Transcription
Welcome to the fundamentals of pathology. The first section that we want to cover is growth adaptations, and this is obviously the first section in chapter one of your text. A few basic principles before we begin: the first is that an organ is in homeostasis with the physiologic stress placed on it. So, uh, we can take any example; take the heart, for example. Uh, the heart has the function of pumping against the systemic blood pressure, and it pretty much is in homeostasis when it deals with that physiologic stress.
Now, if there is an increase in stress, or a decrease in stress, or a change in stress on an organ, then the organ will undergo growth adaptations, and these growth adaptations are what we want to discuss over the next few minutes. And generally speaking, the growth adaptations are very high yield for examinations.
Now, the first of the growth adaptations is hyperplasia and hypertrophy. And the idea here is that if there's an increase in stress on an organ, this will then lead to an increase in organ size. Basically, if the organ has to do more work, the organ will become bigger in order to do that excess work. Now, how will the organ become bigger? Well, there's two ways. One way by which the organ could become bigger is to increase the size of the cells of that organ, and an increase in cell size is actually called hypertrophy. So, one way by which the organ becomes bigger is is to increase the cell size, i.e., hypertrophy. Another way by which the organ can become bigger would be to increase the number of cells of the organ, and an increase in the number of cells is called hyperplasia. So, basically speaking, these two mechanisms, hyperplasia and hypertrophy, allow for the organ to increase in size in the face of an increase in stress.
Now, it's not enough to simply know the definition of hypertrophy and hyperplasia, but we've got to go one step further, and examiners like to ask about these, uh, about the mechanism that underlies these changes. So let's take hypertrophy first. Recall that hypertrophy is what hypertrophy is when we take a cell and we make that cell bigger; we increase the cell size. Now, if we're going to increase the cell size, a couple of important things: first of all, recall that a cell has a skeleton, which is called the cytoskeleton, and that cytoskeleton is what gives the cell its size and its shape. If we want the cell to become bigger, we're going to have to increase the production of that cytoskeleton, uh, and the cytoskeleton is predominantly made of protein. So, one of the very important mechanisms for hypertrophy would be protein synthesis. Now, obviously, in order to produce proteins, genes are going to need to be activated. So, you could put this story together, uh, by basically saying that one mechanism of hypertrophy is gene activation and protein synthesis. Another important thing that will have to occur in hypertrophy is the production of organelles. If the cell is going to go from this size to this size, then it's going to need the organelles that are necessary for cellular function; for example, mitochondria is important for cellular function, and so you will need to increase the number of mitochondria in a cell if we increase its size. So, production of organelles is also an important mechanism of hypertrophy, and both of these hand in hand. So that's why I say here in your text that hypertrophy involves gene activation, protein synthesis, and production of organelles.
Now, hyperplasia, on the other hand, recall hyperplasia being an increase in cell number. So, an increase in cell number is going to involve the production of new cells, and new cells will be produced from stem cells, uh, and that's I think pretty straightforward, uh, to understand. Generally speaking, hyperplasia, which is an increase in the number of cells, and hypertrophy, which is an increase in the size of the cells, usually occur together. So let's take a simple example: when a woman becomes pregnant, uh, the uterus is going to increase in size. Obviously, the uterus has to increase in size because it needs to provide space and a home for the developing fetus. Now, that uterus is going to increase in size in two ways: first, the smooth muscle of the uterus will undergo hyperplasia, i.e., there'll be increased cells produced; and second, the smooth muscle of the uterus will undergo hypertrophy, so the cells will also become bigger. And generally speaking, uh, hyperplasia and hypertrophy will actually occur together.
One important exception to this general principle is permanent tissues. Now, permanent tissues, they do not have stem cells, and because they do not have stem cells, they cannot make new cells. Hence, because they can't make new cells, they won't be able to undergo hyperplasia, and so they'll undergo hypertrophy only. This is a very, um, high-yield, uh, topic. So let's take a step back and remind ourselves that in the human body there's basically three permanent tissues: the first of the permanent tissues are cardiac myocytes; the second permanent tissue is skeletal muscle; and the third permanent tissue is nerve. These three tissues, cardiac muscle, skeletal muscle, and nerve, cannot make new cells and therefore will undergo hypertrophy only and cannot undergo hyperplasia.
Here's a classic picture that likes to show up on exams, uh, this is actually a picture of both the left ventricle and the right ventricle. Here we can clearly see that the left ventricle is very thick, um, and that the right ventricle is basically, um, exhibiting a normal thickness. Now, I could show you this picture, and then I could ask you what's the mechanism by which this change has occurred within this organ, and the answer would clearly be that this change, this increased thickness of the wall of the, um, of the cardiac muscle, has actually occurred via hypertrophy because the heart cannot undergo hyperplasia.
Another important principle regarding, um, hyperplasia is that pathologic hyperplasia can progress to dysplasia and cancer. Now, what, what do I mean by pathologic hyperplasia? Pathologic hyperplasia is when hyperplasia occurs due to some underlying pathologic process, and this pathologic hyperplasia can progress to dysplasia and cancer. Maybe we should take a step back and contrast pathologic hyperplasia to physiologic hyperplasia. An example of physiologic hyperplasia would be pregnancy, where due to some physiology of the organism, um, hyperplasia occurs, and this there is no increased risk for cancer with physiologic hyperplasia. However, with pathologic hyperplasia, there is an increased risk for dysplasia and cancer. A classic example: endometrial hyperplasia. Um, you're well aware from your pathology, uh, lectures that the endometrium, or from, I should say from your physiology lectures, that the endometrium grows with exposure to estrogen and it sheds, um, and it develops and sheds with exposure to progesterone. Now, if the endometrium is overexposed to estrogen for long periods of time, the endometrium will actually undergo endometrial hyperplasia, and this endometrial hyperplasia, um, can eventually progress to the formation of endometrial carcinoma, and we'll talk much more about that when we do the gy lectures, um, later in this series.
Another important point, uh, to be brought up here is that there is, there is one exception or one very classic exception to this, to this general rule, and that is benign prostatic hyperplasia, or BPH. Now, benign prostatic hyperplasia, uh, is a pathologic hyperplasia; however, it is not related to cancer, and there is no increased risk of cancer with BPH. So this again makes for a nice question, examiner's question, because of the fact that it's an exception to a general principle. Okay. The next, uh, growth adaptation is atrophy.
Now, the idea with atrophy is that there is a decrease in stress on, on the organ. So, if there's less stress on an organ, this the organ will actually decrease in size, and that decrease in size is called atrophy. Now, again, really no rocket science: if an organ is going to decrease in size, there's really only two ways for that to occur: number one would, would be for there, for the, for the size of the cells that make up the organ to decrease; or number two would be for the, the number of cells within that organ to decrease. If the size of the cells decreases, the organ would decrease in size, and if the number of cells decreases, the organ would also decrease in size. Both of those happen to be called atrophy because they usually both occur together. One, um, again, it's not important, it's not sufficient to simply know the definition of atrophy; the examiners like to go after the mechanism of atrophy, and so let's touch on that briefly. Well, remember that atrophy is going to occur in two ways: the first would be to decrease the number of cells, uh, and a decrease in number of cells is going to occur via apoptosis. Apoptosis is a mechanism of cellular death that we'll discuss in more detail later on in this chapter, but it's very important to know that a decrease in cell number will actually occur via apoptosis. A decrease in cell size is going to occur by two primary mechanisms: the first is something called the ubiquitin-proteasome degradation pathway. Now, what's the idea here? Well, recall that if you've got a cell that's this big, and you want the cell to shrink down to something that's smaller, in order for the cell to shrink, this skeleton called the cytoskeleton that was maintaining the size and shape of the cell has to be broken down so that the cell can become smaller. The mechanism by which the cytoskeleton is broken down is called the ubiquitin-proteasome degradation pathway. Ubiquitin is a protein; I kind of think of it as a Post-it note. It's a protein that gets posted onto the intermediate filament of the cytoskeleton, and the proteasome is an organelle present within the cell that recognizes tagged ubiquitin and tagged proteins and then trashes those proteins and destroys them. And so the ubiquitin-proteasome degradation pathway is a mechanism for destroying the cytoskeleton and is a, it's, it's a high-yield point to be aware of. Now, at the same time, in order for the cell to shrink in size from this size to, for example, this size, you're going to end up requiring less organelles within the cell, and so some of the cellular components are going to have to be consumed, and the mechanism by which cellular components are consumed is called autophagy. And basically what happens here is that the, um, is that this vacuole, is that the cell consumes its own components in vacuoles. So, for example, if this is the cell here, little vacuoles are created, and those vacuoles, they fuse with lysosomes, uh, and the lysosomes are the, um, contain the hydrolytic enzymes that are necessary to break down and destroy, uh, products, um, into their simple building blocks, uh, and so basically what'll happen is that an autophagic vacuole will be, will be formed, and the cellular components will be consumed and then destroyed by the lysosomes. So two mechanisms by which the cell size, by which the cell size decreases: number one, ubiquitin-proteasome degradation pathway; and number two, autophagy of cellular components.
The third growth adaptation, which is also relatively high yield, is metaplasia. Now, the idea here is that if the stress on an organ changes, then the organ will respond by changing its cell type, and that change in cell type is called metaplasia. Metaplasia most commonly involves surface epithelium. So let me step back and explain that for a minute. Epi means on top, and thelium means layer, and so epithelium is the cell, are the cells that line the sur, line body surfaces. So the entire skin is lined by epithelium; the gut is lined by epithelium; the urogenital tract is lined by epithelium for the most part in the human body. Generally speaking, keeping things very simple, there's three types of epithelium. Recall that there's squamous epithelium, which can be keratinizing or non-keratinizing, but generally speaking, there's squamous epithelium; that's the first type of epithelium. The second type of epithelium is columnar epithelium, um, a lot of the gut, for example, is lined by columnar epithelium; and the third type of epithelium is called transitional, or your transitional epithelium or urothelium, and that's the epithelium that predominantly lines the, uh, the, the, the urinary tract. Metaplasia generally speaking involves, um, surface epithelium, and the idea behind metaplasia is that the metaplastic cells are better, better able to handle the new stress. So that when there's a change in stress, the metaplasia occurs because the new cells that are going to be present are better able to handle that stress. And let's maybe highlight, um, some of this with a, um, with a basic, a simple example, which is Barrett esophagus. Now, what is Barrett esophagus? So let's go back and remind ourselves: now, the esophagus is lined by squamous epithelium, and recall that there is a very sharp demarcation between the esophagus and the underlying stomach, and the stomach, instead of being lined by squamous epithelium, is lined by columnar epithelium. So again, esophagus is lined by squamous epithelium, and the stomach is lined by columnar epithelium. If acid, uh, refluxes from the stomach up into the lower esophagus, then the reflux of acid into the lower esophagus, um, results in a change in stress, um, in that lower portion of the esophagus, and that change in stress, i.e., the presence of acid within the lower portion of the esophagus, will result in the lower portion of the esophagus going from squamous epithelium to a columnar non-ciliated mucinous type of epithelium. Again, it's important to know these details: columnar non-ciliated mucinous type of epithelium; and and the idea here is that columnar epithelium is much better suited to handle acid, and so when acid shoots up from the stomach into the lower esophagus, this the, the, um, the cells in the lower esophagus basically change from squamous to columnar in order to better deal with the stress of acid, and this change to columnar epithelium, this metaplasia, this is called Barrett esophagus, and it's a classic example of metaplasia.
Here's a histologic image that, um, can classically show up on exams, and so I put this here as figure 1.2 in your text, um, this is squamous epithelium here; this is the normal squamous epithelium of the esophagus; and this squamous epithelium should actually come all the way across the esophagus. However, in this portion of the esophagus, we can see that the squamous epithelium has converted to columnar epithelium, and focally that columnar epithelium exhibits goblet cells or mucin, or droplets of, of mucus within the cytoplasm of the cell.
Now, the next point about concerning metaplasia is how metaplasia occurs. We're remember that I told you it's not sufficient to simply know the definition of metaplasia, but you also need to know the mechanism by which it occurs, and the mechanism by which metaplasia occurs is via reprogramming of stem cells. So there are stem cells present, for example, in the lower, for example, in the esophagus, for in this case the lower one-third of the esophagus, and those stem cells have the ability to produce new squamous cells. If they see acid, they begin to say, well, squamous cells aren't good at dealing with acid, and instead they convert themselves to columnar cells, and when they convert themselves to columnar cells, that results, um, in the metaplasia that we've been discussing. Now, very important to know: metaplasia is reversible; that's a high-yield principle. If you remove the driving stress that, or let's say you remove the, um, the key stress that was causing or that led to the metaplasia, that will then result in reversal of the metaplasia, uh, let's just take a very simple example: if we've got gastroesophageal reflux disease and we've got acid shooting up into the lower, lower one-third of the esophagus, that's going to result in a columnar non-ciliated mucinous metaplasia. If the acid reflux is, is, um, ceased, for example, for example via some sort of therapeutics, then a decrease in acid will result in reprogramming of the stem cells back to their original squamous type, and in, and the metaplasia will then reverse. So it's very important, I think the key take-home point from this slide is that metaplasia is reversible.
Now, another important high-yield point is that metaplasia can progress to cancer. This is a very important point, and I think we all would appreciate the fact that Barrett esophagus is a pre, is a risk factor for the development of adenocarcinoma of the esophagus, and we'll talk about adenocarcinoma of the esophagus in much more detail when we, um, cover the GI lecture. Now, one very important exception, which becomes commonly tested, is that apocrine metaplasia does not increase the risk for cancer. Okay, what's apocrine metaplasia? Apocrine metaplasia is one of the changes that's seen in association with fibrocystic change of the breast. The fibrocystic changes can be associated with an increased risk for the future development of breast cancer, um, however, apocrine metaplasia does not increase the risk for future breast cancer, and that's important because although it's a metaplasia, it does not increase the risk for cancer. So please keep that in the back of your mind.
Another important principle concerning metaplasia is that vitamin A deficiency can result in metaplasia. Before you can understand this, uh, we need to go take a step back and maybe, um, stick a couple other high-yield points in here. Let's start with vitamin A deficiency. So when you think about vitamin A deficiency, the very first, um, sort of thing that comes to mind is night blindness, and I think that we're all familiar with the fact that if someone is vitamin A deficient, there's an increased risk for night blindness. Another important, uh, feature of vitamin A deficiency to bear in mind is that patients who are vitamin A deficient, they get, uh, they can become, um, deficient in their immune system as well, and vitamin A is necessary for maturation for proper maturation of the cells of the immune system. A classic example, maybe you recall this, um, when, uh, patients get a 15;17 translocation, they develop a, a disease, um, that's very high yield, which is called acute promyelocytic leukemia. Now let's go back and remind ourselves: the 15;17 translocation, um, involves the vitamin A receptor, retinoic acid receptor, in fact, and so when that 15;17 translocation occurs, it disrupts the vitamin A receptor, and that disruption of vitamin A receptor causes the cells to remain trapped in the blast state, and therefore they accumulate, resulting in a promyelocytic leukemia. And if you want to dig a little deeper, you can remind yourselves that from pharmacology, the treatment of one of the treatments for PML, or promyelocytic leukemia, is all-trans retinoic acid, and it's a derivative of vitamin A. So this, um, derivative of vitamin A has the ability to bind the mutated receptor, which then allows the cells to actually mature, uh, and become neutrophils. I just went off on that tangent, um, because it allows me to remember that vitamin A is necessary for maturation of the, um, of the immune system; that's the second principle. And by the way, we'll talk about, um, promyelocytic leukemia in much more detail when we do the leukemia lectures. The third consequence of vitamin A deficiency is that it can result in metaplasia, and that's what we want to talk about here. Now, let me just take you back a step and remind you that, um, vitamin A is necessary for maintenance of specialized epithelia in the body; for example, the conjunctiva of the eye. The conjunctiva of the eye refers to a very, very thin, delicate membrane that covers the surface of the eye, and for the most part, we don't even appreciate that membrane; the time that you recognize that that membrane is there is when it becomes inflamed. And so for, for example, when, when a patient gets a cold and they come in with, um, pinkness or redness to the eye, uh, that is an example of the conjunctiva becoming inflamed and hence becoming red. But for the most part, the conjunctiva is not visible; it's a very thin, delicate, um, membrane that overlies the surface of the eye. The conjunctiva is actually a very highly specialized squamous epithelium, and that highly specialized squamous epithelium requires vitamin A in order for it to remain in that state. If there's a vitamin A deficiency, that can then result in metaplasia of those cells, and metaplasia of those cells that line the surface of the eye can then become, result, result in a thickness, in a thickening of that surface, which is called keratomalacia. I'll show you a classic picture; this is a picture of the conjunctiva of the eye. Now, normally the conjunctiva of the eye should be absolutely transparent, um, however, we can see here that it's become thicker, and it's become thicker because there's a vitamin A deficiency, and the vitamin A deficiency results in an inability to maintain that highly specialized surface that covers the eye. Again, this is relatively high yield, uh, the, an addition, the next principle concerning metaplasia is that mesenchymal tissues can also undergo metaplasia. All right, take a step back. So what are mesenchymal tissues? Well, the mesenchymal tissues include things like bone, blood vessel, fat, cartilage; these are all mesenchymal, also known as connective tissues. Now, these mesenchymal tissues can also undergo metaplasia, and the classic example is myositis ossificans. So what, what happens in myositis ossificans? Well, in myositis ossificans, um, inflammation of the skeletal muscle results in a metaplastic production of bone within the skeletal muscle. Now, why would the skeletal muscle be inflamed? It's usually due to trauma. So a patient undergoes trauma of the skeletal muscle, and when the skeletal muscle is healing, there's a certain degree of inflammation, and as part of that healing, the skeletal muscle actually converts into bone, and some bone is produced within the skeletal muscle; that's called myositis ossificans, um, and that is a relatively high yield as well. This is a classic picture, uh, it's figure 1.4 in your text, and this circular area here that looks ossified within the muscle, this is the meo, this is the, um, the myositis ossificans, or the presence of bone within skeletal muscle. Now be careful because examiners like to tell you or make you think that, or confuse you perhaps, that this is actually an osteosarcoma, uh, however, notice that this, number one, this bone is normal; the bone adjacent to it is normal; and number two, if you look very carefully, you can see that there is a distinct separation of this, um, bony metaplasia with this, with the actual bone next to it, highlighting that this is actually occurring within the muscle and and it's not growing off the bone, and osteosarcoma, which is a malignant bone tumor, would actually grow off the bone. So that's an important image to be familiar with.
The next principle, um, in growth adaptations is dysplasia. Dys means bad, and plasia means growth, and the idea with dysplasia is that there is disordered cellular growth. For the most part, this the term dysplasia is used to refer to a proliferation of precancerous cells. The classic example of dysplasia is CIN; we're all familiar with this in the cervix: cervical intraepithelial neoplasia. Recall that CIN can be subdivided into three types: CIN 1, CIN 2, and CIN 3, um, and it's important to remember that CIN is actually dysplasia. Dysplasia usually arises from longstanding pathologic hyperplasia. What would be an example of longstanding pathologic hyperplasia? Endometrial hyperplasia, which can eventually undergo dysplasia and then become endometrial carcinoma. Dysplasia can also arise from metaplasia. What would be an example of metaplasia? Barrett esophagus. Barrett esophagus can become dysplastic, and the dysplasia can eventually become adenocarcinoma of the esophagus. Now, important to remember that dysplasia is reversible; I can't stress this enough: dysplasia is reversible, um, if you remove the inciting stress, the dysplasia can potentially reverse. For example, if a patient has gastroesophageal reflux disease and the, uh, GERD is treated, um, then the dysplasia can actually reverse. If the stress persists, the dysplasia can progress to carcinoma, and carcinoma is irreversible. This is, uh, this is the key distinction between dysplasia and cancer: that is, dysplasia is reversible, and cancer is not reversible.
A couple more quote-unquote plasias that we should discuss; they're not really growth adaptations, but they, um, I threw them in here because they fit well with the, with the discussions that we've been having, uh, the first is aplasia. A means without, and plasia means growth, and, um, this is a failure, uh, of growth during embryogenesis of cell production or organ growth during embryogenesis. And the classic example is unilateral renal agenesis, where a patient fails to develop one kidney, uh, during embryogenesis. Another important, um, entity to be familiar with, this hypoplasia, or another important term I should say to be familiar with, is hypoplasia. Hypo means low, and plasia means growth, and so in hypoplasia there is a decrease in cell production during embryogenesis. This results in a relatively small organ. The classic example, uh, would be a streak ovary in Turner syndrome, um, and that's also an, that's an example of hypoplasia.
All right, so that concludes this section, uh, a lot of high yield, a lot of important things to be familiar with. Again, important to know terms, important to know mechanisms behind those terms, and important to know examples, uh, luckily we're going to have many opportunities to review some of these principles as we go through the remainder of the text. So why don't you take some time to review what we've covered, and I'll see you when we get back to the next section.