Carcinoma of the Breast: Pathophysiology

00:01 Pathophysiology. We can break down further whether the tumors that are occurring are noninvasive, that is to say they have not gone beyond the basement membrane.

00:13 So their in situ cancers. And we can have ductal or lobular carcinoma in situ.

00:18 And again, the distinction is whether it's in the ducts, or in the lobules.

00:22 So, pretty easy and straightforward.

00:25 If we see only in situ carcinoma, we will treat things differently than if we have invasive cancers.

00:32 And clearly, if you can have in situ cancers of the ducts and in situ cancers of the lobules, you can also have infiltrating ductal carcinoma and infiltrating lobular carcinoma.

00:43 The other kinds of tumors that are designated there, tubular, and colloid, medullary, micropapillary are all kinds of variations that are recognized largely by the pathologist, not so much recognized on gross exam or by mammography.

00:59 Not too important that you be able to distinguish those now, but should you become a breast oncologist, these different categories will have different import to you.

01:10 And finally, there can be involvement of other structures in the breast, the nipple, as in Paget's disease or the skin in inflammatory carcinoma.

01:19 Again, want to emphasize that we may have tumors that involve the lobules, or ducts, sometimes both.

01:26 And they may be noninvasive, or they may even be invasive and they may involve other structures.

01:32 We are looking at initially noninvasive breast cancers.

01:36 And we have Ductalar carcinoma in situ (DCIS) or lobular carcinoma in situ.

01:43 The presentation for DCIS is usually unifocal.

01:46 It tends not to be a disease that hits different parts of the breast.

01:52 In comparison, LCIS, lobular carcinoma in situ tends to be multifocal. And if you find it in one breast, it's very likely to be present multifocally in the same breast and/or in the contralateral breast.

02:04 Calcifications on mammography, more commonly seen in ductal than in lobular and the risk of invasive cancer is much higher for ductal carcinoma in situ than it is for lobular carcinoma in situ.

02:16 However, both can become invasive.

02:20 For invasive carcinomas, the infiltrating ductal variety is going to be our most common about three quarters of the time.

02:28 Lobular carcinoma, as infiltrating, will be the second most common.

02:33 The presentation for infiltrating ductal tends to be a rock hard mass.

02:39 Infiltrating ductal carcinoma tends to incite a rather profound fibrosing otherwise called desmoplastic response that makes the tumors firm. And that's why on breast exam you're feeling for something that feels irregular and really hard.

02:54 Infiltrating lobular. Even though it's infiltrating doesn't tend to elicit that same fibrosing or desmoplastic response.

03:01 It may actually be very difficult to palpate or even to detect on mammography.

03:07 So, it's a little bit more of a sneakier tumor than is the infiltrating ductal.

03:12 Fortunately, infiltrating ductal is going to be much much much more common than the lobular.

03:17 These are some of those other variants that we discussed previously.

03:20 Tubular carcinoma is a very infrequent entity.

03:27 It is associated with low grade, ductal carcinoma in situ overall tends to have a better prognosis.

03:34 Paget's disease, that's involvement of the tumor infiltrating all the way up along the ducts and into the nipple is seen rarely. Is more common and more elderly individuals who develop breast cancer.

03:49 Tends to give you a worse prognosis.

03:53 Inflammatory carcinoma will lead to infiltration of the skin, usually along dermal lymphatics, that will give a characteristic "peau d'orange" appearance that looks a bit like orange peel.

04:06 And that is characteristic thickening when we see the cutaneous involvement, and also suggests a more aggressive poor prognosis when we have that manifestation.

04:20 And finally, Phyllodes tumors. We haven't talked about these.

04:23 We'll see an example in shortly in this talk.

04:27 But Phyllodes tumors. are not epithelial tumors.

04:29 They are tumors of the mesenchymal elements of the stromal elements of the breast and the epithelium is actually completely normal.

04:38 They tend to have a usually benign course although they can be quite impressive in terms of size.

04:46 But there is a malignant potential in them about a quarter of them will become cancerous.

04:53 We're going to walk our way through this there are a variety of changes.

04:56 Again, in terms of the histology, we're just showing you examples I don't expect you and you should not be expected as medical students to be able to make the distinction.

05:07 When you become a pathologist and come train with me, then we will learn all of the various subsets.

05:14 So, we start with normal breast epithelium, and in the setting of say a germline BRCA2 mutation or other mutations.

05:23 And again, it doesn't have to start with BRCA2.

05:25 The majority of breast cancers spontaneously arise and don't have BRCA2 mutations.

05:31 But this is just an example of how we can go from something that is normal to something that is malignant.

05:37 So, we develop proliferation, we acquire additional mutations that may involve tyrosine kinases, other intracellular second message proteins, etc.

05:49 And we go from an epithelial proliferation to atypia, with hyperplasia, and then formally into a ductal carcinoma in situ.

05:58 Again, has not yet learned the trick of invasion beyond the basement membrane.

06:02 And then with additional mutations, and additional rounds of proliferation, you may eventually develop invasive cancer.

06:10 You need not have this sequence of changes in terms of the genetic accumulation of mutation.

06:18 We've seen examples of other cancers in other talks within the Lecturio series, and we can show a sequence of events.

06:27 They don't have to happen in that sequence, and other mutations can precede or follow anything that has been shown here.

06:37 That pathway that we just showed, with kind of epithelial atypia, the ductal hyperplasia, ductal carcinoma in situ, and then finally, invasive cancer is going to be the most common variety, that's going to be our luminal estrogen receptor-positive pathway tumors.

06:57 You can also have tumors that, say, for example, begin with normal epithelium and then a germline mutation say in p53.

07:07 P53 is going to be important for recognizing chromosomal breaks, mutations, etc.

07:14 And stopping proliferation at that point.

07:16 If you have a mutation, and p53 is abnormal, we don't put a stop on the proliferative pathway.

07:23 In these tumors, you may have an upregulation because of a genetic expansion, or reduplication.

07:33 We may overlap, amplify or overexpress HER2.

07:37 And now we have a tumor that is going to be responsive to even very low levels of epidermal growth factor.

07:43 And then we can drive proliferation in that way.

07:46 This may be a ductal carcinoma that has atypia initially and then in situ, and then develops additional mutations that allow it to invade.

07:55 This is going to be our HER2-enriched invasive cancer.

08:00 And then there are the surely estrogen receptor-negative pathways.

08:04 And these are going to be our basal-like tumors involving the myoepithelial cells.

08:09 These are classically associated with BRCA1 mutations.

08:15 They don't have to be. And the majority of these tumors will not have germline BRCA mutations.

08:22 Having said that, if you have a germline BRCA mutation, you're at a much much much increased risk of developing basal cell basal-like tumors.

08:33 So, we have the BRCA mutation, there are additional mutations including p53.

08:39 We may have loss of heterozygosity in the BRCA1, and then we progress to a ductal carcinoma in situ and eventually invasive tumor.

08:48 In this case, however, it is a tumor that is estrogen receptor-negative, progesterone receptor-negative, and HER2-negative.

08:56 And this is going to be our basal-like triple negative tumor involving the myoepithelial cells.

09:02 And again, this is the worst actor of all three that we're talking about.

09:07 Here's an example what Phyllodes tumor looks like.

09:09 So, it is a stromal proliferation.

09:11 The epithelium here is actually remarkably normal.

09:14 And it's kind of an afterthought overall in the tumor.

09:17 It is an expansion of the mesenchyma of the stromal elements.

09:22 The fibrous connective tissue and or the smooth muscle elements.

09:25 The mutations can be those that involve the TERT molecule or TERT gene that is responsible for a telomerase activation.

09:36 It could be other that are involved in mismatch repair, or in genetic editing, or maybe even involved in epidermal growth factor receptor amplification.