just shows little um papillary projections into the lumen of um a doctor involved by D C I S. Mhm I'm sorry. Um And then these pictures are just to show L C I S. Um So this is usually neoplastic cells filling a lobule. Um and they are much more monotonous looking and sort of small round cells compared with the DCs we saw, they, they don't look as horrible. Um This is just uh uh you tell type L C I S it's um not pleomorphic. So it doesn't have wild looking cells in it. And the picture on the right hand side is showing an EKG here in stain. So LCS like invasive lobular cancer will be uh had here in negative usually. Um So on this stain, you can see the blue colored nuclei and the Luminal epithelial cells are staining sort of brown. Um So that's normal and then you can see underneath that layer. Um There are cells that are not staining. Um and these are the L C I S um cells that are sort of lying along the basement membrane underneath the epithelial layer. Um And I'm just gonna quickly talk about invasive carcinoma. So, the most common subtype of invasive carcinoma um is invasive carcinoma of no special type. This was previously called ductal um because of its phenotype and just uh mentioned invasive carcinoma is carcinoma that has penetrated the basement membrane. So it's now got an infiltrating um margin extended beyond the basement membrane and have had some metastatic potential. So, the invasive ductal or ductal carcinoma with no special type accounts for up to 75% of all invasive breast disease. And there are other special types of which lobular carcinoma is probably the most well characterized. Um Then there's tubular metal plastic medullary pillory and others. I won't list them all. Um But it is important to type them um because it does have prognostic value and provides information on behavior and likely pattern of metastases for different tumor's. For example, a great one, tubular carcinoma has a very good prognosis even when compared to other grade one carcinomas. So even though um other grade one of us might have a good prognosis, it will have one of the best prognoses. Um I just want to mention a little bit about um lobular carcinoma. I haven't really said too much about it here. Um So I'm going to show a picture of invasive carcinoma, no special type. So all these images are invasive carcinoma, no special type. And you can see that can have quite a variety of appearances um both on imaging um and macroscopically. So, imaging on the left panel of microscopically, right, mac macroscopic pictures in the central panel and then microscopic pictures on the right hand panel and you can see from top to bottom, it has a different appearances, but these are all um invasive carcinoma of no special type. So it can still have quite a variety even within that one. And then just say about mobile carcinoma, haven't included a picture of that here. Um But the cells have a similar appearance to the L C I S cells um that we were looking at before but tend to infiltrate um in a sort of single file um manner is often described like that. Um They can be quite discohesive and have signet ring type cells. Um And I'll come on to talk about receptors, but they're usually you are positive and her two negative and we'll have loss of C D H one expression, which is what makes them tick adherent negative like the L C I S that we were looking at a minute ago um doesn't produce much of desmoplastic response. Um So that can make it difficult to detect either a mammography or by palpations. Um I'd say about that. Um Let's move on. Mhm Right. So last uh lesion I want to mention um is pageant disease. So this usually presents as either skin or nipple changes, immitis changes um of the nipple or areola. Um And there's often an associated itch. So pretty rare um only present in about 1 to 4% of all cancers. Um And underlying malignancy is usually D C I S. Um they can also be an underlying invasive carcinoma. Um So the diagram on the right actually shows quite nicely um what's happening. So usually a duct um that extends um up to the nipple surface. So um it gets involved by D T I s and the, the sales of the geese I S um actually spread along the squamous epithelium and out onto the surface of the nipple. Um and this causes a reaction in the surrounding squamous cells that leads to the scale and crossed on the surface. So you get um hyperkeratosis leading to that scale. Um and it's basically a spread of individual malignant cells up and along and out um of the duct but not penetrating the basement membrane. Um So it is individual cancer cells. Um it's not invading because it's just extending up and out um of the end of the duct rather than actually penetrating the basement membrane becoming invasive. Okay, just a quick word about grading. So this is prognostically important. Um There's three components um to the grading and each get a score from 1 to 3. So we get a score for tubular asana or glandular information. So that's how, how like normal breast does it look? Really? And then there's a degree for rating for nuclear atypia opium orf is um how um wild or atypical do the cells appear or um how different from normal breast? Um and then frequency of mitosis which will be low in normal tissue. Um So scores get combined, giving you a score between three and 93 to 5 are grade one, better prognosis, 6 to 7, grade two, intermediate and 8 to 9. Grade three is worse prognosis, um not apply to all of the breast regions and then ever affecting the zoom out on me. Um So this is um staging. Um I haven't gone through the whole uh TNM. But as you can see, um for the T staging is largely based on size for the breast um until you get to T four. Um when you're looking at where it's spread to, um and I haven't included the end because the nose has got a lot of breakdown. But, and your own time interest, I haven't seen any questions come up about staging if necessary. Uh Adam studies. So um for each cancer, we will do E R and pr and her to um E R is positive in the majority of cancers and pr and over half as well. So, steroid receptors status is used to determine whether or not patient benefit from endocrine therapy, either adjuvant therapy or from metastatic disease. Um Most important is er but we always do P R as well. Um We do a semi, semi quantitative assessment using immune, it's chemistry and we give them an all red score. Um anything three and above is um classes positive. Um It's a squirt of eight. So I just said um I'm not going to show a picture of that. The other study we always do is her too. So between 30 and 20% of tumor's will over express her to not expose her to. Um is our secretary Zinke Knees. It promotes cell proliferation and opposes apoptosis by stimulating the vase and pick um P I three K A K T signaling pathways. So, over expression of her to protein mainly due to gene application um in breast cancers associated with an aggressive histological um phenotype and has poor prognosis. Um This is the most common subtype seen in patient's with germline p 53 mutations. Um those with lee from any syndrome and there are substantial survival benefits for patients who have her two positive breast cancer um that are treated with anti her two therapies such as trastuzumab and these benefits are not seen in her two negative patient's. So this in combination with the side effects that these drugs can have and evidence of higher response rates to neoadjuvant chemo for her two positive patient's um emphasizes the need for accurate assessment of her two status. So we assess that by IHC and um in situ hybridization. Um I think some places use just in situ hybridization but we use reflex testing. So um you do IHC and if it's um negative, you don't progress to um in situ hybridization in situ hybridization to confirm if it's borderline, then you do in situ hybridization to confirm if it's positive negative. If it's strongly positive, then you don't need to do any further tests. It's positive. Lastly, a couple of about genetics. So approximately 30% of cancers are due to inheritance of susceptibility genes. Um A proportion of these are due to single gene mutations with either high or moderate penetrates. So that's the risk of the individual with the gene developing the cancer. Um So, most of the high penitence genes from familiar breast cancers are due to mutations in tumor suppressor genes. These either regulate genomic stability or are involved in um pro growth signaling pathways. They have an autism inal dominant inheritance. Um And there's a single copy of JEAN lost um due to the mutation and the cancer development is then associated with a sporadic loss of function of the second working copy of the gene. So, a classic example and um most important for breast cancer is the B R C A or Bracha gene. So, mutations in BRCA one and two responsible for 80 to 90% of single gene familial breast cancers and 3 to 6% of all breast cancers. So, braca one is responsible for this is a breakdown of all, not all but a lot of the uh single gene. Um cancer's um these are the best known high penetrates genes. There are also a few moderate penetrates ones that are responsible for about the other 10% that's missing off of this total of uh percentage of single gene cancers. But you can see here that BRACA one is responsible for 55% of all um single gene cancers. Um The risk of breast cancer to age 70 is up to 90% in females and 1% in males and it has other associated cancer is very in floppy tube, pancreas, prostate. Rachael wanna usually triple negative cancers um So triple negative cancers don't have E R P R or her two expression. Um And they're often associated with defects in DNA repair or genomic stability. Um and have a relatively poor prognosis. Um Bracha to um is responsible for the, the rest, the majority of the rest of the single gene cancers, about 35% slightly less risk of breast cancer. Um and uh about higher risk for males also socially with ovarian pancreas and prostate cancers. Um and these are usually er positive unlike the braca one cancers. Um then p 53 mutations um seen inlay from any syndrome responsible for less than 1%. But I have seen questions about lee from any or not necessarily specific um to breast. Um So as a tumor suppressor gene as well, 50 to 60% of females will develop breast cancer by the age of 70. Um it's also associated with sarcoma, leukemias brain tumor. I think it was mentioned in the top you just had before mine. Um It's usually er, and her two positive. Um then a few other um genes like P 10 seen in Cowden syndrome uh that has variable risk from 20 to 80% and has associated thyroid and endometrial cancers. Uh puts Yeager's, which is STK 11 gene mutations again, less than 1% of all single gene breast cancers. But um 40 to 60% risk by age 70 of developing it has associated ovarian colonic and pancreatic cancers as well. And then, uh, C D H one, um, again, less than 1% but 50% risk of cancer by age 70. Um, and it's associated the gastric significant cell carcinoma and colon carcinoma. I think that's the end we'll have to present. That's me finished. Thank you. Um, have an abrupt end but give him a break there and no. Thank you so much for giving us your time and for giving us your talk.