WEBVTT 00:00:10.057 --> 00:00:15.639 (From M1 Patients and Populations at University of Michigan Medical School. Lecture by Gerald Abrams, MD.) I think a good place to start is with this slide again, just to remind you that 00:00:15.639 --> 00:00:16.078 one of the defining 00:00:16.078 --> 00:00:19.749 traits of malignant 00:00:19.749 --> 00:00:25.039 neoplasms is the ability to invade 00:00:25.039 --> 00:00:27.289 more importantly even 00:00:27.289 --> 00:00:29.009 as 00:00:29.009 --> 00:00:34.089 a second defining characteristic is the ability to set up 00:00:34.089 --> 00:00:37.007 underlying distant 00:00:37.007 --> 00:00:38.062 and 00:00:38.062 --> 00:00:39.099 discontinuous 00:00:39.099 --> 00:00:45.004 secondary foci of growth. What this involves is cells 00:00:45.004 --> 00:00:49.055 breaking off, leaving, what we call, the primary cells 00:00:49.055 --> 00:00:51.019 getting 00:00:51.019 --> 00:00:55.076 into the moving currents or fluids that flow into the body, let's say into the blood 00:00:55.076 --> 00:00:57.088 or into the lymph 00:00:57.088 --> 00:00:58.579 lodging at a 00:00:58.579 --> 00:01:01.058 distance, in other words, here is the primary 00:01:01.058 --> 00:01:03.087 clump of cells, these cells 00:01:03.087 --> 00:01:06.042 float over there, they lodge and 00:01:06.042 --> 00:01:08.609 get out of the vessel they are in 00:01:08.609 --> 00:01:11.039 and they form a new nodule. 00:01:11.039 --> 00:01:13.006 That's the process of metastasis. 00:01:13.006 --> 00:01:18.052 That's what the process is called. The focus itself is called him a metastasis (or plural metastases). 00:01:18.052 --> 00:01:18.999 00:01:18.999 --> 00:01:21.076 and the 00:01:21.076 --> 00:01:24.062 ability to metastasize 00:01:24.062 --> 00:01:27.009 by all odds is the most lethal aspect of cancer. 00:01:27.009 --> 00:01:29.081 And 00:01:29.081 --> 00:01:33.024 that's the the feature that most often 00:01:33.024 --> 00:01:35.051 makes a cancer incurable. 00:01:35.051 --> 00:01:39.068 Sometimes a cancer is incurable because of local invasion, you know, 00:01:39.068 --> 00:01:45.001 something wraps around the aorta or some other structure, you can't get at it, 00:01:45.001 --> 00:01:45.579 that could be 00:01:45.579 --> 00:01:51.057 lethal but it's usually metastasis. The sad fact is that 00:01:51.057 --> 00:01:55.021 if you exclude skin cancers, many of which are in a different category, if you exclude those 00:01:55.021 --> 00:01:57.006 about 00:01:57.006 --> 00:02:01.082 thirty to fifty percent of patients who present to their doctors 00:02:01.082 --> 00:02:05.023 with some signs and symptoms that turn out to be cancer, about thirty to 00:02:05.023 --> 00:02:08.829 fifty percent already have metastases. 00:02:08.829 --> 00:02:11.519 So it's something that really 00:02:11.519 --> 00:02:13.034 is the biggest roadblock 00:02:13.034 --> 00:02:13.709 00:02:13.709 --> 00:02:16.819 to successful treatment. 00:02:16.819 --> 00:02:20.659 So again these defining characteristics 00:02:20.659 --> 00:02:25.499 are invasion and metastasis. Now 00:02:25.499 --> 00:02:28.061 these abilities, to talk first about invasion and metastasis together, 00:02:28.061 --> 00:02:30.077 00:02:30.077 --> 00:02:34.459 are not just a matter of cell proliferation 00:02:34.459 --> 00:02:36.064 in other words, it's not the matter of fact 00:02:36.064 --> 00:02:40.004 that the cancers proliferating in the primary so much that the cells get squeezed 00:02:40.004 --> 00:02:42.026 out and they move. That's nonsense. 00:02:42.026 --> 00:02:44.629 Some primaries grow very large and then 00:02:44.629 --> 00:02:46.599 never leave 00:02:46.599 --> 00:02:52.619 the local area. These neoplasms acquire 00:02:52.619 --> 00:02:53.042 the 00:02:53.042 --> 00:02:58.017 cells in the neoplasm gradually acquire the ability to invade 00:02:58.017 --> 00:03:02.189 and to metastasize, and again these represent an accumulation 00:03:02.189 --> 00:03:05.779 of different kinds of mutations very likely giving the cells the 00:03:05.779 --> 00:03:06.084 the ability to 00:03:06.084 --> 00:03:08.369 do this. 00:03:08.369 --> 00:03:10.062 Now metastasis I would emphasize 00:03:10.062 --> 00:03:13.004 is a very complex cascade of events, 00:03:13.004 --> 00:03:14.093 00:03:14.093 --> 00:03:16.529 it's not just whoops! 00:03:16.529 --> 00:03:17.065 but involves the 00:03:17.065 --> 00:03:21.084 cells first of all invading, getting through that extracellular matrix, 00:03:21.084 --> 00:03:23.779 breaking through basement membrane, 00:03:23.779 --> 00:03:28.599 getting into a vessel whether it's a blood vessel or a lymphatic, floating 00:03:28.599 --> 00:03:32.749 with the stream and surviving during that flotation, which is another 00:03:32.749 --> 00:03:34.319 nice trick, lodging 00:03:34.319 --> 00:03:35.095 somewhere, 00:03:35.095 --> 00:03:40.279 being able to extravasate, get out of that vessel where it lodged, 00:03:40.279 --> 00:03:45.289 and set up housekeeping and get all of the requirements for growing another nodule. 00:03:45.289 --> 00:03:49.189 this is sort of, its been likened to, a decathlon event. You have to 00:03:49.189 --> 00:03:49.051 win 00:03:49.051 --> 00:03:52.189 a lot of events to be a successful metastasis. 00:03:52.189 --> 00:03:54.729 and 00:03:54.729 --> 00:03:58.299 there are three primary roots, this one is the lesser but 00:03:58.299 --> 00:03:59.038 cells 00:03:59.038 --> 00:04:04.025 can metastasize via the bloodstream, via the lymph flow 00:04:04.025 --> 00:04:05.093 and sometimes directly. 00:04:05.093 --> 00:04:08.119 Now here 00:04:08.119 --> 00:04:11.319 for instance, just to illustrate this, 00:04:11.319 --> 00:04:13.899 here is a clump of cancer cells within a 00:04:13.899 --> 00:04:16.008 tiny vein 00:04:16.008 --> 00:04:18.269 within adipose tissue. 00:04:18.269 --> 00:04:19.069 This was actually 00:04:19.069 --> 00:04:24.011 in a breast that had been removed by mastectomy, this was, in other words, 00:04:24.011 --> 00:04:26.259 primary cancer of the breast. 00:04:26.259 --> 00:04:27.076 What had happened here 00:04:27.076 --> 00:04:29.819 a tongue of cells had 00:04:29.819 --> 00:04:34.028 broken through a venule wall somewhere upstream 00:04:34.028 --> 00:04:36.094 and here you see it caught in the act of floating 00:04:36.094 --> 00:04:38.899 with the blood. 00:04:38.899 --> 00:04:43.749 Now there's a certain predictability to where the metastasis will go. In this case, 00:04:43.749 --> 00:04:47.129 this is coming from the breast. Eventually 00:04:47.129 --> 00:04:50.629 these venules are going to go into veins which are going to flow into 00:04:50.629 --> 00:04:52.699 the superior vena cava. The cells 00:04:52.699 --> 00:04:55.066 aren't going to lodge anywhere along there because the vessels are getting bigger 00:04:55.066 --> 00:04:57.073 and bigger. And 00:04:57.073 --> 00:04:58.149 they 00:04:58.149 --> 00:05:01.082 go to the right side of the heart out the pulmonary artery. 00:05:01.082 --> 00:05:02.096 Pretty soon, these cells 00:05:02.096 --> 00:05:08.379 are going to encounter the capillaries in the lungs where they are going to lodge. 00:05:08.379 --> 00:05:09.004 Metastasis, 00:05:09.004 --> 00:05:13.689 a cell clump like this, if it's successful, may 00:05:13.689 --> 00:05:14.081 very well 00:05:14.081 --> 00:05:17.199 end up in the lungs. 00:05:17.199 --> 00:05:21.259 Now you haven't studied this in gross anatomy yet, you're just beginning gross, 00:05:21.259 --> 00:05:22.037 but 00:05:22.037 --> 00:05:24.027 I'll tell you that for instance 00:05:24.027 --> 00:05:29.043 the blood flow drainage, the venous drainage of the GI tract 00:05:29.043 --> 00:05:31.569 goes into what we call the portal vein, which is 00:05:31.569 --> 00:05:33.189 a big vein 00:05:33.189 --> 00:05:35.129 that goes into the liver. 00:05:35.129 --> 00:05:40.052 Now the cells, if these cells had broken out of a gastric cancer, 00:05:40.052 --> 00:05:41.028 and 00:05:41.028 --> 00:05:43.093 were in the veins draining the stomach, they would 00:05:43.093 --> 00:05:47.004 go into this portal vein and then the first capillary bed 00:05:47.004 --> 00:05:48.036 they hit is the liver. 00:05:48.036 --> 00:05:50.002 So you'd 00:05:50.002 --> 00:05:55.539 find metastases in the liver, you'd predict metastases in the liver. 00:05:55.539 --> 00:05:58.048 Or if you had a malignancy in the soft tissues of the leg, 00:05:58.048 --> 00:06:02.006 the cells would eventually get to the inferior vena cava, up to the heart, 00:06:02.006 --> 00:06:04.439 and into the lungs. 00:06:04.439 --> 00:06:06.759 So it turns out that the lungs 00:06:06.759 --> 00:06:10.409 and the liver constitute the two big filters in the body 00:06:10.409 --> 00:06:14.008 and they catch a lot of metastases. 00:06:14.008 --> 00:06:15.669 Now this is nowhere 00:06:15.669 --> 00:06:18.041 near being entirely predictable for the 00:06:18.041 --> 00:06:20.094 following reasons, 00:06:20.094 --> 00:06:23.095 the cancer cells don't necessarily lodge 00:06:23.095 --> 00:06:24.979 permanently 00:06:24.979 --> 00:06:28.239 in the lungs or the liver. 00:06:28.239 --> 00:06:32.589 they change their shape, they squiggle around, 00:06:32.589 --> 00:06:35.729 let's say coming from the GI tract, they may get through the liver 00:06:35.729 --> 00:06:36.004 into the 00:06:36.004 --> 00:06:38.026 inferior vena cava up to the 00:06:38.026 --> 00:06:41.149 heart and out anywhere in the body. 00:06:41.149 --> 00:06:43.699 So it turns out that really practically 00:06:43.699 --> 00:06:47.249 speaking, cancer cells once again in circulation are all 00:06:47.249 --> 00:06:49.072 over the place 00:06:49.072 --> 00:06:50.379 and 00:06:50.379 --> 00:06:53.027 it also turns out that there are secondary factors 00:06:53.027 --> 00:06:56.499 that determine where the metastases will occur 00:06:56.499 --> 00:06:58.339 For instance, 00:06:58.339 --> 00:07:01.839 we know that cancer cells get out systemically. We rarely see metastases 00:07:01.839 --> 00:07:04.031 in skeletal muscle. I have no idea 00:07:04.031 --> 00:07:05.639 why. 00:07:05.639 --> 00:07:07.056 But we rarely do. 00:07:07.056 --> 00:07:11.039 It turns out that certain cancers have a propensity 00:07:11.039 --> 00:07:13.899 to set up metastases in one 00:07:13.899 --> 00:07:16.042 set of tissues and certain cancers 00:07:16.042 --> 00:07:20.012 have a propensity to set up metastases in another set of tissues. It's as if they 00:07:20.012 --> 00:07:22.959 favor the "taste" 00:07:22.959 --> 00:07:23.058 of 00:07:23.058 --> 00:07:24.569 one tissue 00:07:24.569 --> 00:07:28.011 over another, and you'll learn these patterns, I'm not going to afflict you with them. 00:07:28.011 --> 00:07:30.669 They are 00:07:30.669 --> 00:07:34.799 to an extent predictable. 00:07:34.799 --> 00:07:39.789 So that's the situation with hematogenous metastases, liver, lung, 00:07:39.789 --> 00:07:44.219 many other places as well. It's a systemic process 00:07:44.219 --> 00:07:46.469 Here are cancer cells in a lymphatic. 00:07:46.469 --> 00:07:50.009 You probably know less about lymphatic channels than you do about blood channels but these are 00:07:50.009 --> 00:07:51.449 basically 00:07:51.449 --> 00:07:52.639 they start from small, thin walled 00:07:52.639 --> 00:07:54.061 vessels like this and 00:07:54.061 --> 00:07:57.399 and any particular organ 00:07:57.399 --> 00:08:00.077 almost all organs in the body have a rich lymphatic drainage. The lymph 00:08:00.077 --> 00:08:01.429 is drained 00:08:01.429 --> 00:08:02.879 into bigger 00:08:02.879 --> 00:08:07.096 bigger lymphatics. These enter what we call regional lymph nodes. 00:08:07.096 --> 00:08:11.879 which we'll study in detail, but these are basically like little filter beans 00:08:11.879 --> 00:08:13.029 and 00:08:13.029 --> 00:08:15.309 a clump of 00:08:15.309 --> 00:08:20.419 cells like that may well lodge in a regional lymph node. 00:08:20.419 --> 00:08:21.009 Now 00:08:21.009 --> 00:08:23.031 what denotes a regional lymph node? 00:08:23.031 --> 00:08:25.139 In the case of the bowel, 00:08:25.139 --> 00:08:29.369 the regional lymph nodes are in the mesentery. In the case of the 00:08:29.369 --> 00:08:30.689 breast, the regional 00:08:30.689 --> 00:08:34.249 lymph nodes are in the armpit, that's where the lymph is draining. 00:08:34.249 --> 00:08:34.098 In the 00:08:34.098 --> 00:08:39.079 case of the mouth and throat, the regional lymph nodes are here in the neck. 00:08:39.079 --> 00:08:41.003 And there's 00:08:41.003 --> 00:08:43.069 a certain predictability 00:08:43.069 --> 00:08:46.083 so that if you have a big cancer in the mouth, you're going to 00:08:46.083 --> 00:08:50.003 worry about the cervical lymph nodes or the 00:08:50.003 --> 00:08:53.067 or the breast you're going to worry about what's going on in the axilla. 00:08:53.067 --> 00:08:57.003 Cancer operations generally involve 00:08:57.003 --> 00:09:01.059 either excavation or sampling of the regional lymph nodes to see whether the cancer 00:09:01.059 --> 00:09:04.024 has spread from the primary there. 00:09:04.024 --> 00:09:06.044 Now 00:09:06.044 --> 00:09:10.004 this predictability again can break down because 00:09:10.004 --> 00:09:13.023 lymph nodes are not perfect filters, 00:09:13.023 --> 00:09:15.042 whatever you might think, 00:09:15.042 --> 00:09:19.001 these cells might lodge temporarily in a lymph node and some of their progeny 00:09:19.001 --> 00:09:22.001 maybe goes scooting out the other side in the 00:09:22.001 --> 00:09:23.014 efferent lymph which 00:09:23.014 --> 00:09:27.339 is going to go to other lymphatic channels and eventually dump into the 00:09:27.339 --> 00:09:29.049 superior vena cava and 00:09:29.049 --> 00:09:31.083 join 00:09:31.083 --> 00:09:33.046 the systemic circulation. 00:09:33.046 --> 00:09:35.081 So it turns out that cancer, 00:09:35.081 --> 00:09:44.045 we have to conceive of it is a potentially systemic disease, 00:09:44.045 --> 00:09:46.063 One comment 00:09:46.063 --> 00:09:50.055 here about metastasis is the possibility of direct metastasis. 00:09:50.055 --> 00:09:51.059 By that I mean 00:09:51.059 --> 00:09:53.889 the cells are not picked up in the blood or lymph, but 00:09:53.889 --> 00:09:55.058 if they enter 00:09:55.058 --> 00:09:59.013 a cavity, let's say the peritoneal cavity, 00:09:59.013 --> 00:10:01.056 and can drift 00:10:01.056 --> 00:10:03.052 or swim or float 00:10:03.052 --> 00:10:05.084 across the peritoneal cavity and lodge 00:10:05.084 --> 00:10:06.085 anywhere in the lining 00:10:06.085 --> 00:10:09.076 of the peritoneal cavity, it's a sort of direct 00:10:09.076 --> 00:10:11.029 metastasis. 00:10:11.029 --> 00:10:13.019 We see this 00:10:13.019 --> 00:10:14.055 one 00:10:14.055 --> 00:10:16.439 that comes to mind is the ovary. 00:10:16.439 --> 00:10:19.005 The ovary sit out in the pelvis, 00:10:19.005 --> 00:10:24.005 in the open so to speak, in the peritoneal cavity. Ovarian cancers notoriously 00:10:24.005 --> 00:10:28.034 will just seed cells into the peritoneum and they'll land 00:10:28.034 --> 00:10:28.088 anywhere in the peritoneum 00:10:28.088 --> 00:10:29.088 and set up these metastases. 00:10:29.088 --> 00:10:32.067 A variation on 00:10:32.067 --> 00:10:36.048 this that we don't often see is that the surgeon's knife 00:10:36.048 --> 00:10:37.077 may pick up 00:10:37.077 --> 00:10:40.021 some cancer cells and 00:10:40.021 --> 00:10:44.078 we'll find a recurrence in the incision or something of that sort. 00:10:44.078 --> 00:10:46.089 More or less 00:10:46.089 --> 00:10:49.061 a direct, iatrogenic (physician caused) metastasis. 00:10:49.061 --> 00:10:51.001 But again 00:10:51.001 --> 00:10:52.075 metastases 00:10:52.075 --> 00:10:57.042 represent a hop skip and jump, it's not direct invasion to 00:10:57.042 --> 00:10:59.064 get over here, it's a jump 00:10:59.064 --> 00:11:04.088 to get over there. 00:11:04.088 --> 00:11:07.072 A thing to point out is that the 00:11:07.072 --> 00:11:11.046 metastasis does not have the 00:11:11.046 --> 00:11:16.001 the characteristics of the organ that it lands in, it keeps the 00:11:16.001 --> 00:11:17.063 characteristics of the primary tumor. In other words, 00:11:17.063 --> 00:11:23.065 these metastasizing cells are the genetic progeny 00:11:23.065 --> 00:11:29.001 of the primary, so they're going to look like it. If the neoplasm 00:11:29.001 --> 00:11:32.043 neoplasm in the primary was making funny glands, the metastasis 00:11:32.043 --> 00:11:36.001 will probably make funny glands. 00:11:36.001 --> 00:11:39.057 It's a chip off the old block. 00:11:39.057 --> 00:11:43.016 That has some some interesting implications there which you'll get into 00:11:43.016 --> 00:11:46.000 in future years. 00:11:46.000 --> 00:11:47.034 But just 00:11:47.034 --> 00:11:52.008 think of it as as a process whereby a single primary can give rise to many metastases. 00:11:52.008 --> 00:11:54.019 They can be 00:11:54.019 --> 00:11:57.023 at a great distance, it can be four feet away from 00:11:57.023 --> 00:11:59.031 the primary and 00:11:59.031 --> 00:12:00.055 it can 00:12:00.055 --> 00:12:02.879 be very devastating and I will show you 00:12:02.879 --> 00:12:06.031 some examples of this. 00:12:06.031 --> 00:12:11.014 This is carcinomatosis which refers to a diffuse spread 00:12:11.014 --> 00:12:11.057 of 00:12:11.057 --> 00:12:13.031 cancer. 00:12:13.031 --> 00:12:17.066 This was the lining of the diaphragm, in other words if i took a piece of diaphragm, 00:12:17.066 --> 00:12:18.066 cut it out 00:12:18.066 --> 00:12:19.329 and you're 00:12:19.329 --> 00:12:22.095 looking at the under surface of the diaphragm lined by peritoneum, 00:12:22.095 --> 00:12:23.087 00:12:23.087 --> 00:12:27.035 this was from a patient with ovarian cancer, 00:12:27.035 --> 00:12:30.039 and every one of these little plaques is a 00:12:30.039 --> 00:12:33.048 few million cancer cells growing as a direct 00:12:33.048 --> 00:12:36.091 metastasis. 00:12:36.091 --> 00:12:41.084 Now I'm going to give you a long shaggy dog story, here is a 00:12:41.084 --> 00:12:44.002 specimen of peritoneum, 00:12:44.002 --> 00:12:47.096 this is if I took a couple of pieces of body wall 00:12:47.096 --> 00:12:51.004 cut them out and you're looking at the peritoneal surface 00:12:51.004 --> 00:12:53.069 of the inside of those pieces 00:12:53.069 --> 00:12:55.007 and you can see studded 00:12:55.007 --> 00:12:58.000 with a couple a hundred little tiny black 00:12:58.000 --> 00:13:01.078 spots and here it's actually become kind of almost a confluent 00:13:01.078 --> 00:13:04.069 sheet of neoplasm. 00:13:04.069 --> 00:13:05.053 And 00:13:05.053 --> 00:13:08.043 you'd say yeah this looks like 00:13:08.043 --> 00:13:14.039 many little nodules, why do you suppose it's black like that? 00:13:14.039 --> 00:13:18.022 Any thoughts? 00:13:18.022 --> 00:13:22.098 Well, the cells are making melanin, this is a malignant melanoma 00:13:22.098 --> 00:13:25.024 which may have heard about. Now 00:13:25.024 --> 00:13:26.023 I'm 00:13:26.023 --> 00:13:29.075 getting ahead of your knowledge of histology, but there are no cells in the 00:13:29.075 --> 00:13:31.062 peritoneum that make 00:13:31.062 --> 00:13:36.079 melanin normally, so that means these are visitors from somewhere else, 00:13:36.079 --> 00:13:38.016 so clearly just by 00:13:38.016 --> 00:13:41.032 the sheer numbers and by the fact that it's melanoma 00:13:41.032 --> 00:13:45.048 we can say that these are metastases from somewhere else. 00:13:45.048 --> 00:13:49.096 I'll let the plot thicken a little bit, here was the liver 00:13:49.096 --> 00:13:52.063 from the same case. 00:13:52.063 --> 00:13:57.037 The normal liver is studded with probably thousands of metastases. 00:13:57.037 --> 00:13:59.097 This is grown together in a big, horrible 00:13:59.097 --> 00:14:04.007 mass which had broken through the hepatic capsule, 00:14:04.007 --> 00:14:08.389 and the normal liver does not contain melanin producing cells. 00:14:08.389 --> 00:14:12.025 That fact and the fact that that these are so multiple 00:14:12.025 --> 00:14:16.093 says that this liver is riddled with hematogenous metastases. 00:14:16.093 --> 00:14:21.048 Where do you think the primary was? 00:14:21.048 --> 00:14:23.029 Someone said it. 00:14:23.029 --> 00:14:25.005 Skin. That'd be your first bet. 00:14:25.005 --> 00:14:28.004 Because melanoma is a common story. 00:14:28.004 --> 00:14:32.023 But you're wrong. Eyeball. 00:14:32.023 --> 00:14:36.028 This is a bad picture, I screwed up and am not a photographer, but there you see the 00:14:36.028 --> 00:14:38.459 reflex from the flash, but just behind it 00:14:38.459 --> 00:14:39.048 there's a little lump 00:14:39.048 --> 00:14:40.061 there 00:14:40.061 --> 00:14:43.055 and that is the primary neoplasm. 00:14:43.055 --> 00:14:46.029 Now this tells another story. 00:14:46.029 --> 00:14:49.061 This patient presented with a visual disturbance and the ophthalmologist saw this 00:14:49.061 --> 00:14:51.081 and said this eyeball has to come out. 00:14:51.081 --> 00:14:53.005 And the eyeball was taken out. 00:14:53.005 --> 00:14:56.081 It is our job as pathologist to assess whether the excision 00:14:56.081 --> 00:14:59.035 has been complete. 00:14:59.035 --> 00:15:03.086 And so we sample the various coats of the eye thoroughly to see if the melanoma 00:15:03.086 --> 00:15:07.002 cells had penetrated through and if there any left in the in the orbit. 00:15:07.002 --> 00:15:07.072 And the answer 00:15:07.072 --> 00:15:09.032 to it is no. 00:15:09.032 --> 00:15:12.078 Looks clean. 00:15:12.078 --> 00:15:16.004 I hope the surgeon didn't say this but this sometimes gives rise to the statement: 00:15:16.004 --> 00:15:18.099 we got it all! 00:15:18.099 --> 00:15:23.042 Now this patient did fine after removal of the eyeball, did fine for several years. 00:15:23.042 --> 00:15:24.049 With 00:15:24.049 --> 00:15:27.085 absolutely no evidence of metastases. 00:15:27.085 --> 00:15:31.049 Then something happened, God knows what, 00:15:31.049 --> 00:15:32.061 the patient just 00:15:32.061 --> 00:15:34.093 went downhill within a period of weeks and died 00:15:34.093 --> 00:15:37.075 and had metastases all over the body. 00:15:37.075 --> 00:15:41.077 That brings up another interesting point which I'll just tease you with and 00:15:41.077 --> 00:15:45.004 that's the phenomenon we call dormancy. 00:15:45.004 --> 00:15:49.064 It was very clear from the story 00:15:49.064 --> 00:15:52.002 that we had taken out the primary 00:15:52.002 --> 00:15:55.037 and there was never any recurrence in the orbit and so that what that says is 00:15:55.037 --> 00:15:58.031 these melanoma cells have gotten into circulation 00:15:58.031 --> 00:16:02.085 that there were tiny occult metastases 00:16:02.085 --> 00:16:05.035 at the time the eyeball was taken out 00:16:05.035 --> 00:16:07.007 and they chose not to grow 00:16:07.007 --> 00:16:08.088 for several years 00:16:08.088 --> 00:16:12.004 and then something changed and they grew. 00:16:12.004 --> 00:16:14.029 And we see that sometimes. 00:16:14.029 --> 00:16:18.469 In other words earth eighteen months survival or two years survival or five year survival 00:16:18.469 --> 00:16:20.095 is a statistical thing, but 00:16:20.095 --> 00:16:22.075 sometimes 00:16:22.075 --> 00:16:23.092 it doesn't 00:16:23.092 --> 00:16:25.046 matter. 00:16:25.046 --> 00:16:27.058 So this illustrates 00:16:27.058 --> 00:16:31.075 the fact that that metastases can be very distant from the primary, 00:16:31.075 --> 00:16:32.061 they can 00:16:32.061 --> 00:16:33.599 00:16:33.599 --> 00:16:34.098 be 00:16:34.098 --> 00:16:38.021 millions of metastases from one primary 00:16:38.021 --> 00:16:42.083 and also I threw in this whole phenomenon of dormancy which is a bit unusual 00:16:42.083 --> 00:16:44.064 but it happens. 00:16:44.064 --> 00:16:46.056 I'll show you some other mets. 00:16:46.056 --> 00:16:48.069 Here's a lung of a youngster. 00:16:48.069 --> 00:16:52.074 Every one of these is a nodule of neoplasm, the other lung looked just like this. 00:16:52.074 --> 00:16:53.059 This happens 00:16:53.059 --> 00:16:57.008 to have been a primary in the kidney which 00:16:57.008 --> 00:17:00.005 got to the lungs through the renal veins, the vena cava, and on up. 00:17:00.005 --> 00:17:01.012 00:17:01.012 --> 00:17:05.032 The good news is that we can cure many of these, not at this stage, but we 00:17:05.032 --> 00:17:06.959 can prevent it from reaching this 00:17:06.959 --> 00:17:10.029 stage now. 00:17:10.029 --> 00:17:14.009 Here's an interesting one that we see very often, this is a vertebral column which 00:17:14.009 --> 00:17:17.042 I sliced in a band saw 00:17:17.042 --> 00:17:20.097 so you're looking at a couple of mirror images and this is a pretty normal 00:17:20.097 --> 00:17:24.051 vertebra up here, this is an intervertebral disc up here. 00:17:24.051 --> 00:17:28.022 These two lower vertebrae you see these whitish areas 00:17:28.022 --> 00:17:28.085 here and here. 00:17:28.085 --> 00:17:30.092 These were very 00:17:30.092 --> 00:17:34.049 dense bone, and interestingly 00:17:34.049 --> 00:17:38.027 what this represents is metastasis to the bone, 00:17:38.027 --> 00:17:42.031 it stimulates bone formation around the cancer cells, it's something 00:17:42.031 --> 00:17:45.022 we call an osteoblastic 00:17:45.022 --> 00:17:46.049 phenomenon 00:17:46.049 --> 00:17:47.027 or an osteoblastic metastasis. 00:17:47.027 --> 00:17:48.005 This would have shown up 00:17:48.005 --> 00:17:51.029 as a density on the x-ray 00:17:51.029 --> 00:17:55.089 under the microscope, there's a lot of bone there but cancer cells throughout 00:17:55.089 --> 00:17:59.013 and usually cancer cells reach the bone 00:17:59.013 --> 00:18:01.029 via the hematogenous route. 00:18:01.029 --> 00:18:04.094 Could be anything, I mean if someone showed me this, I'd say it's metastatic something or other 00:18:04.094 --> 00:18:07.077 from somewhere or other 00:18:07.077 --> 00:18:09.929 but you will learn for instance that breast 00:18:09.929 --> 00:18:14.085 very often breast cancer very often goes to bone. Prostate cancer notoriously goes to bone. 00:18:14.085 --> 00:18:16.059 00:18:16.059 --> 00:18:20.038 I won't bore you with the list, but you're going to learn as you study oncology 00:18:20.038 --> 00:18:21.097 what the likelihood of 00:18:21.097 --> 00:18:24.024 I mean if this came from a 00:18:24.024 --> 00:18:26.033 middle-aged woman with 00:18:26.033 --> 00:18:30.019 with a breast nodule, I'd say breast cancer. If it came from an elderly guy with 00:18:30.019 --> 00:18:34.019 urinary tract obstruction, I'd say look at his prostate. 00:18:34.019 --> 00:18:38.015 So that is an osteoblastic kind of metastasis. 00:18:38.015 --> 00:18:41.002 Here is a different one, 00:18:41.002 --> 00:18:43.007 this one has another story associated with it. 00:18:43.007 --> 00:18:46.015 This was a 42-year old guy 00:18:46.015 --> 00:18:49.093 who came in with back pain and he was a manual laborer that did heavy labor 00:18:49.093 --> 00:18:53.084 and everyone thought at first well you know it's some orthopedic 00:18:53.084 --> 00:18:54.044 injury 00:18:54.044 --> 00:18:57.889 until they got an x-ray of his back and discovered that one of the vertebrae was 00:18:57.889 --> 00:18:59.062 essentially turned to mush. 00:18:59.062 --> 00:19:01.097 Here's a normal vertebra here and here. 00:19:01.097 --> 00:19:04.037 Here's a disc and this is a 00:19:04.037 --> 00:19:08.024 osteolytic metastasis, it turned out that there was a metastasis 00:19:08.024 --> 00:19:13.012 that completely destroyed the bone and it simply collapsed. 00:19:13.012 --> 00:19:18.007 Now this man presented because of his metastasis, that sometimes happens, 00:19:18.007 --> 00:19:20.071 it may not be the primary, it turned out he was a heavy smoker 00:19:20.071 --> 00:19:22.065 and had a small, 00:19:22.065 --> 00:19:24.056 inapparent 00:19:24.056 --> 00:19:27.079 bronchogenic primary, in other words, a lung cancer 00:19:27.079 --> 00:19:31.007 and it metastasize to his bone without even causing any ruckus. 00:19:31.007 --> 00:19:35.099 He probably had a little cough as all smokers do 00:19:35.099 --> 00:19:36.083 00:19:36.083 --> 00:19:38.048 but presented because of the metastasis 00:19:38.048 --> 00:19:41.024 This was 00:19:41.024 --> 00:19:44.071 another smoker incidence, I remember 00:19:44.071 --> 00:19:47.017 this one very well, 00:19:47.017 --> 00:19:49.043 the patient came in convulsing, signs of 00:19:49.043 --> 00:19:52.084 increased intracranial pressure. 00:19:52.084 --> 00:19:53.074 They 00:19:53.074 --> 00:19:57.057 had to take him to the operating room very quickly to decompress the brain 00:19:57.057 --> 00:20:00.005 and save him from dying from 00:20:00.005 --> 00:20:02.045 the pressure and 00:20:02.045 --> 00:20:04.025 my colleague 00:20:04.025 --> 00:20:06.093 sent me a piece of this 00:20:06.093 --> 00:20:10.037 to look at it quickly with what we call a frozen section. You freeze a tissue and 00:20:10.037 --> 00:20:12.002 make a quick section of it 00:20:12.002 --> 00:20:14.051 It was easy to say this isn't 00:20:14.051 --> 00:20:16.078 cancer arising in the brain 00:20:16.078 --> 00:20:19.059 because it didn't look like that. It looked like a cancer that came from somewhere else. 00:20:19.059 --> 00:20:22.071 This is not rocket science, you'll learn how to do it in the spring. 00:20:22.071 --> 00:20:23.057 00:20:23.057 --> 00:20:24.779 But it's because the 00:20:24.779 --> 00:20:29.067 metastasis resembles the primary that we looked at it and said, no, this isn't brain, this is 00:20:29.067 --> 00:20:32.001 metastasis to the brain. 00:20:32.001 --> 00:20:36.049 Poor fellow died shortly after operation, it turned out again he was riddled with metastases 00:20:36.049 --> 00:20:38.051 with a small lung primary. 00:20:38.051 --> 00:20:40.061 Lung primary 00:20:40.061 --> 00:20:42.009 very often goes to brain like that. 00:20:42.009 --> 00:20:44.097 Oh 00:20:44.097 --> 00:20:49.053 one last lovely image 00:20:49.053 --> 00:20:52.034 there is a liver 00:20:52.034 --> 00:20:54.045 riddled with metastases. 00:20:54.045 --> 00:20:56.088 And if 00:20:56.088 --> 00:21:00.034 someone showed me this liver and said where did this come from, I'd say 00:21:00.034 --> 00:21:03.015 gee, well look at the GI tract. 00:21:03.015 --> 00:21:06.066 It can be elsewhere, this was a lung cancer 00:21:06.066 --> 00:21:10.084 that had metastasized and gotten into the bloodstream, had gotten around and liked the taste 00:21:10.084 --> 00:21:12.005 of liver 00:21:12.005 --> 00:21:15.078 and produced metastases in the liver. There were metastases in many other 00:21:15.078 --> 00:21:17.009 places as well. 00:21:17.009 --> 00:21:19.012 Well, i guess that 00:21:19.012 --> 00:21:25.015 gives you a little bit of an example, a little bit of a feeling for the the destructiveness 00:21:25.015 --> 00:21:28.044 of this process of metastasis. Again benign neoplasm 00:21:28.044 --> 00:21:31.062 do not metastasize, only malignant 00:21:31.062 --> 00:21:33.065 ones do. 00:21:33.065 --> 00:21:44.008 Benign neoplasms do not invade, only malignant ones. 00:21:44.008 --> 00:22:00.043 00:22:00.043 --> 00:22:03.047 With 00:22:03.047 --> 00:22:06.049 those concepts 00:22:06.049 --> 00:22:09.919 of neoplasia, hope you've all got benign and malignant invasion, metastasis sort of 00:22:09.919 --> 00:22:11.036 under your belts. 00:22:11.036 --> 00:22:18.015 I want to talk for a little bit on how neoplasms are 00:22:18.015 --> 00:22:20.032 put together microscopically. 00:22:20.032 --> 00:22:23.899 Again, don't worry about being able to do this kind of diagnosis yourself, 00:22:23.899 --> 00:22:25.089 just listen to the concepts. 00:22:25.089 --> 00:22:28.046 I want to review the concept of stroma, 00:22:28.046 --> 00:22:30.008 the concept of differentiation, 00:22:30.008 --> 00:22:33.001 and ideas of grading 00:22:33.001 --> 00:22:36.041 and staging. 00:22:36.041 --> 00:22:41.091 All right, let's let's begin with the business of stroma and angiogenesis. 00:22:41.091 --> 00:22:43.086 One of things that I should emphasize 00:22:43.086 --> 00:22:48.004 that I didn't really emphasize so far is that 00:22:48.004 --> 00:22:50.062 a given module of neoplasm 00:22:50.062 --> 00:22:53.084 take one of those metastases in the liver for instance 00:22:53.084 --> 00:22:55.089 A given nodule of neoplasm 00:22:55.089 --> 00:22:57.064 is just not a spherical 00:22:57.064 --> 00:23:03.000 collection of 100% cancer cells. 00:23:03.000 --> 00:23:05.011 This is a very important concept 00:23:05.011 --> 00:23:06.042 and it makes perfect sense 00:23:06.042 --> 00:23:08.029 because 00:23:08.029 --> 00:23:10.289 you could not possibly grow 00:23:10.289 --> 00:23:11.064 a lump literally that big 00:23:11.064 --> 00:23:12.092 and have 00:23:12.092 --> 00:23:14.071 a blood supply 00:23:14.071 --> 00:23:17.032 for the cells in the center, 00:23:17.032 --> 00:23:18.045 you follow me? 00:23:18.045 --> 00:23:20.035 In other words, if they were pure cancer cells 00:23:20.035 --> 00:23:22.007 the blood would be out here 00:23:22.007 --> 00:23:24.036 and the cells would be proliferating here. 00:23:24.036 --> 00:23:29.063 It doesn't work that way, the cancer needs a blood supply in order to grow. 00:23:29.063 --> 00:23:30.047 and it turns 00:23:30.047 --> 00:23:31.096 out that 00:23:31.096 --> 00:23:34.022 cancers 00:23:34.022 --> 00:23:38.044 are able and this is an very interesting phenomenon 00:23:38.044 --> 00:23:39.078 to 00:23:39.078 --> 00:23:43.004 induce the formation of what we call a stroma 00:23:43.004 --> 00:23:45.065 it's a fibrous 00:23:45.065 --> 00:23:49.000 particularly a vascular framework 00:23:49.000 --> 00:23:52.003 which supports the neoplasm. 00:23:52.003 --> 00:23:54.013 Now the stroma 00:23:54.013 --> 00:23:56.047 is not part of the malignant clone 00:23:56.047 --> 00:23:59.069 or the neoplastic clone. 00:23:59.069 --> 00:24:00.095 It comes from 00:24:00.095 --> 00:24:06.066 the connective tissue cells and the blood vessels cells 00:24:06.066 --> 00:24:07.007 around 00:24:07.007 --> 00:24:09.000 the neoplasm. 00:24:09.000 --> 00:24:11.031 The neoplastic cells 00:24:11.031 --> 00:24:14.092 and probably some of the inflammatory cells accompanying the neoplasm are able 00:24:14.092 --> 00:24:16.047 to induce 00:24:16.047 --> 00:24:19.056 the formation of this stroma. It's 00:24:19.056 --> 00:24:20.046 very much 00:24:20.046 --> 00:24:24.058 like the the induction of granulation tissue which you're very familiar with from 00:24:24.058 --> 00:24:25.027 last week. 00:24:25.027 --> 00:24:26.047 And 00:24:26.047 --> 00:24:27.239 what 00:24:27.239 --> 00:24:28.779 happens 00:24:28.779 --> 00:24:34.919 is this fibrous and vascular stroma grows into the nodule and enables it 00:24:34.919 --> 00:24:36.044 to proliferate. 00:24:36.044 --> 00:24:37.054 00:24:37.054 --> 00:24:39.088 Now we talk about 00:24:39.088 --> 00:24:45.084 tumor angiogenesis, I mean the emphasis being on the blood vessels. 00:24:45.084 --> 00:24:48.095 There is abundant 00:24:48.095 --> 00:24:50.789 experimental evidence to show 00:24:50.789 --> 00:24:51.089 that 00:24:51.089 --> 00:24:55.279 and i won't go into the details, but if you create a situation where you got 00:24:55.279 --> 00:24:58.048 a bunch of neoplastic cells growing pure 00:24:58.048 --> 00:25:01.054 where they can't pick up a stroma, 00:25:01.054 --> 00:25:06.015 the module will never get bigger than a millimeter or two at the very most, 00:25:06.015 --> 00:25:07.003 probably less because 00:25:07.003 --> 00:25:12.027 because the oxygen and nutrients cannot diffuse in the solid mass any further. 00:25:12.027 --> 00:25:14.031 There are many experiments that show 00:25:14.031 --> 00:25:19.006 you grow neoplastic cells in these little balls and they stopped growing. 00:25:19.006 --> 00:25:23.003 and then if you do something to induce angiogenesis, BOOM, 00:25:23.003 --> 00:25:24.081 as soon as they pick up 00:25:24.081 --> 00:25:27.025 the vascular stroma 00:25:27.025 --> 00:25:28.119 they begin 00:25:28.119 --> 00:25:29.015 to grow 00:25:29.015 --> 00:25:33.005 so tumor angiogenesis is exceedingly important. You can 00:25:33.005 --> 00:25:34.041 read a 00:25:34.041 --> 00:25:38.049 I won't bother you with the details, but we are beginning to know a little bit about how 00:25:38.049 --> 00:25:43.001 this is mediated and what it looks like is this: 00:25:43.001 --> 00:25:44.077 again without too much detail 00:25:44.077 --> 00:25:47.041 this was a lump in a breast. 00:25:47.041 --> 00:25:51.002 This was a breast cancer. 00:25:51.002 --> 00:25:54.022 These dark clumps are the cancer cells 00:25:54.022 --> 00:25:56.058 and the 00:25:56.058 --> 00:25:58.055 pink in the background 00:25:58.055 --> 00:26:00.024 is the stroma. 00:26:00.024 --> 00:26:04.085 I'll emphasize in particular there is a capillary there, 00:26:04.085 --> 00:26:08.081 there is a capillary cut lengthwise there, there's another capillary here 00:26:08.081 --> 00:26:10.409 and so forth 00:26:10.409 --> 00:26:11.042 so that any given 00:26:11.042 --> 00:26:15.015 clump of cancer cells isn't very far from 00:26:15.015 --> 00:26:17.169 a capillary. 00:26:17.169 --> 00:26:19.045 That's the concept 00:26:19.045 --> 00:26:23.979 of the stroma and tumor angiogenesis and what it means. 00:26:23.979 --> 00:26:27.024 If we could stop angiogenesis 00:26:27.024 --> 00:26:29.001 we could stop tumor growth. 00:26:29.001 --> 00:26:33.015 It would be wonderful and some of these attempts have reached the clinical testing 00:26:33.015 --> 00:26:35.025 testing stage but nothing terribly dramatic yet. 00:26:35.025 --> 00:26:38.038 But it's certainly a handle. 00:26:38.038 --> 00:26:43.013 Here is kind of a loose stroma, not very fibrous but a lot of blood vessels. 00:26:43.013 --> 00:26:44.074 Sometimes 00:26:44.074 --> 00:26:45.046 you can be 00:26:45.046 --> 00:26:47.029 very dense. 00:26:47.029 --> 00:26:48.659 These are cancer cells 00:26:48.659 --> 00:26:52.049 in a very dense collagenous stroma. 00:26:52.049 --> 00:26:54.007 This kind of a lump has a 00:26:54.007 --> 00:26:56.041 consistency about like wood. 00:26:56.041 --> 00:27:00.069 We call that, it's an adjective you'll hear occasionally, it's a scirrhous 00:27:00.069 --> 00:27:02.005 s-c-i-r-r-h-o-u-s 00:27:02.005 --> 00:27:05.048 scirrhous 00:27:05.048 --> 00:27:07.093 mode of growth 00:27:07.093 --> 00:27:11.086 But whatever the variation, any 00:27:11.086 --> 00:27:12.069 lump of 00:27:12.069 --> 00:27:15.077 neoplasm has this vascular stroma 00:27:15.077 --> 00:27:19.024 that it has induced. 00:27:19.024 --> 00:27:20.021 Okay. 00:27:20.021 --> 00:27:26.019 Now go onto the next concept, that is related to the fact that 00:27:26.019 --> 00:27:28.096 since neoplastic cells are derived 00:27:28.096 --> 00:27:33.669 from a previously normal cell population, they're 00:27:33.669 --> 00:27:37.077 going to share many of the genetic traits and are going to have some new ones 00:27:37.077 --> 00:27:41.005 because of these mutations but they're going to share a tremendous genetic 00:27:41.005 --> 00:27:42.081 background 00:27:42.081 --> 00:27:46.026 with the parent issues so they're going to resemble the parent tissue 00:27:46.026 --> 00:27:49.006 to some variable extent. 00:27:49.006 --> 00:27:54.099 I mean sometimes very sharp resemblance, sometimes maybe not much of a resemblance. 00:27:54.099 --> 00:27:56.007 00:27:56.007 --> 00:27:58.072 When the neoplastic tissue 00:27:58.072 --> 00:28:03.042 resembles the parental tissue, the normal tissue, 00:28:03.042 --> 00:28:05.399 through a high degree 00:28:05.399 --> 00:28:09.092 very close resemblance we speak about that neoplasm as being well-differentiated. 00:28:09.092 --> 00:28:13.005 Funny phrase, I didn't invent it. 00:28:13.005 --> 00:28:18.036 When we say well differentiated, it means looks just like mom and pop. 00:28:18.036 --> 00:28:22.023 On the other extreme, it may look nothing, I'll show you some examples, 00:28:22.023 --> 00:28:26.023 it may look nothing like the parental tissue, we say that is a poorly differentiated 00:28:26.023 --> 00:28:27.409 or 00:28:27.409 --> 00:28:32.031 undifferentiated 00:28:32.031 --> 00:28:32.083 tissue. 00:28:32.083 --> 00:28:37.052 There's another phrase, another word we sometimes use, that's anaplastic. 00:28:37.052 --> 00:28:40.047 Anaplastic refers to 00:28:40.047 --> 00:28:44.049 well, some people say de-differentiated, but undifferentiated 00:28:44.049 --> 00:28:47.034 just immature or undifferentiated tissue 00:28:47.034 --> 00:28:48.419 we refer to 00:28:48.419 --> 00:28:51.012 as anaplastic. 00:28:51.012 --> 00:28:53.799 There's a complete range 00:28:53.799 --> 00:28:56.098 of possibilities. 00:28:56.098 --> 00:28:58.033 Let me illustrate 00:28:58.033 --> 00:29:02.309 this for you in two extremes 00:29:02.309 --> 00:29:05.022 Here is normal colonic 00:29:05.022 --> 00:29:08.071 mucosa, and we're going to talk about this in detail on Wednesday. 00:29:08.071 --> 00:29:10.769 The mucosa has these 00:29:10.769 --> 00:29:14.139 kind of tubular glands, that's all I want you to get out of this, this is perfectly normal 00:29:14.139 --> 00:29:15.009 00:29:15.009 --> 00:29:21.059 The next slide will be a cancer derived from this mucosa, looks like that. 00:29:21.059 --> 00:29:23.035 Now you say, that doesn't look anything like it, but 00:29:23.035 --> 00:29:26.056 in a sense it does. 00:29:26.056 --> 00:29:31.049 it's got glands, they're kind of funky and kinky and so forth 00:29:31.049 --> 00:29:33.027 but they're clearly glands. 00:29:33.027 --> 00:29:36.008 You'll also notice that the pink to blue ratio has changed, a lot of hyperchromatism 00:29:36.008 --> 00:29:40.026 a lot more nuclei here and so forth but basically 00:29:40.026 --> 00:29:44.063 a pathologist looking at this would take about a nanosecond as you will learn 00:29:44.063 --> 00:29:46.053 this spring and say oh! 00:29:46.053 --> 00:29:48.002 this is a glandular type of 00:29:48.002 --> 00:29:49.047 neoplasm. 00:29:49.047 --> 00:29:50.014 So we say 00:29:50.014 --> 00:29:54.031 this is at least moderately differentiated. 00:29:54.031 --> 00:29:56.069 Now I'll show you a step down, 00:29:56.069 --> 00:30:01.015 here's a normal bronchial mucosa, again don't worry about the details, but they're these tall 00:30:01.015 --> 00:30:02.489 columnar cells, 00:30:02.489 --> 00:30:04.409 some of them are secreting mucus 00:30:04.409 --> 00:30:05.008 others have cilia on them 00:30:05.008 --> 00:30:06.071 they're very well 00:30:06.071 --> 00:30:08.061 organized there 00:30:08.061 --> 00:30:11.087 The next line is a neoplasm derived 00:30:11.087 --> 00:30:15.073 from that cell population 00:30:15.073 --> 00:30:20.023 If someone showed me that I'd say that I don't know what that is, 00:30:20.023 --> 00:30:22.719 that is an undifferentiated, malignant 00:30:22.719 --> 00:30:25.036 neoplasm, 00:30:25.036 --> 00:30:27.075 or anaplastic neoplasm. 00:30:27.075 --> 00:30:29.069 And when 00:30:29.069 --> 00:30:33.004 you look at that, what it really says is it's a population of cells 00:30:33.004 --> 00:30:34.022 that's not maturing 00:30:34.022 --> 00:30:38.009 you can't tell what it's doing or where it came from, 00:30:38.009 --> 00:30:43.037 but it sure as the dickens looks malignant, look at those huge nuclei 00:30:43.037 --> 00:30:47.021 increased n-to-c ratio (nucleus to cytoplasm) 00:30:47.021 --> 00:30:50.006 they are actually pleomorphic, they are hyperchromatic, 00:30:50.006 --> 00:30:51.037 there are 00:30:51.037 --> 00:30:54.002 tumor giant cells there. 00:30:54.002 --> 00:30:57.075 Really, you'll learn to look at those things and loathe them, to say that is an ugly 00:30:57.075 --> 00:30:59.054 cell population 00:30:59.054 --> 00:31:02.029 so that is a highly anaplastic cell population. 00:31:02.029 --> 00:31:04.034 Now, 00:31:04.034 --> 00:31:06.071 it turns out 00:31:06.071 --> 00:31:07.081 well, let me give you 00:31:07.081 --> 00:31:11.071 a rule of thumb first. 00:31:11.071 --> 00:31:13.057 Benign neoplasms 00:31:13.057 --> 00:31:17.089 are always splendidly well differentiated, sometimes you get in the 00:31:17.089 --> 00:31:21.099 middle of a benign neoplasm, you can't tell it from the normal tissues, so a benign 00:31:21.099 --> 00:31:23.088 neoplasms are always 00:31:23.088 --> 00:31:25.002 well-differentiated. 00:31:25.002 --> 00:31:29.017 Almost perfectly differentiated. 00:31:29.017 --> 00:31:32.299 Malignant neoplasms show the whole range, 00:31:32.299 --> 00:31:37.038 there are very well differentiated but nonetheless malignant neoplasms 00:31:37.038 --> 00:31:38.065 and there are highly anaplastic 00:31:38.065 --> 00:31:43.046 like this. 00:31:43.046 --> 00:31:46.092 In some situations, in many situations, 00:31:46.092 --> 00:31:49.073 in malignant neoplasms, 00:31:49.073 --> 00:31:54.036 there is a a rough correlation, I emphasize rough, 00:31:54.036 --> 00:31:55.021 between the degree 00:31:55.021 --> 00:31:59.078 of differentiation and the behavior. 00:31:59.078 --> 00:32:02.799 This is not uniform for all neoplasms 00:32:02.799 --> 00:32:06.084 and remember well differentiated neoplasms/cancers can still kill. 00:32:06.084 --> 00:32:07.084 But for 00:32:07.084 --> 00:32:09.064 some situations, it's a 00:32:09.064 --> 00:32:11.006 useful label that we 00:32:11.006 --> 00:32:14.095 give it to send to our colleagues 00:32:14.095 --> 00:32:16.359 where we say 00:32:16.359 --> 00:32:19.009 we label it 00:32:19.009 --> 00:32:24.559 depending on the degree of differentiation we call this ''grading'', 00:32:24.559 --> 00:32:27.093 histological grading of neoplasm. 00:32:27.093 --> 00:32:31.015 The grading of neoplasms is really 00:32:31.015 --> 00:32:36.037 an assessment of the degree of differentiation of the neoplasm based on, 00:32:36.037 --> 00:32:38.061 i mean we look under the microscope, 00:32:38.061 --> 00:32:42.008 and we say oh! this looks just like 00:32:42.008 --> 00:32:44.529 such-and-such tissue that's well differentiated 00:32:44.529 --> 00:32:48.083 we sometimes take into account in these grading systems 00:32:48.083 --> 00:32:51.036 the number of mitoses 00:32:51.036 --> 00:32:52.086 that's a little less usual 00:32:52.086 --> 00:32:55.329 but it's based basically on the degree of differentiation 00:32:55.329 --> 00:33:00.129 and we talk about grade one, usually grade one means 00:33:00.129 --> 00:33:04.419 the best differentiated grade, grade two to grade three, some grading systems are all 00:33:04.419 --> 00:33:06.659 the way through grade four. 00:33:06.659 --> 00:33:11.038 You get the idea, I mean you will get the details, but when we label with the grade 00:33:11.038 --> 00:33:16.036 we say this is well differentiated and our colleagues at the other end say, well 00:33:16.036 --> 00:33:21.052 maybe that'll behave a little better than if Abrams said it was anaplastic. 00:33:21.052 --> 00:33:24.071 And Illl show you what this amounts to visually, again don't worry about being 00:33:24.071 --> 00:33:26.074 able to pick these out. 00:33:26.074 --> 00:33:28.429 Here is a carcinoma, 00:33:28.429 --> 00:33:29.096 00:33:29.096 --> 00:33:34.032 cancer derived from a squamous epithelium, like the epidermis of the skin 00:33:34.032 --> 00:33:37.033 and a trained pathologist, which you will be 00:33:37.033 --> 00:33:42.016 next spring, would look at this kind of arrangement or all this pinky cytoplasm 00:33:42.016 --> 00:33:44.059 which represents keratin and 00:33:44.059 --> 00:33:45.159 in the cells 00:33:45.159 --> 00:33:46.072 and you'd say oh easy! 00:33:46.072 --> 00:33:47.065 That's a well-differentiated 00:33:47.065 --> 00:33:51.044 squamous cell carcinoma, this might be a grade one 00:33:51.044 --> 00:33:52.059 for 00:33:52.059 --> 00:33:54.025 instance 00:33:54.025 --> 00:33:56.049 This one is might not look like much to you, but 00:33:56.049 --> 00:34:00.031 a trained pathologist would look at this and say, well, 00:34:00.031 --> 00:34:01.019 this isn't terribly 00:34:01.019 --> 00:34:06.149 well differentiated but I can still see areas where I'll bet that's coming 00:34:06.149 --> 00:34:11.019 from the squamous epithelium, so that would be maybe a grade two or moderately 00:34:11.019 --> 00:34:13.021 differentiated 00:34:13.021 --> 00:34:14.093 Here again is a completely 00:34:14.093 --> 00:34:18.057 anaplastic cell population, someone showed me that and said where is this coming from 00:34:18.057 --> 00:34:19.056 and I'd say 00:34:19.056 --> 00:34:21.759 God only knows this is cancer. 00:34:21.759 --> 00:34:24.299 When i don't know what kind, 00:34:24.299 --> 00:34:29.999 this is really an anaplastic, probably grade three to grade four cancer 00:34:29.999 --> 00:34:32.999 and again there's a rough correlation between 00:34:32.999 --> 00:34:36.389 the degree of differentiation and how it might behave. 00:34:36.389 --> 00:34:37.649 behave 00:34:37.649 --> 00:34:39.209 Now grading, 00:34:39.209 --> 00:34:42.879 this is all microscopic, grading is different than staging. 00:34:42.879 --> 00:34:46.029 Please keep these two straight 00:34:46.029 --> 00:34:48.389 and read and understand, you're going to deal 00:34:48.389 --> 00:34:50.589 with these two concepts all your lives. 00:34:50.589 --> 00:34:54.119 Staging a neoplasm is very important 00:34:54.119 --> 00:34:57.569 because of the stage that we assigned to a neoplasm tells the observer 00:34:57.569 --> 00:34:59.939 00:34:59.939 --> 00:35:05.249 how far along in its natural history that neoplasm is, in other words, 00:35:05.249 --> 00:35:09.829 how big is it at the primary, how much tissue has it penetrated, 00:35:09.829 --> 00:35:12.003 has it advanced to the point where it's spread 00:35:12.003 --> 00:35:14.019 elsewhere in the body. 00:35:14.019 --> 00:35:18.049 That is staging. 00:35:18.049 --> 00:35:23.739 It's based on first of all the size and the extent of the primary, 00:35:23.739 --> 00:35:29.709 the presence or absence of regional lymph node metastases, and 00:35:29.709 --> 00:35:32.939 the presence or absence of distant metastases. 00:35:32.939 --> 00:35:36.659 This is sometimes referred to as the TNM system, T for tumor, 00:35:36.659 --> 00:35:37.067 00:35:37.067 --> 00:35:39.599 what's he doing with the primary, 00:35:39.599 --> 00:35:41.709 N for regional nodes, 00:35:41.709 --> 00:35:43.739 M for distant metastases. 00:35:43.739 --> 00:35:45.002 Every organ has 00:35:45.002 --> 00:35:49.579 a slightly different staging scheme, but they're all based on this 00:35:49.579 --> 00:35:51.008 and what it gives you, 00:35:51.008 --> 00:35:52.909 if it's a low stage 00:35:52.909 --> 00:35:56.041 or a favorable stage, that says this tumor hasn't advanced 00:35:56.041 --> 00:35:58.479 as far, maybe it's restricted just to 00:35:58.479 --> 00:36:01.029 the organ, the lymph nodes are negative, 00:36:01.029 --> 00:36:04.269 and there are no distant metastases, 00:36:04.269 --> 00:36:07.699 or it may be that it's penetrated quite a way through 00:36:07.699 --> 00:36:10.043 whatever organ it's started in, and there are already 00:36:10.043 --> 00:36:15.469 lymph node mets but we don't know of distant mets 00:36:15.469 --> 00:36:19.018 that's quite a different situation which may take a different therapeutic approach 00:36:19.018 --> 00:36:22.066 and finally if they're already distant mets, that's a very different thing. 00:36:22.066 --> 00:36:23.689 00:36:23.689 --> 00:36:25.969 So staging 00:36:25.969 --> 00:36:28.299 gives you a very important handle on how far 00:36:28.299 --> 00:36:30.005 along the neoplasm is in the 00:36:30.005 --> 00:36:32.029 particular patient and 00:36:32.029 --> 00:36:34.419 what you should do therapeutically 00:36:34.419 --> 00:36:38.399 because of that. 00:36:38.399 --> 00:36:39.959 00:36:39.959 --> 00:36:43.909 Now's not the time to dwell on how we tell benign from malignant and 00:36:43.909 --> 00:36:47.969 in our daily work you will again get an appreciation for this next 00:36:47.969 --> 00:36:49.579 spring, but suffice it to say 00:36:49.579 --> 00:36:53.609 that we pathologists can look at a tumor 00:36:53.609 --> 00:36:54.499 and make 00:36:54.499 --> 00:36:58.279 some pretty good predictions about how it may behave. 00:36:58.279 --> 00:37:02.319 In other words, if we look at a tumor and it looks very well-differentiated 00:37:02.319 --> 00:37:05.169 and completely circumscribed and so on and so forth, we 00:37:05.169 --> 00:37:07.409 say it's benign 00:37:07.409 --> 00:37:11.999 and what that says is if you get the whole thing out, patient is home free. 00:37:11.999 --> 00:37:17.049 If it's invasive anaplastic, it's a very different situation. 00:37:17.049 --> 00:37:20.679 I can tell you that that the cornerstone 00:37:20.679 --> 00:37:22.459 of clinical diagnosis 00:37:22.459 --> 00:37:25.729 in the field of oncology is 00:37:25.729 --> 00:37:27.689 getting something under glass, 00:37:27.689 --> 00:37:29.929 getting in the microscope. 00:37:29.929 --> 00:37:31.979 Very few instances where 00:37:31.979 --> 00:37:32.759 00:37:32.759 --> 00:37:34.749 00:37:34.749 --> 00:37:37.043 therapy will be undertaken without confirmation 00:37:37.043 --> 00:37:41.081 of the fact that under the microscope that it is such-and-such a cancer and such and such grade and so forth. 00:37:41.081 --> 00:37:44.002 so it means we need a piece of the tissue 00:37:44.002 --> 00:37:46.779 00:37:46.779 --> 00:37:47.008 or at least 00:37:47.008 --> 00:37:49.066 some cells from the tissue 00:37:49.066 --> 00:37:50.909 to get under the microscope. 00:37:50.909 --> 00:37:53.589 00:37:53.589 --> 00:37:55.091 What we rely on there 00:37:55.091 --> 00:37:59.069 as you might surmise from what you've seen is first of all 00:37:59.069 --> 00:38:01.859 00:38:01.859 --> 00:38:06.739 the cytologic features, how anaplastic looking are the cells, how bad is the 00:38:06.739 --> 00:38:12.339 the pleomorphism, the hyperchromatism, etc, we rely on that 00:38:12.339 --> 00:38:16.539 we rely on the relation of the cells to one another, the loss of polarity in the system 00:38:16.539 --> 00:38:18.869 and so forth, and 00:38:18.869 --> 00:38:24.529 we rely on the relation of the tumor to its surroundings, the nice pushing 00:38:24.529 --> 00:38:28.279 margin vs boy! there goes invasion 00:38:28.279 --> 00:38:32.529 it's that sort of thing. Now 00:38:32.529 --> 00:38:33.839 I'll give you just a 00:38:33.839 --> 00:38:36.064 very quick example of that. 00:38:36.064 --> 00:38:37.097 Here is a 00:38:37.097 --> 00:38:40.014 you can imagine that colon I showed you 00:38:40.014 --> 00:38:41.139 in the cut, 00:38:41.139 --> 00:38:44.077 here is a mucosa, a submucosa, here is a muscular wall, 00:38:44.077 --> 00:38:46.025 here's the tumor arising in the mucosa. 00:38:46.025 --> 00:38:48.479 00:38:48.479 --> 00:38:52.779 You see under the microscope here, you can see kind of glandular spaces there. 00:38:52.779 --> 00:38:53.095 Look what's happening, 00:38:53.095 --> 00:38:55.599 you've got glands 00:38:55.599 --> 00:38:58.779 penetrating clear down through the muscle there. 00:38:58.779 --> 00:39:00.799 00:39:00.799 --> 00:39:02.004 That's a no brainer 00:39:02.004 --> 00:39:07.329 when we see something like that we say it's invading, it's malignant. 00:39:07.329 --> 00:39:10.859 That make sense? 00:39:10.859 --> 00:39:15.199 Sometimes we don't rely entirely on that, we rely on other things 00:39:15.199 --> 00:39:17.029 The cytology, just quickly, 00:39:17.029 --> 00:39:20.719 there are normal colonic epithelial cells 00:39:20.719 --> 00:39:23.769 I'm not going to describe it, just let the pictures speak for themselves. 00:39:23.769 --> 00:39:26.569 You'll catch up with this in the spring. 00:39:26.569 --> 00:39:32.359 Here are neoplastic epithelial cells. Again, normal...neoplastic. 00:39:32.359 --> 00:39:34.999 Here's a normal squamous 00:39:34.999 --> 00:39:39.789 epithelium, we're back to cervix, here's normal squamous 00:39:39.789 --> 00:39:41.589 00:39:41.589 --> 00:39:43.479 here's dysplastic. 00:39:43.479 --> 00:39:50.199 you saw that before, this variation, this loss of polarity, the individual features 00:39:50.199 --> 00:39:52.042 of cytology here, that's a 00:39:52.042 --> 00:39:56.078 degree of dysplasia, it's a step towards cancer. 00:39:56.078 --> 00:40:01.035 This one we said was full thickness 'awfulness' with very anaplastic cells, I won't go into the details again. 00:40:01.035 --> 00:40:02.319 00:40:02.319 --> 00:40:04.359 The concept is important, when dysplasia gets severe 00:40:04.359 --> 00:40:07.239 it's tantamount to 00:40:07.239 --> 00:40:11.439 cancer in situ, whether or not it's invaded, 00:40:11.439 --> 00:40:14.709 you see in the colonic example, we showed you invasion. 00:40:14.709 --> 00:40:18.049 Here we can say this epithelium is cancerous, dammit! 00:40:18.049 --> 00:40:21.989 Whether it invaded or not, we got to get it out or something bad is going to happen because 00:40:21.989 --> 00:40:26.099 virtually 100% of these severe dysplasias will invade. 00:40:26.099 --> 00:40:26.062 And that is 00:40:26.062 --> 00:40:27.094 carcinoma in situ. 00:40:27.094 --> 00:40:29.479 00:40:29.479 --> 00:40:32.007 You'll hear a lot more about that 00:40:32.007 --> 00:40:35.509 Now 00:40:35.509 --> 00:40:38.499 00:40:38.499 --> 00:40:41.289 clearly if you look at something like this 00:40:41.289 --> 00:40:46.719 you realize that that individual cells in that population bear the 00:40:46.719 --> 00:40:48.279 imprint 00:40:48.279 --> 00:40:51.179 of their malignancy, in other words, they have these anaplastic traits and you 00:40:51.179 --> 00:40:53.159 can say these are malignant cells. 00:40:53.159 --> 00:40:56.349 A guy named the george papanicolaou 00:40:56.349 --> 00:40:58.849 over half a century ago 00:40:58.849 --> 00:41:02.093 realized that that this was a great handle, that if you 00:41:02.093 --> 00:41:08.319 took cells that exfoliated, that is dropped off the surface, of 00:41:08.319 --> 00:41:09.869 a place where there might be a tumor 00:41:09.869 --> 00:41:12.006 that these exfoliated cells 00:41:12.006 --> 00:41:13.669 would bear 00:41:13.669 --> 00:41:17.066 some of these traits, these anaplastic traits, and all you'd have to do 00:41:17.066 --> 00:41:20.039 is look at these cells and say WOW 00:41:20.039 --> 00:41:22.065 this is so and so. 00:41:22.065 --> 00:41:27.529 This is, as I'm sure you're aware, the origin of the so-called Pap smear, 00:41:27.529 --> 00:41:29.099 and the beauty of the Pap smear is that you don't have to 00:41:29.099 --> 00:41:32.879 cut out a piece of tissue from the person. 00:41:32.879 --> 00:41:33.097 00:41:33.097 --> 00:41:35.087 All you need is a sample 00:41:35.087 --> 00:41:37.007 of the usually it's mucus 00:41:37.007 --> 00:41:38.019 00:41:38.019 --> 00:41:40.189 00:41:40.189 --> 00:41:41.056 over the area, now 00:41:41.056 --> 00:41:45.041 this has been perfected, this has changed the whole face of 00:41:45.041 --> 00:41:49.739 how we deal with cervix cancer 00:41:49.739 --> 00:41:53.609 but you can imagine a cervix...no let's back up, 00:41:53.609 --> 00:41:55.459 00:41:55.459 --> 00:41:57.569 looking like that 00:41:57.569 --> 00:41:58.719 and that are 00:41:58.719 --> 00:42:02.319 exfoliated, remember they come off here and getting a Pap smear 00:42:02.319 --> 00:42:04.073 involves getting a little bit of mucus 00:42:04.073 --> 00:42:08.979 scraped off the surface of the middle of some of these cells and 00:42:08.979 --> 00:42:10.809 from a normal epithelium like this 00:42:10.809 --> 00:42:14.009 you're going to see 00:42:14.009 --> 00:42:17.007 and i'll show you a Pap smear 00:42:17.007 --> 00:42:19.189 whereas from this 00:42:19.189 --> 00:42:20.309 00:42:20.309 --> 00:42:23.919 or this, you're going to get a different kind of cell exfoliating out 00:42:23.919 --> 00:42:24.083 00:42:24.083 --> 00:42:29.058 and without really having to get a big piece of tissue, you get a little bit a swatch of 00:42:29.058 --> 00:42:32.709 mucus you can tell what you're dealing with. 00:42:32.709 --> 00:42:34.709 I'll let you see this for yourselves. 00:42:34.709 --> 00:42:36.109 00:42:36.109 --> 00:42:40.499 Well, here are just some of cellular features of anaplasia. 00:42:40.499 --> 00:42:44.076 Any look at a cell population like this with the huge nuclei 00:42:44.076 --> 00:42:47.219 there's a tripolar division figure there, 00:42:47.219 --> 00:42:52.009 those are the kinds of features we look for, all right here is a normal Pap smear. 00:42:52.009 --> 00:42:54.639 00:42:54.639 --> 00:42:58.449 You look at that without any training at all and you say well those cells look like one another 00:42:58.449 --> 00:42:59.819 00:42:59.819 --> 00:43:02.014 look like they're all out of the same cookie cutter, same N-C ratio 00:43:02.014 --> 00:43:07.089 the nuclei are not pleomorphic, they are not very regular 00:43:07.089 --> 00:43:08.699 etcetera etcetera etcetera 00:43:08.699 --> 00:43:11.219 Normal pap smear next case, 00:43:11.219 --> 00:43:14.589 now suppose that epithelium looked like 00:43:14.589 --> 00:43:19.039 the bad one I showed you, there you are, 00:43:19.039 --> 00:43:20.829 I'm showing you the extremes, 00:43:20.829 --> 00:43:22.019 00:43:22.019 --> 00:43:25.092 instead of being very regular, these are extremely pleomorphic cells with increased N-C ratio 00:43:25.092 --> 00:43:28.001 hyperchromatism 00:43:28.001 --> 00:43:31.099 and so forth, 00:43:31.099 --> 00:43:35.889 the cytopathologist looking at this doesn't have to pause very often and say 00:43:35.889 --> 00:43:37.079 this 00:43:37.079 --> 00:43:40.449 has been exfoliated from a malignant cell population 00:43:40.449 --> 00:43:41.839 and the nice thing is 00:43:41.839 --> 00:43:44.479 that in between the cytopathologist can also 00:43:44.479 --> 00:43:48.449 look at this and say well this probably came from a cervix with 00:43:48.449 --> 00:43:50.609 moderate dysplasia 00:43:50.609 --> 00:43:53.539 or minimal dysplasia or something like that, 00:43:53.539 --> 00:43:58.149 so that not only can we catch cancers when they're perhaps too small to appreciate 00:43:58.149 --> 00:43:59.659 by ordinary examination 00:43:59.659 --> 00:44:01.189 we can actually 00:44:01.189 --> 00:44:03.209 catch dysplastic epithelium 00:44:03.209 --> 00:44:07.119 before it's become cancer or carcinoma in situ 00:44:07.119 --> 00:44:11.299 before it's invaded, these things are all invisible pretty much 00:44:11.299 --> 00:44:11.999 00:44:11.999 --> 00:44:15.048 and they will show up on the cytological exam, 00:44:15.048 --> 00:44:19.349 so it's become a very powerful screening tool 00:44:19.349 --> 00:44:20.049 00:44:20.049 --> 00:44:23.079 and it's changed the face of what we 00:44:23.079 --> 00:44:28.129 see in the way of cervix cancer, when i was a kid in pathology we used to see 00:44:28.129 --> 00:44:30.439 nothing but very advanced cervix cancer 00:44:30.439 --> 00:44:31.092 00:44:31.092 --> 00:44:32.969 00:44:32.969 --> 00:44:36.469 that were clear into the rectal wall and bladder wall and so forth, 00:44:36.469 --> 00:44:40.599 i haven't seen one of those thankfully in decades 00:44:40.599 --> 00:44:47.369 because of the application of the Pap smear as screening. 00:44:47.369 --> 00:44:51.579 That's something you'll hear a lot more about 00:44:51.579 --> 00:44:56.439 so going back to generalities, a definition 00:44:56.439 --> 00:45:00.092 of, or the diagnosis of neoplasm, requires getting something 00:45:00.092 --> 00:45:02.669 under the microscope. 00:45:02.669 --> 00:45:04.011 Now sometimes it's the whole 00:45:04.011 --> 00:45:07.078 tumor, patient presents with lump sum or 00:45:07.078 --> 00:45:12.015 you cut out the whole thing -- that's called an excisional, excisional biopsy, 00:45:12.015 --> 00:45:15.539 and that's very nice because if it's benign, you're done. 00:45:15.539 --> 00:45:18.169 If it's malignant, 00:45:18.169 --> 00:45:21.099 you have to do some other things very likely. 00:45:21.099 --> 00:45:24.209 Sometimes only a piece of tissue is removed, if it's a big mass 00:45:24.209 --> 00:45:27.459 you don't want to go and do a commando operation until you know what you're 00:45:27.459 --> 00:45:28.005 dealing with. 00:45:28.005 --> 00:45:32.289 That may be an incisional biopsy, you take a wedge of it out. 00:45:32.289 --> 00:45:36.089 There are various biting forceps where 00:45:36.089 --> 00:45:37.069 00:45:37.069 --> 00:45:39.259 bite a piece out 00:45:39.259 --> 00:45:41.509 and there are punch forceps 00:45:41.509 --> 00:45:44.979 particularly for skin things where you take a punch, 00:45:44.979 --> 00:45:46.459 it's a little boring, 00:45:46.459 --> 00:45:47.009 finally 00:45:47.009 --> 00:45:48.319 00:45:48.319 --> 00:45:52.239 very often there are a variety of needles that are used where you can 00:45:52.239 --> 00:45:56.489 put a needle into a mass with very, 00:45:56.489 --> 00:45:58.689 nothing beyond local anesthesia even, 00:45:58.689 --> 00:46:01.065 put a needle in and draw out a core of cells 00:46:01.065 --> 00:46:02.043 and get those 00:46:02.043 --> 00:46:05.399 under the microscope 00:46:05.399 --> 00:46:07.032 and the extreme of this 00:46:07.032 --> 00:46:09.041 is putting in, and this can be done 00:46:09.041 --> 00:46:12.409 you know with CT guidance into internal organs 00:46:12.409 --> 00:46:14.929 put a very fine skinny needle in there 00:46:14.929 --> 00:46:16.969 suck out some juice 00:46:16.969 --> 00:46:18.003 from the 00:46:18.003 --> 00:46:19.519 lump 00:46:19.519 --> 00:46:22.057 and that juice will usually contain a few floating cells 00:46:22.057 --> 00:46:26.002 and the trained cytopathologist could look at the degree of anaplasia and so forth 00:46:26.002 --> 00:46:29.089 in those cells and make a diagnosis. 00:46:29.089 --> 00:46:32.038 So, this is 00:46:32.038 --> 00:46:37.079 always, almost always, what we do before undertaking treatment. 00:46:37.079 --> 00:46:38.579 And 00:46:38.579 --> 00:46:40.069 00:46:40.069 --> 00:46:43.749 just to tell you, in conclusion, that this visual exam 00:46:43.749 --> 00:46:49.099 under the scope is frequently augmented by other things. 00:46:49.099 --> 00:46:51.859 Someone asked me, for instance, 00:46:51.859 --> 00:46:54.829 can you always tell, looking at a met, where it came from, if it's an unknown 00:46:54.829 --> 00:46:56.159 primary. 00:46:56.159 --> 00:46:59.279 My answer was no, unfortunately 00:46:59.279 --> 00:47:02.309 many different glandular neoplasms 00:47:02.309 --> 00:47:04.269 look the same under the microscope, 00:47:04.269 --> 00:47:06.199 00:47:06.199 --> 00:47:10.499 so all we can say is this came from a glandular tissue. Sometimes we can use 00:47:10.499 --> 00:47:13.099 immuno histochemical techniques, 00:47:13.099 --> 00:47:18.209 in other words, there maybe certain proteins on the surface of certain cells 00:47:18.209 --> 00:47:21.539 that identify them 00:47:21.539 --> 00:47:26.589 we have a library of of antibodies directed against these various proteins 00:47:26.589 --> 00:47:29.709 and they're labeled in a certain way and we can 00:47:29.709 --> 00:47:35.016 make a cut of the tissue we have and put this on and if it lights up 00:47:35.016 --> 00:47:37.339 we know that protein is represented, and to 00:47:37.339 --> 00:47:41.599 give you a concrete example, suppose we had a lymph node that had a glandular cancer 00:47:41.599 --> 00:47:43.269 and one of the possibilities 00:47:43.269 --> 00:47:47.489 would be from the prostate 00:47:47.489 --> 00:47:52.229 we could take an antibiotic to PSA (prostate specific antigen) 00:47:52.229 --> 00:47:54.041 stain that tissue, and if it lit up, 00:47:54.041 --> 00:47:57.149 those cancer cells had the prostate antigen, easy! 00:47:57.149 --> 00:47:58.599 this came from prostate. 00:47:58.599 --> 00:48:01.067 So we use those sorts of things 00:48:01.067 --> 00:48:08.119 we've gotten into molecular methods of identifying this or that molecule and 00:48:08.119 --> 00:48:12.039 in the cell population that augments what we can do visually and the ultimate 00:48:12.039 --> 00:48:13.579 00:48:13.579 --> 00:48:18.349 is something you're going to hear a lot more about and that is subjecting 00:48:18.349 --> 00:48:23.092 the tumor to analysis with what we call microarrays which are the system 00:48:23.092 --> 00:48:28.769 whereby you can screen for thousands of genes and see which ones 00:48:28.769 --> 00:48:30.159 are activated 00:48:30.159 --> 00:48:32.479 and we're beginning to 00:48:32.479 --> 00:48:33.709 ''beginning'' 00:48:33.709 --> 00:48:38.949 to be able to say well with this, this, this, these genes activated 00:48:38.949 --> 00:48:42.559 this neoplasm is more likely to do this, and with this, this, this set of genes 00:48:42.559 --> 00:48:48.989 activated it's more likely to do that. That's where it is all going. 00:48:48.989 --> 99:59:59.999 Okay we'll continue this on Wednesday and feed you the rest.