1 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 2 00:00:15,639 --> 00:00:16,078 one of the defining 3 00:00:16,078 --> 00:00:19,749 traits of malignant 4 00:00:19,749 --> 00:00:25,039 neoplasms is the ability to invade 5 00:00:25,039 --> 00:00:27,289 more importantly even 6 00:00:27,289 --> 00:00:29,009 as 7 00:00:29,009 --> 00:00:34,089 a second defining characteristic is the ability to set up 8 00:00:34,089 --> 00:00:37,007 underlying distant 9 00:00:37,007 --> 00:00:38,062 and 10 00:00:38,062 --> 00:00:39,099 discontinuous 11 00:00:39,099 --> 00:00:45,004 secondary foci of growth. What this involves is cells 12 00:00:45,004 --> 00:00:49,055 breaking off, leaving, what we call, the primary cells 13 00:00:49,055 --> 00:00:51,019 getting 14 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 15 00:00:55,076 --> 00:00:57,088 or into the lymph 16 00:00:57,088 --> 00:00:58,579 lodging at a 17 00:00:58,579 --> 00:01:01,058 distance, in other words, here is the primary 18 00:01:01,058 --> 00:01:03,087 clump of cells, these cells 19 00:01:03,087 --> 00:01:06,042 float over there, they lodge and 20 00:01:06,042 --> 00:01:08,609 get out of the vessel they are in 21 00:01:08,609 --> 00:01:11,039 and they form a new nodule. 22 00:01:11,039 --> 00:01:13,006 That's the process of metastasis. 23 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). 24 00:01:18,052 --> 00:01:18,999 25 00:01:18,999 --> 00:01:21,076 and the 26 00:01:21,076 --> 00:01:24,062 ability to metastasize 27 00:01:24,062 --> 00:01:27,009 by all odds is the most lethal aspect of cancer. 28 00:01:27,009 --> 00:01:29,081 And 29 00:01:29,081 --> 00:01:33,024 that's the the feature that most often 30 00:01:33,024 --> 00:01:35,051 makes a cancer incurable. 31 00:01:35,051 --> 00:01:39,068 Sometimes a cancer is incurable because of local invasion, you know, 32 00:01:39,068 --> 00:01:45,001 something wraps around the aorta or some other structure, you can't get at it, 33 00:01:45,001 --> 00:01:45,579 that could be 34 00:01:45,579 --> 00:01:51,057 lethal but it's usually metastasis. The sad fact is that 35 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 36 00:01:55,021 --> 00:01:57,006 about 37 00:01:57,006 --> 00:02:01,082 thirty to fifty percent of patients who present to their doctors 38 00:02:01,082 --> 00:02:05,023 with some signs and symptoms that turn out to be cancer, about thirty to 39 00:02:05,023 --> 00:02:08,829 fifty percent already have metastases. 40 00:02:08,829 --> 00:02:11,519 So it's something that really 41 00:02:11,519 --> 00:02:13,034 is the biggest roadblock 42 00:02:13,034 --> 00:02:13,709 43 00:02:13,709 --> 00:02:16,819 to successful treatment. 44 00:02:16,819 --> 00:02:20,659 So again these defining characteristics 45 00:02:20,659 --> 00:02:25,499 are invasion and metastasis. Now 46 00:02:25,499 --> 00:02:28,061 these abilities, to talk first about invasion and metastasis together, 47 00:02:28,061 --> 00:02:30,077 48 00:02:30,077 --> 00:02:34,459 are not just a matter of cell proliferation 49 00:02:34,459 --> 00:02:36,064 in other words, it's not the matter of fact 50 00:02:36,064 --> 00:02:40,004 that the cancers proliferating in the primary so much that the cells get squeezed 51 00:02:40,004 --> 00:02:42,026 out and they move. That's nonsense. 52 00:02:42,026 --> 00:02:44,629 Some primaries grow very large and then 53 00:02:44,629 --> 00:02:46,599 never leave 54 00:02:46,599 --> 00:02:52,619 the local area. These neoplasms acquire 55 00:02:52,619 --> 00:02:53,042 the 56 00:02:53,042 --> 00:02:58,017 cells in the neoplasm gradually acquire the ability to invade 57 00:02:58,017 --> 00:03:02,189 and to metastasize, and again these represent an accumulation 58 00:03:02,189 --> 00:03:05,779 of different kinds of mutations very likely giving the cells the 59 00:03:05,779 --> 00:03:06,084 the ability to 60 00:03:06,084 --> 00:03:08,369 do this. 61 00:03:08,369 --> 00:03:10,062 Now metastasis I would emphasize 62 00:03:10,062 --> 00:03:13,004 is a very complex cascade of events, 63 00:03:13,004 --> 00:03:14,093 64 00:03:14,093 --> 00:03:16,529 it's not just whoops! 65 00:03:16,529 --> 00:03:17,065 but involves the 66 00:03:17,065 --> 00:03:21,084 cells first of all invading, getting through that extracellular matrix, 67 00:03:21,084 --> 00:03:23,779 breaking through basement membrane, 68 00:03:23,779 --> 00:03:28,599 getting into a vessel whether it's a blood vessel or a lymphatic, floating 69 00:03:28,599 --> 00:03:32,749 with the stream and surviving during that flotation, which is another 70 00:03:32,749 --> 00:03:34,319 nice trick, lodging 71 00:03:34,319 --> 00:03:35,095 somewhere, 72 00:03:35,095 --> 00:03:40,279 being able to extravasate, get out of that vessel where it lodged, 73 00:03:40,279 --> 00:03:45,289 and set up housekeeping and get all of the requirements for growing another nodule. 74 00:03:45,289 --> 00:03:49,189 this is sort of, its been likened to, a decathlon event. You have to 75 00:03:49,189 --> 00:03:49,051 win 76 00:03:49,051 --> 00:03:52,189 a lot of events to be a successful metastasis. 77 00:03:52,189 --> 00:03:54,729 and 78 00:03:54,729 --> 00:03:58,299 there are three primary roots, this one is the lesser but 79 00:03:58,299 --> 00:03:59,038 cells 80 00:03:59,038 --> 00:04:04,025 can metastasize via the bloodstream, via the lymph flow 81 00:04:04,025 --> 00:04:05,093 and sometimes directly. 82 00:04:05,093 --> 00:04:08,119 Now here 83 00:04:08,119 --> 00:04:11,319 for instance, just to illustrate this, 84 00:04:11,319 --> 00:04:13,899 here is a clump of cancer cells within a 85 00:04:13,899 --> 00:04:16,008 tiny vein 86 00:04:16,008 --> 00:04:18,269 within adipose tissue. 87 00:04:18,269 --> 00:04:19,069 This was actually 88 00:04:19,069 --> 00:04:24,011 in a breast that had been removed by mastectomy, this was, in other words, 89 00:04:24,011 --> 00:04:26,259 primary cancer of the breast. 90 00:04:26,259 --> 00:04:27,076 What had happened here 91 00:04:27,076 --> 00:04:29,819 a tongue of cells had 92 00:04:29,819 --> 00:04:34,028 broken through a venule wall somewhere upstream 93 00:04:34,028 --> 00:04:36,094 and here you see it caught in the act of floating 94 00:04:36,094 --> 00:04:38,899 with the blood. 95 00:04:38,899 --> 00:04:43,749 Now there's a certain predictability to where the metastasis will go. In this case, 96 00:04:43,749 --> 00:04:47,129 this is coming from the breast. Eventually 97 00:04:47,129 --> 00:04:50,629 these venules are going to go into veins which are going to flow into 98 00:04:50,629 --> 00:04:52,699 the superior vena cava. The cells 99 00:04:52,699 --> 00:04:55,066 aren't going to lodge anywhere along there because the vessels are getting bigger 100 00:04:55,066 --> 00:04:57,073 and bigger. And 101 00:04:57,073 --> 00:04:58,149 they 102 00:04:58,149 --> 00:05:01,082 go to the right side of the heart out the pulmonary artery. 103 00:05:01,082 --> 00:05:02,096 Pretty soon, these cells 104 00:05:02,096 --> 00:05:08,379 are going to encounter the capillaries in the lungs where they are going to lodge. 105 00:05:08,379 --> 00:05:09,004 Metastasis, 106 00:05:09,004 --> 00:05:13,689 a cell clump like this, if it's successful, may 107 00:05:13,689 --> 00:05:14,081 very well 108 00:05:14,081 --> 00:05:17,199 end up in the lungs. 109 00:05:17,199 --> 00:05:21,259 Now you haven't studied this in gross anatomy yet, you're just beginning gross, 110 00:05:21,259 --> 00:05:22,037 but 111 00:05:22,037 --> 00:05:24,027 I'll tell you that for instance 112 00:05:24,027 --> 00:05:29,043 the blood flow drainage, the venous drainage of the GI tract 113 00:05:29,043 --> 00:05:31,569 goes into what we call the portal vein, which is 114 00:05:31,569 --> 00:05:33,189 a big vein 115 00:05:33,189 --> 00:05:35,129 that goes into the liver. 116 00:05:35,129 --> 00:05:40,052 Now the cells, if these cells had broken out of a gastric cancer, 117 00:05:40,052 --> 00:05:41,028 and 118 00:05:41,028 --> 00:05:43,093 were in the veins draining the stomach, they would 119 00:05:43,093 --> 00:05:47,004 go into this portal vein and then the first capillary bed 120 00:05:47,004 --> 00:05:48,036 they hit is the liver. 121 00:05:48,036 --> 00:05:50,002 So you'd 122 00:05:50,002 --> 00:05:55,539 find metastases in the liver, you'd predict metastases in the liver. 123 00:05:55,539 --> 00:05:58,048 Or if you had a malignancy in the soft tissues of the leg, 124 00:05:58,048 --> 00:06:02,006 the cells would eventually get to the inferior vena cava, up to the heart, 125 00:06:02,006 --> 00:06:04,439 and into the lungs. 126 00:06:04,439 --> 00:06:06,759 So it turns out that the lungs 127 00:06:06,759 --> 00:06:10,409 and the liver constitute the two big filters in the body 128 00:06:10,409 --> 00:06:14,008 and they catch a lot of metastases. 129 00:06:14,008 --> 00:06:15,669 Now this is nowhere 130 00:06:15,669 --> 00:06:18,041 near being entirely predictable for the 131 00:06:18,041 --> 00:06:20,094 following reasons, 132 00:06:20,094 --> 00:06:23,095 the cancer cells don't necessarily lodge 133 00:06:23,095 --> 00:06:24,979 permanently 134 00:06:24,979 --> 00:06:28,239 in the lungs or the liver. 135 00:06:28,239 --> 00:06:32,589 they change their shape, they squiggle around, 136 00:06:32,589 --> 00:06:35,729 let's say coming from the GI tract, they may get through the liver 137 00:06:35,729 --> 00:06:36,004 into the 138 00:06:36,004 --> 00:06:38,026 inferior vena cava up to the 139 00:06:38,026 --> 00:06:41,149 heart and out anywhere in the body. 140 00:06:41,149 --> 00:06:43,699 So it turns out that really practically 141 00:06:43,699 --> 00:06:47,249 speaking, cancer cells once again in circulation are all 142 00:06:47,249 --> 00:06:49,072 over the place 143 00:06:49,072 --> 00:06:50,379 and 144 00:06:50,379 --> 00:06:53,027 it also turns out that there are secondary factors 145 00:06:53,027 --> 00:06:56,499 that determine where the metastases will occur 146 00:06:56,499 --> 00:06:58,339 For instance, 147 00:06:58,339 --> 00:07:01,839 we know that cancer cells get out systemically. We rarely see metastases 148 00:07:01,839 --> 00:07:04,031 in skeletal muscle. I have no idea 149 00:07:04,031 --> 00:07:05,639 why. 150 00:07:05,639 --> 00:07:07,056 But we rarely do. 151 00:07:07,056 --> 00:07:11,039 It turns out that certain cancers have a propensity 152 00:07:11,039 --> 00:07:13,899 to set up metastases in one 153 00:07:13,899 --> 00:07:16,042 set of tissues and certain cancers 154 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 155 00:07:20,012 --> 00:07:22,959 favor the "taste" 156 00:07:22,959 --> 00:07:23,058 of 157 00:07:23,058 --> 00:07:24,569 one tissue 158 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. 159 00:07:28,011 --> 00:07:30,669 They are 160 00:07:30,669 --> 00:07:34,799 to an extent predictable. 161 00:07:34,799 --> 00:07:39,789 So that's the situation with hematogenous metastases, liver, lung, 162 00:07:39,789 --> 00:07:44,219 many other places as well. It's a systemic process 163 00:07:44,219 --> 00:07:46,469 Here are cancer cells in a lymphatic. 164 00:07:46,469 --> 00:07:50,009 You probably know less about lymphatic channels than you do about blood channels but these are 165 00:07:50,009 --> 00:07:51,449 basically 166 00:07:51,449 --> 00:07:52,639 they start from small, thin walled 167 00:07:52,639 --> 00:07:54,061 vessels like this and 168 00:07:54,061 --> 00:07:57,399 and any particular organ 169 00:07:57,399 --> 00:08:00,077 almost all organs in the body have a rich lymphatic drainage. The lymph 170 00:08:00,077 --> 00:08:01,429 is drained 171 00:08:01,429 --> 00:08:02,879 into bigger 172 00:08:02,879 --> 00:08:07,096 bigger lymphatics. These enter what we call regional lymph nodes. 173 00:08:07,096 --> 00:08:11,879 which we'll study in detail, but these are basically like little filter beans 174 00:08:11,879 --> 00:08:13,029 and 175 00:08:13,029 --> 00:08:15,309 a clump of 176 00:08:15,309 --> 00:08:20,419 cells like that may well lodge in a regional lymph node. 177 00:08:20,419 --> 00:08:21,009 Now 178 00:08:21,009 --> 00:08:23,031 what denotes a regional lymph node? 179 00:08:23,031 --> 00:08:25,139 In the case of the bowel, 180 00:08:25,139 --> 00:08:29,369 the regional lymph nodes are in the mesentery. In the case of the 181 00:08:29,369 --> 00:08:30,689 breast, the regional 182 00:08:30,689 --> 00:08:34,249 lymph nodes are in the armpit, that's where the lymph is draining. 183 00:08:34,249 --> 00:08:34,098 In the 184 00:08:34,098 --> 00:08:39,079 case of the mouth and throat, the regional lymph nodes are here in the neck. 185 00:08:39,079 --> 00:08:41,003 And there's 186 00:08:41,003 --> 00:08:43,069 a certain predictability 187 00:08:43,069 --> 00:08:46,083 so that if you have a big cancer in the mouth, you're going to 188 00:08:46,083 --> 00:08:50,003 worry about the cervical lymph nodes or the 189 00:08:50,003 --> 00:08:53,067 or the breast you're going to worry about what's going on in the axilla. 190 00:08:53,067 --> 00:08:57,003 Cancer operations generally involve 191 00:08:57,003 --> 00:09:01,059 either excavation or sampling of the regional lymph nodes to see whether the cancer 192 00:09:01,059 --> 00:09:04,024 has spread from the primary there. 193 00:09:04,024 --> 00:09:06,044 Now 194 00:09:06,044 --> 00:09:10,004 this predictability again can break down because 195 00:09:10,004 --> 00:09:13,023 lymph nodes are not perfect filters, 196 00:09:13,023 --> 00:09:15,042 whatever you might think, 197 00:09:15,042 --> 00:09:19,001 these cells might lodge temporarily in a lymph node and some of their progeny 198 00:09:19,001 --> 00:09:22,001 maybe goes scooting out the other side in the 199 00:09:22,001 --> 00:09:23,014 efferent lymph which 200 00:09:23,014 --> 00:09:27,339 is going to go to other lymphatic channels and eventually dump into the 201 00:09:27,339 --> 00:09:29,049 superior vena cava and 202 00:09:29,049 --> 00:09:31,083 join 203 00:09:31,083 --> 00:09:33,046 the systemic circulation. 204 00:09:33,046 --> 00:09:35,081 So it turns out that cancer, 205 00:09:35,081 --> 00:09:44,045 we have to conceive of it is a potentially systemic disease, 206 00:09:44,045 --> 00:09:46,063 One comment 207 00:09:46,063 --> 00:09:50,055 here about metastasis is the possibility of direct metastasis. 208 00:09:50,055 --> 00:09:51,059 By that I mean 209 00:09:51,059 --> 00:09:53,889 the cells are not picked up in the blood or lymph, but 210 00:09:53,889 --> 00:09:55,058 if they enter 211 00:09:55,058 --> 00:09:59,013 a cavity, let's say the peritoneal cavity, 212 00:09:59,013 --> 00:10:01,056 and can drift 213 00:10:01,056 --> 00:10:03,052 or swim or float 214 00:10:03,052 --> 00:10:05,084 across the peritoneal cavity and lodge 215 00:10:05,084 --> 00:10:06,085 anywhere in the lining 216 00:10:06,085 --> 00:10:09,076 of the peritoneal cavity, it's a sort of direct 217 00:10:09,076 --> 00:10:11,029 metastasis. 218 00:10:11,029 --> 00:10:13,019 We see this 219 00:10:13,019 --> 00:10:14,055 one 220 00:10:14,055 --> 00:10:16,439 that comes to mind is the ovary. 221 00:10:16,439 --> 00:10:19,005 The ovary sit out in the pelvis, 222 00:10:19,005 --> 00:10:24,005 in the open so to speak, in the peritoneal cavity. Ovarian cancers notoriously 223 00:10:24,005 --> 00:10:28,034 will just seed cells into the peritoneum and they'll land 224 00:10:28,034 --> 00:10:28,088 anywhere in the peritoneum 225 00:10:28,088 --> 00:10:29,088 and set up these metastases. 226 00:10:29,088 --> 00:10:32,067 A variation on 227 00:10:32,067 --> 00:10:36,048 this that we don't often see is that the surgeon's knife 228 00:10:36,048 --> 00:10:37,077 may pick up 229 00:10:37,077 --> 00:10:40,021 some cancer cells and 230 00:10:40,021 --> 00:10:44,078 we'll find a recurrence in the incision or something of that sort. 231 00:10:44,078 --> 00:10:46,089 More or less 232 00:10:46,089 --> 00:10:49,061 a direct, iatrogenic (physician caused) metastasis. 233 00:10:49,061 --> 00:10:51,001 But again 234 00:10:51,001 --> 00:10:52,075 metastases 235 00:10:52,075 --> 00:10:57,042 represent a hop skip and jump, it's not direct invasion to 236 00:10:57,042 --> 00:10:59,064 get over here, it's a jump 237 00:10:59,064 --> 00:11:04,088 to get over there. 238 00:11:04,088 --> 00:11:07,072 A thing to point out is that the 239 00:11:07,072 --> 00:11:11,046 metastasis does not have the 240 00:11:11,046 --> 00:11:16,001 the characteristics of the organ that it lands in, it keeps the 241 00:11:16,001 --> 00:11:17,063 characteristics of the primary tumor. In other words, 242 00:11:17,063 --> 00:11:23,065 these metastasizing cells are the genetic progeny 243 00:11:23,065 --> 00:11:29,001 of the primary, so they're going to look like it. If the neoplasm 244 00:11:29,001 --> 00:11:32,043 neoplasm in the primary was making funny glands, the metastasis 245 00:11:32,043 --> 00:11:36,001 will probably make funny glands. 246 00:11:36,001 --> 00:11:39,057 It's a chip off the old block. 247 00:11:39,057 --> 00:11:43,016 That has some some interesting implications there which you'll get into 248 00:11:43,016 --> 00:11:46,000 in future years. 249 00:11:46,000 --> 00:11:47,034 But just 250 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. 251 00:11:52,008 --> 00:11:54,019 They can be 252 00:11:54,019 --> 00:11:57,023 at a great distance, it can be four feet away from 253 00:11:57,023 --> 00:11:59,031 the primary and 254 00:11:59,031 --> 00:12:00,055 it can 255 00:12:00,055 --> 00:12:02,879 be very devastating and I will show you 256 00:12:02,879 --> 00:12:06,031 some examples of this. 257 00:12:06,031 --> 00:12:11,014 This is carcinomatosis which refers to a diffuse spread 258 00:12:11,014 --> 00:12:11,057 of 259 00:12:11,057 --> 00:12:13,031 cancer. 260 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, 261 00:12:17,066 --> 00:12:18,066 cut it out 262 00:12:18,066 --> 00:12:19,329 and you're 263 00:12:19,329 --> 00:12:22,095 looking at the under surface of the diaphragm lined by peritoneum, 264 00:12:22,095 --> 00:12:23,087 265 00:12:23,087 --> 00:12:27,035 this was from a patient with ovarian cancer, 266 00:12:27,035 --> 00:12:30,039 and every one of these little plaques is a 267 00:12:30,039 --> 00:12:33,048 few million cancer cells growing as a direct 268 00:12:33,048 --> 00:12:36,091 metastasis. 269 00:12:36,091 --> 00:12:41,084 Now I'm going to give you a long shaggy dog story, here is a 270 00:12:41,084 --> 00:12:44,002 specimen of peritoneum, 271 00:12:44,002 --> 00:12:47,096 this is if I took a couple of pieces of body wall 272 00:12:47,096 --> 00:12:51,004 cut them out and you're looking at the peritoneal surface 273 00:12:51,004 --> 00:12:53,069 of the inside of those pieces 274 00:12:53,069 --> 00:12:55,007 and you can see studded 275 00:12:55,007 --> 00:12:58,000 with a couple a hundred little tiny black 276 00:12:58,000 --> 00:13:01,078 spots and here it's actually become kind of almost a confluent 277 00:13:01,078 --> 00:13:04,069 sheet of neoplasm. 278 00:13:04,069 --> 00:13:05,053 And 279 00:13:05,053 --> 00:13:08,043 you'd say yeah this looks like 280 00:13:08,043 --> 00:13:14,039 many little nodules, why do you suppose it's black like that? 281 00:13:14,039 --> 00:13:18,022 Any thoughts? 282 00:13:18,022 --> 00:13:22,098 Well, the cells are making melanin, this is a malignant melanoma 283 00:13:22,098 --> 00:13:25,024 which may have heard about. Now 284 00:13:25,024 --> 00:13:26,023 I'm 285 00:13:26,023 --> 00:13:29,075 getting ahead of your knowledge of histology, but there are no cells in the 286 00:13:29,075 --> 00:13:31,062 peritoneum that make 287 00:13:31,062 --> 00:13:36,079 melanin normally, so that means these are visitors from somewhere else, 288 00:13:36,079 --> 00:13:38,016 so clearly just by 289 00:13:38,016 --> 00:13:41,032 the sheer numbers and by the fact that it's melanoma 290 00:13:41,032 --> 00:13:45,048 we can say that these are metastases from somewhere else. 291 00:13:45,048 --> 00:13:49,096 I'll let the plot thicken a little bit, here was the liver 292 00:13:49,096 --> 00:13:52,063 from the same case. 293 00:13:52,063 --> 00:13:57,037 The normal liver is studded with probably thousands of metastases. 294 00:13:57,037 --> 00:13:59,097 This is grown together in a big, horrible 295 00:13:59,097 --> 00:14:04,007 mass which had broken through the hepatic capsule, 296 00:14:04,007 --> 00:14:08,389 and the normal liver does not contain melanin producing cells. 297 00:14:08,389 --> 00:14:12,025 That fact and the fact that that these are so multiple 298 00:14:12,025 --> 00:14:16,093 says that this liver is riddled with hematogenous metastases. 299 00:14:16,093 --> 00:14:21,048 Where do you think the primary was? 300 00:14:21,048 --> 00:14:23,029 Someone said it. 301 00:14:23,029 --> 00:14:25,005 Skin. That'd be your first bet. 302 00:14:25,005 --> 00:14:28,004 Because melanoma is a common story. 303 00:14:28,004 --> 00:14:32,023 But you're wrong. Eyeball. 304 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 305 00:14:36,028 --> 00:14:38,459 reflex from the flash, but just behind it 306 00:14:38,459 --> 00:14:39,048 there's a little lump 307 00:14:39,048 --> 00:14:40,061 there 308 00:14:40,061 --> 00:14:43,055 and that is the primary neoplasm. 309 00:14:43,055 --> 00:14:46,029 Now this tells another story. 310 00:14:46,029 --> 00:14:49,061 This patient presented with a visual disturbance and the ophthalmologist saw this 311 00:14:49,061 --> 00:14:51,081 and said this eyeball has to come out. 312 00:14:51,081 --> 00:14:53,005 And the eyeball was taken out. 313 00:14:53,005 --> 00:14:56,081 It is our job as pathologist to assess whether the excision 314 00:14:56,081 --> 00:14:59,035 has been complete. 315 00:14:59,035 --> 00:15:03,086 And so we sample the various coats of the eye thoroughly to see if the melanoma 316 00:15:03,086 --> 00:15:07,002 cells had penetrated through and if there any left in the in the orbit. 317 00:15:07,002 --> 00:15:07,072 And the answer 318 00:15:07,072 --> 00:15:09,032 to it is no. 319 00:15:09,032 --> 00:15:12,078 Looks clean. 320 00:15:12,078 --> 00:15:16,004 I hope the surgeon didn't say this but this sometimes gives rise to the statement: 321 00:15:16,004 --> 00:15:18,099 we got it all! 322 00:15:18,099 --> 00:15:23,042 Now this patient did fine after removal of the eyeball, did fine for several years. 323 00:15:23,042 --> 00:15:24,049 With 324 00:15:24,049 --> 00:15:27,085 absolutely no evidence of metastases. 325 00:15:27,085 --> 00:15:31,049 Then something happened, God knows what, 326 00:15:31,049 --> 00:15:32,061 the patient just 327 00:15:32,061 --> 00:15:34,093 went downhill within a period of weeks and died 328 00:15:34,093 --> 00:15:37,075 and had metastases all over the body. 329 00:15:37,075 --> 00:15:41,077 That brings up another interesting point which I'll just tease you with and 330 00:15:41,077 --> 00:15:45,004 that's the phenomenon we call dormancy. 331 00:15:45,004 --> 00:15:49,064 It was very clear from the story 332 00:15:49,064 --> 00:15:52,002 that we had taken out the primary 333 00:15:52,002 --> 00:15:55,037 and there was never any recurrence in the orbit and so that what that says is 334 00:15:55,037 --> 00:15:58,031 these melanoma cells have gotten into circulation 335 00:15:58,031 --> 00:16:02,085 that there were tiny occult metastases 336 00:16:02,085 --> 00:16:05,035 at the time the eyeball was taken out 337 00:16:05,035 --> 00:16:07,007 and they chose not to grow 338 00:16:07,007 --> 00:16:08,088 for several years 339 00:16:08,088 --> 00:16:12,004 and then something changed and they grew. 340 00:16:12,004 --> 00:16:14,029 And we see that sometimes. 341 00:16:14,029 --> 00:16:18,469 In other words earth eighteen months survival or two years survival or five year survival 342 00:16:18,469 --> 00:16:20,095 is a statistical thing, but 343 00:16:20,095 --> 00:16:22,075 sometimes 344 00:16:22,075 --> 00:16:23,092 it doesn't 345 00:16:23,092 --> 00:16:25,046 matter. 346 00:16:25,046 --> 00:16:27,058 So this illustrates 347 00:16:27,058 --> 00:16:31,075 the fact that that metastases can be very distant from the primary, 348 00:16:31,075 --> 00:16:32,061 they can 349 00:16:32,061 --> 00:16:33,599 350 00:16:33,599 --> 00:16:34,098 be 351 00:16:34,098 --> 00:16:38,021 millions of metastases from one primary 352 00:16:38,021 --> 00:16:42,083 and also I threw in this whole phenomenon of dormancy which is a bit unusual 353 00:16:42,083 --> 00:16:44,064 but it happens. 354 00:16:44,064 --> 00:16:46,056 I'll show you some other mets. 355 00:16:46,056 --> 00:16:48,069 Here's a lung of a youngster. 356 00:16:48,069 --> 00:16:52,074 Every one of these is a nodule of neoplasm, the other lung looked just like this. 357 00:16:52,074 --> 00:16:53,059 This happens 358 00:16:53,059 --> 00:16:57,008 to have been a primary in the kidney which 359 00:16:57,008 --> 00:17:00,005 got to the lungs through the renal veins, the vena cava, and on up. 360 00:17:00,005 --> 00:17:01,012 361 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 362 00:17:05,032 --> 00:17:06,959 can prevent it from reaching this 363 00:17:06,959 --> 00:17:10,029 stage now. 364 00:17:10,029 --> 00:17:14,009 Here's an interesting one that we see very often, this is a vertebral column which 365 00:17:14,009 --> 00:17:17,042 I sliced in a band saw 366 00:17:17,042 --> 00:17:20,097 so you're looking at a couple of mirror images and this is a pretty normal 367 00:17:20,097 --> 00:17:24,051 vertebra up here, this is an intervertebral disc up here. 368 00:17:24,051 --> 00:17:28,022 These two lower vertebrae you see these whitish areas 369 00:17:28,022 --> 00:17:28,085 here and here. 370 00:17:28,085 --> 00:17:30,092 These were very 371 00:17:30,092 --> 00:17:34,049 dense bone, and interestingly 372 00:17:34,049 --> 00:17:38,027 what this represents is metastasis to the bone, 373 00:17:38,027 --> 00:17:42,031 it stimulates bone formation around the cancer cells, it's something 374 00:17:42,031 --> 00:17:45,022 we call an osteoblastic 375 00:17:45,022 --> 00:17:46,049 phenomenon 376 00:17:46,049 --> 00:17:47,027 or an osteoblastic metastasis. 377 00:17:47,027 --> 00:17:48,005 This would have shown up 378 00:17:48,005 --> 00:17:51,029 as a density on the x-ray 379 00:17:51,029 --> 00:17:55,089 under the microscope, there's a lot of bone there but cancer cells throughout 380 00:17:55,089 --> 00:17:59,013 and usually cancer cells reach the bone 381 00:17:59,013 --> 00:18:01,029 via the hematogenous route. 382 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 383 00:18:04,094 --> 00:18:07,077 from somewhere or other 384 00:18:07,077 --> 00:18:09,929 but you will learn for instance that breast 385 00:18:09,929 --> 00:18:14,085 very often breast cancer very often goes to bone. Prostate cancer notoriously goes to bone. 386 00:18:14,085 --> 00:18:16,059 387 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 388 00:18:20,038 --> 00:18:21,097 what the likelihood of 389 00:18:21,097 --> 00:18:24,024 I mean if this came from a 390 00:18:24,024 --> 00:18:26,033 middle-aged woman with 391 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 392 00:18:30,019 --> 00:18:34,019 urinary tract obstruction, I'd say look at his prostate. 393 00:18:34,019 --> 00:18:38,015 So that is an osteoblastic kind of metastasis. 394 00:18:38,015 --> 00:18:41,002 Here is a different one, 395 00:18:41,002 --> 00:18:43,007 this one has another story associated with it. 396 00:18:43,007 --> 00:18:46,015 This was a 42-year old guy 397 00:18:46,015 --> 00:18:49,093 who came in with back pain and he was a manual laborer that did heavy labor 398 00:18:49,093 --> 00:18:53,084 and everyone thought at first well you know it's some orthopedic 399 00:18:53,084 --> 00:18:54,044 injury 400 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 401 00:18:57,889 --> 00:18:59,062 essentially turned to mush. 402 00:18:59,062 --> 00:19:01,097 Here's a normal vertebra here and here. 403 00:19:01,097 --> 00:19:04,037 Here's a disc and this is a 404 00:19:04,037 --> 00:19:08,024 osteolytic metastasis, it turned out that there was a metastasis 405 00:19:08,024 --> 00:19:13,012 that completely destroyed the bone and it simply collapsed. 406 00:19:13,012 --> 00:19:18,007 Now this man presented because of his metastasis, that sometimes happens, 407 00:19:18,007 --> 00:19:20,071 it may not be the primary, it turned out he was a heavy smoker 408 00:19:20,071 --> 00:19:22,065 and had a small, 409 00:19:22,065 --> 00:19:24,056 inapparent 410 00:19:24,056 --> 00:19:27,079 bronchogenic primary, in other words, a lung cancer 411 00:19:27,079 --> 00:19:31,007 and it metastasize to his bone without even causing any ruckus. 412 00:19:31,007 --> 00:19:35,099 He probably had a little cough as all smokers do 413 00:19:35,099 --> 00:19:36,083 414 00:19:36,083 --> 00:19:38,048 but presented because of the metastasis 415 00:19:38,048 --> 00:19:41,024 This was 416 00:19:41,024 --> 00:19:44,071 another smoker incidence, I remember 417 00:19:44,071 --> 00:19:47,017 this one very well, 418 00:19:47,017 --> 00:19:49,043 the patient came in convulsing, signs of 419 00:19:49,043 --> 00:19:52,084 increased intracranial pressure. 420 00:19:52,084 --> 00:19:53,074 They 421 00:19:53,074 --> 00:19:57,057 had to take him to the operating room very quickly to decompress the brain 422 00:19:57,057 --> 00:20:00,005 and save him from dying from 423 00:20:00,005 --> 00:20:02,045 the pressure and 424 00:20:02,045 --> 00:20:04,025 my colleague 425 00:20:04,025 --> 00:20:06,093 sent me a piece of this 426 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 427 00:20:10,037 --> 00:20:12,002 make a quick section of it 428 00:20:12,002 --> 00:20:14,051 It was easy to say this isn't 429 00:20:14,051 --> 00:20:16,078 cancer arising in the brain 430 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. 431 00:20:19,059 --> 00:20:22,071 This is not rocket science, you'll learn how to do it in the spring. 432 00:20:22,071 --> 00:20:23,057 433 00:20:23,057 --> 00:20:24,779 But it's because the 434 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 435 00:20:29,067 --> 00:20:32,001 metastasis to the brain. 436 00:20:32,001 --> 00:20:36,049 Poor fellow died shortly after operation, it turned out again he was riddled with metastases 437 00:20:36,049 --> 00:20:38,051 with a small lung primary. 438 00:20:38,051 --> 00:20:40,061 Lung primary 439 00:20:40,061 --> 00:20:42,009 very often goes to brain like that. 440 00:20:42,009 --> 00:20:44,097 Oh 441 00:20:44,097 --> 00:20:49,053 one last lovely image 442 00:20:49,053 --> 00:20:52,034 there is a liver 443 00:20:52,034 --> 00:20:54,045 riddled with metastases. 444 00:20:54,045 --> 00:20:56,088 And if 445 00:20:56,088 --> 00:21:00,034 someone showed me this liver and said where did this come from, I'd say 446 00:21:00,034 --> 00:21:03,015 gee, well look at the GI tract. 447 00:21:03,015 --> 00:21:06,066 It can be elsewhere, this was a lung cancer 448 00:21:06,066 --> 00:21:10,084 that had metastasized and gotten into the bloodstream, had gotten around and liked the taste 449 00:21:10,084 --> 00:21:12,005 of liver 450 00:21:12,005 --> 00:21:15,078 and produced metastases in the liver. There were metastases in many other 451 00:21:15,078 --> 00:21:17,009 places as well. 452 00:21:17,009 --> 00:21:19,012 Well, i guess that 453 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 454 00:21:25,015 --> 00:21:28,044 of this process of metastasis. Again benign neoplasm 455 00:21:28,044 --> 00:21:31,062 do not metastasize, only malignant 456 00:21:31,062 --> 00:21:33,065 ones do. 457 00:21:33,065 --> 00:21:44,008 Benign neoplasms do not invade, only malignant ones. 458 00:21:44,008 --> 00:22:00,043 459 00:22:00,043 --> 00:22:03,047 With 460 00:22:03,047 --> 00:22:06,049 those concepts 461 00:22:06,049 --> 00:22:09,919 of neoplasia, hope you've all got benign and malignant invasion, metastasis sort of 462 00:22:09,919 --> 00:22:11,036 under your belts. 463 00:22:11,036 --> 00:22:18,015 I want to talk for a little bit on how neoplasms are 464 00:22:18,015 --> 00:22:20,032 put together microscopically. 465 00:22:20,032 --> 00:22:23,899 Again, don't worry about being able to do this kind of diagnosis yourself, 466 00:22:23,899 --> 00:22:25,089 just listen to the concepts. 467 00:22:25,089 --> 00:22:28,046 I want to review the concept of stroma, 468 00:22:28,046 --> 00:22:30,008 the concept of differentiation, 469 00:22:30,008 --> 00:22:33,001 and ideas of grading 470 00:22:33,001 --> 00:22:36,041 and staging. 471 00:22:36,041 --> 00:22:41,091 All right, let's let's begin with the business of stroma and angiogenesis. 472 00:22:41,091 --> 00:22:43,086 One of things that I should emphasize 473 00:22:43,086 --> 00:22:48,004 that I didn't really emphasize so far is that 474 00:22:48,004 --> 00:22:50,062 a given module of neoplasm 475 00:22:50,062 --> 00:22:53,084 take one of those metastases in the liver for instance 476 00:22:53,084 --> 00:22:55,089 A given nodule of neoplasm 477 00:22:55,089 --> 00:22:57,064 is just not a spherical 478 00:22:57,064 --> 00:23:03,000 collection of 100% cancer cells. 479 00:23:03,000 --> 00:23:05,011 This is a very important concept 480 00:23:05,011 --> 00:23:06,042 and it makes perfect sense 481 00:23:06,042 --> 00:23:08,029 because 482 00:23:08,029 --> 00:23:10,289 you could not possibly grow 483 00:23:10,289 --> 00:23:11,064 a lump literally that big 484 00:23:11,064 --> 00:23:12,092 and have 485 00:23:12,092 --> 00:23:14,071 a blood supply 486 00:23:14,071 --> 00:23:17,032 for the cells in the center, 487 00:23:17,032 --> 00:23:18,045 you follow me? 488 00:23:18,045 --> 00:23:20,035 In other words, if they were pure cancer cells 489 00:23:20,035 --> 00:23:22,007 the blood would be out here 490 00:23:22,007 --> 00:23:24,036 and the cells would be proliferating here. 491 00:23:24,036 --> 00:23:29,063 It doesn't work that way, the cancer needs a blood supply in order to grow. 492 00:23:29,063 --> 00:23:30,047 and it turns 493 00:23:30,047 --> 00:23:31,096 out that 494 00:23:31,096 --> 00:23:34,022 cancers 495 00:23:34,022 --> 00:23:38,044 are able and this is an very interesting phenomenon 496 00:23:38,044 --> 00:23:39,078 to 497 00:23:39,078 --> 00:23:43,004 induce the formation of what we call a stroma 498 00:23:43,004 --> 00:23:45,065 it's a fibrous 499 00:23:45,065 --> 00:23:49,000 particularly a vascular framework 500 00:23:49,000 --> 00:23:52,003 which supports the neoplasm. 501 00:23:52,003 --> 00:23:54,013 Now the stroma 502 00:23:54,013 --> 00:23:56,047 is not part of the malignant clone 503 00:23:56,047 --> 00:23:59,069 or the neoplastic clone. 504 00:23:59,069 --> 00:24:00,095 It comes from 505 00:24:00,095 --> 00:24:06,066 the connective tissue cells and the blood vessels cells 506 00:24:06,066 --> 00:24:07,007 around 507 00:24:07,007 --> 00:24:09,000 the neoplasm. 508 00:24:09,000 --> 00:24:11,031 The neoplastic cells 509 00:24:11,031 --> 00:24:14,092 and probably some of the inflammatory cells accompanying the neoplasm are able 510 00:24:14,092 --> 00:24:16,047 to induce 511 00:24:16,047 --> 00:24:19,056 the formation of this stroma. It's 512 00:24:19,056 --> 00:24:20,046 very much 513 00:24:20,046 --> 00:24:24,058 like the the induction of granulation tissue which you're very familiar with from 514 00:24:24,058 --> 00:24:25,027 last week. 515 00:24:25,027 --> 00:24:26,047 And 516 00:24:26,047 --> 00:24:27,239 what 517 00:24:27,239 --> 00:24:28,779 happens 518 00:24:28,779 --> 00:24:34,919 is this fibrous and vascular stroma grows into the nodule and enables it 519 00:24:34,919 --> 00:24:36,044 to proliferate. 520 00:24:36,044 --> 00:24:37,054 521 00:24:37,054 --> 00:24:39,088 Now we talk about 522 00:24:39,088 --> 00:24:45,084 tumor angiogenesis, I mean the emphasis being on the blood vessels. 523 00:24:45,084 --> 00:24:48,095 There is abundant 524 00:24:48,095 --> 00:24:50,789 experimental evidence to show 525 00:24:50,789 --> 00:24:51,089 that 526 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 527 00:24:55,279 --> 00:24:58,048 a bunch of neoplastic cells growing pure 528 00:24:58,048 --> 00:25:01,054 where they can't pick up a stroma, 529 00:25:01,054 --> 00:25:06,015 the module will never get bigger than a millimeter or two at the very most, 530 00:25:06,015 --> 00:25:07,003 probably less because 531 00:25:07,003 --> 00:25:12,027 because the oxygen and nutrients cannot diffuse in the solid mass any further. 532 00:25:12,027 --> 00:25:14,031 There are many experiments that show 533 00:25:14,031 --> 00:25:19,006 you grow neoplastic cells in these little balls and they stopped growing. 534 00:25:19,006 --> 00:25:23,003 and then if you do something to induce angiogenesis, BOOM, 535 00:25:23,003 --> 00:25:24,081 as soon as they pick up 536 00:25:24,081 --> 00:25:27,025 the vascular stroma 537 00:25:27,025 --> 00:25:28,119 they begin 538 00:25:28,119 --> 00:25:29,015 to grow 539 00:25:29,015 --> 00:25:33,005 so tumor angiogenesis is exceedingly important. You can 540 00:25:33,005 --> 00:25:34,041 read a 541 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 542 00:25:38,049 --> 00:25:43,001 this is mediated and what it looks like is this: 543 00:25:43,001 --> 00:25:44,077 again without too much detail 544 00:25:44,077 --> 00:25:47,041 this was a lump in a breast. 545 00:25:47,041 --> 00:25:51,002 This was a breast cancer. 546 00:25:51,002 --> 00:25:54,022 These dark clumps are the cancer cells 547 00:25:54,022 --> 00:25:56,058 and the 548 00:25:56,058 --> 00:25:58,055 pink in the background 549 00:25:58,055 --> 00:26:00,024 is the stroma. 550 00:26:00,024 --> 00:26:04,085 I'll emphasize in particular there is a capillary there, 551 00:26:04,085 --> 00:26:08,081 there is a capillary cut lengthwise there, there's another capillary here 552 00:26:08,081 --> 00:26:10,409 and so forth 553 00:26:10,409 --> 00:26:11,042 so that any given 554 00:26:11,042 --> 00:26:15,015 clump of cancer cells isn't very far from 555 00:26:15,015 --> 00:26:17,169 a capillary. 556 00:26:17,169 --> 00:26:19,045 That's the concept 557 00:26:19,045 --> 00:26:23,979 of the stroma and tumor angiogenesis and what it means. 558 00:26:23,979 --> 00:26:27,024 If we could stop angiogenesis 559 00:26:27,024 --> 00:26:29,001 we could stop tumor growth. 560 00:26:29,001 --> 00:26:33,015 It would be wonderful and some of these attempts have reached the clinical testing 561 00:26:33,015 --> 00:26:35,025 testing stage but nothing terribly dramatic yet. 562 00:26:35,025 --> 00:26:38,038 But it's certainly a handle. 563 00:26:38,038 --> 00:26:43,013 Here is kind of a loose stroma, not very fibrous but a lot of blood vessels. 564 00:26:43,013 --> 00:26:44,074 Sometimes 565 00:26:44,074 --> 00:26:45,046 you can be 566 00:26:45,046 --> 00:26:47,029 very dense. 567 00:26:47,029 --> 00:26:48,659 These are cancer cells 568 00:26:48,659 --> 00:26:52,049 in a very dense collagenous stroma. 569 00:26:52,049 --> 00:26:54,007 This kind of a lump has a 570 00:26:54,007 --> 00:26:56,041 consistency about like wood. 571 00:26:56,041 --> 00:27:00,069 We call that, it's an adjective you'll hear occasionally, it's a scirrhous 572 00:27:00,069 --> 00:27:02,005 s-c-i-r-r-h-o-u-s 573 00:27:02,005 --> 00:27:05,048 scirrhous 574 00:27:05,048 --> 00:27:07,093 mode of growth 575 00:27:07,093 --> 00:27:11,086 But whatever the variation, any 576 00:27:11,086 --> 00:27:12,069 lump of 577 00:27:12,069 --> 00:27:15,077 neoplasm has this vascular stroma 578 00:27:15,077 --> 00:27:19,024 that it has induced. 579 00:27:19,024 --> 00:27:20,021 Okay. 580 00:27:20,021 --> 00:27:26,019 Now go onto the next concept, that is related to the fact that 581 00:27:26,019 --> 00:27:28,096 since neoplastic cells are derived 582 00:27:28,096 --> 00:27:33,669 from a previously normal cell population, they're 583 00:27:33,669 --> 00:27:37,077 going to share many of the genetic traits and are going to have some new ones 584 00:27:37,077 --> 00:27:41,005 because of these mutations but they're going to share a tremendous genetic 585 00:27:41,005 --> 00:27:42,081 background 586 00:27:42,081 --> 00:27:46,026 with the parent issues so they're going to resemble the parent tissue 587 00:27:46,026 --> 00:27:49,006 to some variable extent. 588 00:27:49,006 --> 00:27:54,099 I mean sometimes very sharp resemblance, sometimes maybe not much of a resemblance. 589 00:27:54,099 --> 00:27:56,007 590 00:27:56,007 --> 00:27:58,072 When the neoplastic tissue 591 00:27:58,072 --> 00:28:03,042 resembles the parental tissue, the normal tissue, 592 00:28:03,042 --> 00:28:05,399 through a high degree 593 00:28:05,399 --> 00:28:09,092 very close resemblance we speak about that neoplasm as being well-differentiated. 594 00:28:09,092 --> 00:28:13,005 Funny phrase, I didn't invent it. 595 00:28:13,005 --> 00:28:18,036 When we say well differentiated, it means looks just like mom and pop. 596 00:28:18,036 --> 00:28:22,023 On the other extreme, it may look nothing, I'll show you some examples, 597 00:28:22,023 --> 00:28:26,023 it may look nothing like the parental tissue, we say that is a poorly differentiated 598 00:28:26,023 --> 00:28:27,409 or 599 00:28:27,409 --> 00:28:32,031 undifferentiated 600 00:28:32,031 --> 00:28:32,083 tissue. 601 00:28:32,083 --> 00:28:37,052 There's another phrase, another word we sometimes use, that's anaplastic. 602 00:28:37,052 --> 00:28:40,047 Anaplastic refers to 603 00:28:40,047 --> 00:28:44,049 well, some people say de-differentiated, but undifferentiated 604 00:28:44,049 --> 00:28:47,034 just immature or undifferentiated tissue 605 00:28:47,034 --> 00:28:48,419 we refer to 606 00:28:48,419 --> 00:28:51,012 as anaplastic. 607 00:28:51,012 --> 00:28:53,799 There's a complete range 608 00:28:53,799 --> 00:28:56,098 of possibilities. 609 00:28:56,098 --> 00:28:58,033 Let me illustrate 610 00:28:58,033 --> 00:29:02,309 this for you in two extremes 611 00:29:02,309 --> 00:29:05,022 Here is normal colonic 612 00:29:05,022 --> 00:29:08,071 mucosa, and we're going to talk about this in detail on Wednesday. 613 00:29:08,071 --> 00:29:10,769 The mucosa has these 614 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 615 00:29:14,139 --> 00:29:15,009 616 00:29:15,009 --> 00:29:21,059 The next slide will be a cancer derived from this mucosa, looks like that. 617 00:29:21,059 --> 00:29:23,035 Now you say, that doesn't look anything like it, but 618 00:29:23,035 --> 00:29:26,056 in a sense it does. 619 00:29:26,056 --> 00:29:31,049 it's got glands, they're kind of funky and kinky and so forth 620 00:29:31,049 --> 00:29:33,027 but they're clearly glands. 621 00:29:33,027 --> 00:29:36,008 You'll also notice that the pink to blue ratio has changed, a lot of hyperchromatism 622 00:29:36,008 --> 00:29:40,026 a lot more nuclei here and so forth but basically 623 00:29:40,026 --> 00:29:44,063 a pathologist looking at this would take about a nanosecond as you will learn 624 00:29:44,063 --> 00:29:46,053 this spring and say oh! 625 00:29:46,053 --> 00:29:48,002 this is a glandular type of 626 00:29:48,002 --> 00:29:49,047 neoplasm. 627 00:29:49,047 --> 00:29:50,014 So we say 628 00:29:50,014 --> 00:29:54,031 this is at least moderately differentiated. 629 00:29:54,031 --> 00:29:56,069 Now I'll show you a step down, 630 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 631 00:30:01,015 --> 00:30:02,489 columnar cells, 632 00:30:02,489 --> 00:30:04,409 some of them are secreting mucus 633 00:30:04,409 --> 00:30:05,008 others have cilia on them 634 00:30:05,008 --> 00:30:06,071 they're very well 635 00:30:06,071 --> 00:30:08,061 organized there 636 00:30:08,061 --> 00:30:11,087 The next line is a neoplasm derived 637 00:30:11,087 --> 00:30:15,073 from that cell population 638 00:30:15,073 --> 00:30:20,023 If someone showed me that I'd say that I don't know what that is, 639 00:30:20,023 --> 00:30:22,719 that is an undifferentiated, malignant 640 00:30:22,719 --> 00:30:25,036 neoplasm, 641 00:30:25,036 --> 00:30:27,075 or anaplastic neoplasm. 642 00:30:27,075 --> 00:30:29,069 And when 643 00:30:29,069 --> 00:30:33,004 you look at that, what it really says is it's a population of cells 644 00:30:33,004 --> 00:30:34,022 that's not maturing 645 00:30:34,022 --> 00:30:38,009 you can't tell what it's doing or where it came from, 646 00:30:38,009 --> 00:30:43,037 but it sure as the dickens looks malignant, look at those huge nuclei 647 00:30:43,037 --> 00:30:47,021 increased n-to-c ratio (nucleus to cytoplasm) 648 00:30:47,021 --> 00:30:50,006 they are actually pleomorphic, they are hyperchromatic, 649 00:30:50,006 --> 00:30:51,037 there are 650 00:30:51,037 --> 00:30:54,002 tumor giant cells there. 651 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 652 00:30:57,075 --> 00:30:59,054 cell population 653 00:30:59,054 --> 00:31:02,029 so that is a highly anaplastic cell population. 654 00:31:02,029 --> 00:31:04,034 Now, 655 00:31:04,034 --> 00:31:06,071 it turns out 656 00:31:06,071 --> 00:31:07,081 well, let me give you 657 00:31:07,081 --> 00:31:11,071 a rule of thumb first. 658 00:31:11,071 --> 00:31:13,057 Benign neoplasms 659 00:31:13,057 --> 00:31:17,089 are always splendidly well differentiated, sometimes you get in the 660 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 661 00:31:21,099 --> 00:31:23,088 neoplasms are always 662 00:31:23,088 --> 00:31:25,002 well-differentiated. 663 00:31:25,002 --> 00:31:29,017 Almost perfectly differentiated. 664 00:31:29,017 --> 00:31:32,299 Malignant neoplasms show the whole range, 665 00:31:32,299 --> 00:31:37,038 there are very well differentiated but nonetheless malignant neoplasms 666 00:31:37,038 --> 00:31:38,065 and there are highly anaplastic 667 00:31:38,065 --> 00:31:43,046 like this. 668 00:31:43,046 --> 00:31:46,092 In some situations, in many situations, 669 00:31:46,092 --> 00:31:49,073 in malignant neoplasms, 670 00:31:49,073 --> 00:31:54,036 there is a a rough correlation, I emphasize rough, 671 00:31:54,036 --> 00:31:55,021 between the degree 672 00:31:55,021 --> 00:31:59,078 of differentiation and the behavior. 673 00:31:59,078 --> 00:32:02,799 This is not uniform for all neoplasms 674 00:32:02,799 --> 00:32:06,084 and remember well differentiated neoplasms/cancers can still kill. 675 00:32:06,084 --> 00:32:07,084 But for 676 00:32:07,084 --> 00:32:09,064 some situations, it's a 677 00:32:09,064 --> 00:32:11,006 useful label that we 678 00:32:11,006 --> 00:32:14,095 give it to send to our colleagues 679 00:32:14,095 --> 00:32:16,359 where we say 680 00:32:16,359 --> 00:32:19,009 we label it 681 00:32:19,009 --> 00:32:24,559 depending on the degree of differentiation we call this ''grading'', 682 00:32:24,559 --> 00:32:27,093 histological grading of neoplasm. 683 00:32:27,093 --> 00:32:31,015 The grading of neoplasms is really 684 00:32:31,015 --> 00:32:36,037 an assessment of the degree of differentiation of the neoplasm based on, 685 00:32:36,037 --> 00:32:38,061 i mean we look under the microscope, 686 00:32:38,061 --> 00:32:42,008 and we say oh! this looks just like 687 00:32:42,008 --> 00:32:44,529 such-and-such tissue that's well differentiated 688 00:32:44,529 --> 00:32:48,083 we sometimes take into account in these grading systems 689 00:32:48,083 --> 00:32:51,036 the number of mitoses 690 00:32:51,036 --> 00:32:52,086 that's a little less usual 691 00:32:52,086 --> 00:32:55,329 but it's based basically on the degree of differentiation 692 00:32:55,329 --> 00:33:00,129 and we talk about grade one, usually grade one means 693 00:33:00,129 --> 00:33:04,419 the best differentiated grade, grade two to grade three, some grading systems are all 694 00:33:04,419 --> 00:33:06,659 the way through grade four. 695 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 696 00:33:11,038 --> 00:33:16,036 we say this is well differentiated and our colleagues at the other end say, well 697 00:33:16,036 --> 00:33:21,052 maybe that'll behave a little better than if Abrams said it was anaplastic. 698 00:33:21,052 --> 00:33:24,071 And Illl show you what this amounts to visually, again don't worry about being 699 00:33:24,071 --> 00:33:26,074 able to pick these out. 700 00:33:26,074 --> 00:33:28,429 Here is a carcinoma, 701 00:33:28,429 --> 00:33:29,096 702 00:33:29,096 --> 00:33:34,032 cancer derived from a squamous epithelium, like the epidermis of the skin 703 00:33:34,032 --> 00:33:37,033 and a trained pathologist, which you will be 704 00:33:37,033 --> 00:33:42,016 next spring, would look at this kind of arrangement or all this pinky cytoplasm 705 00:33:42,016 --> 00:33:44,059 which represents keratin and 706 00:33:44,059 --> 00:33:45,159 in the cells 707 00:33:45,159 --> 00:33:46,072 and you'd say oh easy! 708 00:33:46,072 --> 00:33:47,065 That's a well-differentiated 709 00:33:47,065 --> 00:33:51,044 squamous cell carcinoma, this might be a grade one 710 00:33:51,044 --> 00:33:52,059 for 711 00:33:52,059 --> 00:33:54,025 instance 712 00:33:54,025 --> 00:33:56,049 This one is might not look like much to you, but 713 00:33:56,049 --> 00:34:00,031 a trained pathologist would look at this and say, well, 714 00:34:00,031 --> 00:34:01,019 this isn't terribly 715 00:34:01,019 --> 00:34:06,149 well differentiated but I can still see areas where I'll bet that's coming 716 00:34:06,149 --> 00:34:11,019 from the squamous epithelium, so that would be maybe a grade two or moderately 717 00:34:11,019 --> 00:34:13,021 differentiated 718 00:34:13,021 --> 00:34:14,093 Here again is a completely 719 00:34:14,093 --> 00:34:18,057 anaplastic cell population, someone showed me that and said where is this coming from 720 00:34:18,057 --> 00:34:19,056 and I'd say 721 00:34:19,056 --> 00:34:21,759 God only knows this is cancer. 722 00:34:21,759 --> 00:34:24,299 When i don't know what kind, 723 00:34:24,299 --> 00:34:29,999 this is really an anaplastic, probably grade three to grade four cancer 724 00:34:29,999 --> 00:34:32,999 and again there's a rough correlation between 725 00:34:32,999 --> 00:34:36,389 the degree of differentiation and how it might behave. 726 00:34:36,389 --> 00:34:37,649 behave 727 00:34:37,649 --> 00:34:39,209 Now grading, 728 00:34:39,209 --> 00:34:42,879 this is all microscopic, grading is different than staging. 729 00:34:42,879 --> 00:34:46,029 Please keep these two straight 730 00:34:46,029 --> 00:34:48,389 and read and understand, you're going to deal 731 00:34:48,389 --> 00:34:50,589 with these two concepts all your lives. 732 00:34:50,589 --> 00:34:54,119 Staging a neoplasm is very important 733 00:34:54,119 --> 00:34:57,569 because of the stage that we assigned to a neoplasm tells the observer 734 00:34:57,569 --> 00:34:59,939 735 00:34:59,939 --> 00:35:05,249 how far along in its natural history that neoplasm is, in other words, 736 00:35:05,249 --> 00:35:09,829 how big is it at the primary, how much tissue has it penetrated, 737 00:35:09,829 --> 00:35:12,003 has it advanced to the point where it's spread 738 00:35:12,003 --> 00:35:14,019 elsewhere in the body. 739 00:35:14,019 --> 00:35:18,049 That is staging. 740 00:35:18,049 --> 00:35:23,739 It's based on first of all the size and the extent of the primary, 741 00:35:23,739 --> 00:35:29,709 the presence or absence of regional lymph node metastases, and 742 00:35:29,709 --> 00:35:32,939 the presence or absence of distant metastases. 743 00:35:32,939 --> 00:35:36,659 This is sometimes referred to as the TNM system, T for tumor, 744 00:35:36,659 --> 00:35:37,067 745 00:35:37,067 --> 00:35:39,599 what's he doing with the primary, 746 00:35:39,599 --> 00:35:41,709 N for regional nodes, 747 00:35:41,709 --> 00:35:43,739 M for distant metastases. 748 00:35:43,739 --> 00:35:45,002 Every organ has 749 00:35:45,002 --> 00:35:49,579 a slightly different staging scheme, but they're all based on this 750 00:35:49,579 --> 00:35:51,008 and what it gives you, 751 00:35:51,008 --> 00:35:52,909 if it's a low stage 752 00:35:52,909 --> 00:35:56,041 or a favorable stage, that says this tumor hasn't advanced 753 00:35:56,041 --> 00:35:58,479 as far, maybe it's restricted just to 754 00:35:58,479 --> 00:36:01,029 the organ, the lymph nodes are negative, 755 00:36:01,029 --> 00:36:04,269 and there are no distant metastases, 756 00:36:04,269 --> 00:36:07,699 or it may be that it's penetrated quite a way through 757 00:36:07,699 --> 00:36:10,043 whatever organ it's started in, and there are already 758 00:36:10,043 --> 00:36:15,469 lymph node mets but we don't know of distant mets 759 00:36:15,469 --> 00:36:19,018 that's quite a different situation which may take a different therapeutic approach 760 00:36:19,018 --> 00:36:22,066 and finally if they're already distant mets, that's a very different thing. 761 00:36:22,066 --> 00:36:23,689 762 00:36:23,689 --> 00:36:25,969 So staging 763 00:36:25,969 --> 00:36:28,299 gives you a very important handle on how far 764 00:36:28,299 --> 00:36:30,005 along the neoplasm is in the 765 00:36:30,005 --> 00:36:32,029 particular patient and 766 00:36:32,029 --> 00:36:34,419 what you should do therapeutically 767 00:36:34,419 --> 00:36:38,399 because of that. 768 00:36:38,399 --> 00:36:39,959 769 00:36:39,959 --> 00:36:43,909 Now's not the time to dwell on how we tell benign from malignant and 770 00:36:43,909 --> 00:36:47,969 in our daily work you will again get an appreciation for this next 771 00:36:47,969 --> 00:36:49,579 spring, but suffice it to say 772 00:36:49,579 --> 00:36:53,609 that we pathologists can look at a tumor 773 00:36:53,609 --> 00:36:54,499 and make 774 00:36:54,499 --> 00:36:58,279 some pretty good predictions about how it may behave. 775 00:36:58,279 --> 00:37:02,319 In other words, if we look at a tumor and it looks very well-differentiated 776 00:37:02,319 --> 00:37:05,169 and completely circumscribed and so on and so forth, we 777 00:37:05,169 --> 00:37:07,409 say it's benign 778 00:37:07,409 --> 00:37:11,999 and what that says is if you get the whole thing out, patient is home free. 779 00:37:11,999 --> 00:37:17,049 If it's invasive anaplastic, it's a very different situation. 780 00:37:17,049 --> 00:37:20,679 I can tell you that that the cornerstone 781 00:37:20,679 --> 00:37:22,459 of clinical diagnosis 782 00:37:22,459 --> 00:37:25,729 in the field of oncology is 783 00:37:25,729 --> 00:37:27,689 getting something under glass, 784 00:37:27,689 --> 00:37:29,929 getting in the microscope. 785 00:37:29,929 --> 00:37:31,979 Very few instances where 786 00:37:31,979 --> 00:37:32,759 787 00:37:32,759 --> 00:37:34,749 788 00:37:34,749 --> 00:37:37,043 therapy will be undertaken without confirmation 789 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. 790 00:37:41,081 --> 00:37:44,002 so it means we need a piece of the tissue 791 00:37:44,002 --> 00:37:46,779 792 00:37:46,779 --> 00:37:47,008 or at least 793 00:37:47,008 --> 00:37:49,066 some cells from the tissue 794 00:37:49,066 --> 00:37:50,909 to get under the microscope. 795 00:37:50,909 --> 00:37:53,589 796 00:37:53,589 --> 00:37:55,091 What we rely on there 797 00:37:55,091 --> 00:37:59,069 as you might surmise from what you've seen is first of all 798 00:37:59,069 --> 00:38:01,859 799 00:38:01,859 --> 00:38:06,739 the cytologic features, how anaplastic looking are the cells, how bad is the 800 00:38:06,739 --> 00:38:12,339 the pleomorphism, the hyperchromatism, etc, we rely on that 801 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 802 00:38:16,539 --> 00:38:18,869 and so forth, and 803 00:38:18,869 --> 00:38:24,529 we rely on the relation of the tumor to its surroundings, the nice pushing 804 00:38:24,529 --> 00:38:28,279 margin vs boy! there goes invasion 805 00:38:28,279 --> 00:38:32,529 it's that sort of thing. Now 806 00:38:32,529 --> 00:38:33,839 I'll give you just a 807 00:38:33,839 --> 00:38:36,064 very quick example of that. 808 00:38:36,064 --> 00:38:37,097 Here is a 809 00:38:37,097 --> 00:38:40,014 you can imagine that colon I showed you 810 00:38:40,014 --> 00:38:41,139 in the cut, 811 00:38:41,139 --> 00:38:44,077 here is a mucosa, a submucosa, here is a muscular wall, 812 00:38:44,077 --> 00:38:46,025 here's the tumor arising in the mucosa. 813 00:38:46,025 --> 00:38:48,479 814 00:38:48,479 --> 00:38:52,779 You see under the microscope here, you can see kind of glandular spaces there. 815 00:38:52,779 --> 00:38:53,095 Look what's happening, 816 00:38:53,095 --> 00:38:55,599 you've got glands 817 00:38:55,599 --> 00:38:58,779 penetrating clear down through the muscle there. 818 00:38:58,779 --> 00:39:00,799 819 00:39:00,799 --> 00:39:02,004 That's a no brainer 820 00:39:02,004 --> 00:39:07,329 when we see something like that we say it's invading, it's malignant. 821 00:39:07,329 --> 00:39:10,859 That make sense? 822 00:39:10,859 --> 00:39:15,199 Sometimes we don't rely entirely on that, we rely on other things 823 00:39:15,199 --> 00:39:17,029 The cytology, just quickly, 824 00:39:17,029 --> 00:39:20,719 there are normal colonic epithelial cells 825 00:39:20,719 --> 00:39:23,769 I'm not going to describe it, just let the pictures speak for themselves. 826 00:39:23,769 --> 00:39:26,569 You'll catch up with this in the spring. 827 00:39:26,569 --> 00:39:32,359 Here are neoplastic epithelial cells. Again, normal...neoplastic. 828 00:39:32,359 --> 00:39:34,999 Here's a normal squamous 829 00:39:34,999 --> 00:39:39,789 epithelium, we're back to cervix, here's normal squamous 830 00:39:39,789 --> 00:39:41,589 831 00:39:41,589 --> 00:39:43,479 here's dysplastic. 832 00:39:43,479 --> 00:39:50,199 you saw that before, this variation, this loss of polarity, the individual features 833 00:39:50,199 --> 00:39:52,042 of cytology here, that's a 834 00:39:52,042 --> 00:39:56,078 degree of dysplasia, it's a step towards cancer. 835 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. 836 00:40:01,035 --> 00:40:02,319 837 00:40:02,319 --> 00:40:04,359 The concept is important, when dysplasia gets severe 838 00:40:04,359 --> 00:40:07,239 it's tantamount to 839 00:40:07,239 --> 00:40:11,439 cancer in situ, whether or not it's invaded, 840 00:40:11,439 --> 00:40:14,709 you see in the colonic example, we showed you invasion. 841 00:40:14,709 --> 00:40:18,049 Here we can say this epithelium is cancerous, dammit! 842 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 843 00:40:21,989 --> 00:40:26,099 virtually 100% of these severe dysplasias will invade. 844 00:40:26,099 --> 00:40:26,062 And that is 845 00:40:26,062 --> 00:40:27,094 carcinoma in situ. 846 00:40:27,094 --> 00:40:29,479 847 00:40:29,479 --> 00:40:32,007 You'll hear a lot more about that 848 00:40:32,007 --> 00:40:35,509 Now 849 00:40:35,509 --> 00:40:38,499 850 00:40:38,499 --> 00:40:41,289 clearly if you look at something like this 851 00:40:41,289 --> 00:40:46,719 you realize that that individual cells in that population bear the 852 00:40:46,719 --> 00:40:48,279 imprint 853 00:40:48,279 --> 00:40:51,179 of their malignancy, in other words, they have these anaplastic traits and you 854 00:40:51,179 --> 00:40:53,159 can say these are malignant cells. 855 00:40:53,159 --> 00:40:56,349 A guy named the george papanicolaou 856 00:40:56,349 --> 00:40:58,849 over half a century ago 857 00:40:58,849 --> 00:41:02,093 realized that that this was a great handle, that if you 858 00:41:02,093 --> 00:41:08,319 took cells that exfoliated, that is dropped off the surface, of 859 00:41:08,319 --> 00:41:09,869 a place where there might be a tumor 860 00:41:09,869 --> 00:41:12,006 that these exfoliated cells 861 00:41:12,006 --> 00:41:13,669 would bear 862 00:41:13,669 --> 00:41:17,066 some of these traits, these anaplastic traits, and all you'd have to do 863 00:41:17,066 --> 00:41:20,039 is look at these cells and say WOW 864 00:41:20,039 --> 00:41:22,065 this is so and so. 865 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, 866 00:41:27,529 --> 00:41:29,099 and the beauty of the Pap smear is that you don't have to 867 00:41:29,099 --> 00:41:32,879 cut out a piece of tissue from the person. 868 00:41:32,879 --> 00:41:33,097 869 00:41:33,097 --> 00:41:35,087 All you need is a sample 870 00:41:35,087 --> 00:41:37,007 of the usually it's mucus 871 00:41:37,007 --> 00:41:38,019 872 00:41:38,019 --> 00:41:40,189 873 00:41:40,189 --> 00:41:41,056 over the area, now 874 00:41:41,056 --> 00:41:45,041 this has been perfected, this has changed the whole face of 875 00:41:45,041 --> 00:41:49,739 how we deal with cervix cancer 876 00:41:49,739 --> 00:41:53,609 but you can imagine a cervix...no let's back up, 877 00:41:53,609 --> 00:41:55,459 878 00:41:55,459 --> 00:41:57,569 looking like that 879 00:41:57,569 --> 00:41:58,719 and that are 880 00:41:58,719 --> 00:42:02,319 exfoliated, remember they come off here and getting a Pap smear 881 00:42:02,319 --> 00:42:04,073 involves getting a little bit of mucus 882 00:42:04,073 --> 00:42:08,979 scraped off the surface of the middle of some of these cells and 883 00:42:08,979 --> 00:42:10,809 from a normal epithelium like this 884 00:42:10,809 --> 00:42:14,009 you're going to see 885 00:42:14,009 --> 00:42:17,007 and i'll show you a Pap smear 886 00:42:17,007 --> 00:42:19,189 whereas from this 887 00:42:19,189 --> 00:42:20,309 888 00:42:20,309 --> 00:42:23,919 or this, you're going to get a different kind of cell exfoliating out 889 00:42:23,919 --> 00:42:24,083 890 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 891 00:42:29,058 --> 00:42:32,709 mucus you can tell what you're dealing with. 892 00:42:32,709 --> 00:42:34,709 I'll let you see this for yourselves. 893 00:42:34,709 --> 00:42:36,109 894 00:42:36,109 --> 00:42:40,499 Well, here are just some of cellular features of anaplasia. 895 00:42:40,499 --> 00:42:44,076 Any look at a cell population like this with the huge nuclei 896 00:42:44,076 --> 00:42:47,219 there's a tripolar division figure there, 897 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. 898 00:42:52,009 --> 00:42:54,639 899 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 900 00:42:58,449 --> 00:42:59,819 901 00:42:59,819 --> 00:43:02,014 look like they're all out of the same cookie cutter, same N-C ratio 902 00:43:02,014 --> 00:43:07,089 the nuclei are not pleomorphic, they are not very regular 903 00:43:07,089 --> 00:43:08,699 etcetera etcetera etcetera 904 00:43:08,699 --> 00:43:11,219 Normal pap smear next case, 905 00:43:11,219 --> 00:43:14,589 now suppose that epithelium looked like 906 00:43:14,589 --> 00:43:19,039 the bad one I showed you, there you are, 907 00:43:19,039 --> 00:43:20,829 I'm showing you the extremes, 908 00:43:20,829 --> 00:43:22,019 909 00:43:22,019 --> 00:43:25,092 instead of being very regular, these are extremely pleomorphic cells with increased N-C ratio 910 00:43:25,092 --> 00:43:28,001 hyperchromatism 911 00:43:28,001 --> 00:43:31,099 and so forth, 912 00:43:31,099 --> 00:43:35,889 the cytopathologist looking at this doesn't have to pause very often and say 913 00:43:35,889 --> 00:43:37,079 this 914 00:43:37,079 --> 00:43:40,449 has been exfoliated from a malignant cell population 915 00:43:40,449 --> 00:43:41,839 and the nice thing is 916 00:43:41,839 --> 00:43:44,479 that in between the cytopathologist can also 917 00:43:44,479 --> 00:43:48,449 look at this and say well this probably came from a cervix with 918 00:43:48,449 --> 00:43:50,609 moderate dysplasia 919 00:43:50,609 --> 00:43:53,539 or minimal dysplasia or something like that, 920 00:43:53,539 --> 00:43:58,149 so that not only can we catch cancers when they're perhaps too small to appreciate 921 00:43:58,149 --> 00:43:59,659 by ordinary examination 922 00:43:59,659 --> 00:44:01,189 we can actually 923 00:44:01,189 --> 00:44:03,209 catch dysplastic epithelium 924 00:44:03,209 --> 00:44:07,119 before it's become cancer or carcinoma in situ 925 00:44:07,119 --> 00:44:11,299 before it's invaded, these things are all invisible pretty much 926 00:44:11,299 --> 00:44:11,999 927 00:44:11,999 --> 00:44:15,048 and they will show up on the cytological exam, 928 00:44:15,048 --> 00:44:19,349 so it's become a very powerful screening tool 929 00:44:19,349 --> 00:44:20,049 930 00:44:20,049 --> 00:44:23,079 and it's changed the face of what we 931 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 932 00:44:28,129 --> 00:44:30,439 nothing but very advanced cervix cancer 933 00:44:30,439 --> 00:44:31,092 934 00:44:31,092 --> 00:44:32,969 935 00:44:32,969 --> 00:44:36,469 that were clear into the rectal wall and bladder wall and so forth, 936 00:44:36,469 --> 00:44:40,599 i haven't seen one of those thankfully in decades 937 00:44:40,599 --> 00:44:47,369 because of the application of the Pap smear as screening. 938 00:44:47,369 --> 00:44:51,579 That's something you'll hear a lot more about 939 00:44:51,579 --> 00:44:56,439 so going back to generalities, a definition 940 00:44:56,439 --> 00:45:00,092 of, or the diagnosis of neoplasm, requires getting something 941 00:45:00,092 --> 00:45:02,669 under the microscope. 942 00:45:02,669 --> 00:45:04,011 Now sometimes it's the whole 943 00:45:04,011 --> 00:45:07,078 tumor, patient presents with lump sum or 944 00:45:07,078 --> 00:45:12,015 you cut out the whole thing -- that's called an excisional, excisional biopsy, 945 00:45:12,015 --> 00:45:15,539 and that's very nice because if it's benign, you're done. 946 00:45:15,539 --> 00:45:18,169 If it's malignant, 947 00:45:18,169 --> 00:45:21,099 you have to do some other things very likely. 948 00:45:21,099 --> 00:45:24,209 Sometimes only a piece of tissue is removed, if it's a big mass 949 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 950 00:45:27,459 --> 00:45:28,005 dealing with. 951 00:45:28,005 --> 00:45:32,289 That may be an incisional biopsy, you take a wedge of it out. 952 00:45:32,289 --> 00:45:36,089 There are various biting forceps where 953 00:45:36,089 --> 00:45:37,069 954 00:45:37,069 --> 00:45:39,259 bite a piece out 955 00:45:39,259 --> 00:45:41,509 and there are punch forceps 956 00:45:41,509 --> 00:45:44,979 particularly for skin things where you take a punch, 957 00:45:44,979 --> 00:45:46,459 it's a little boring, 958 00:45:46,459 --> 00:45:47,009 finally 959 00:45:47,009 --> 00:45:48,319 960 00:45:48,319 --> 00:45:52,239 very often there are a variety of needles that are used where you can 961 00:45:52,239 --> 00:45:56,489 put a needle into a mass with very, 962 00:45:56,489 --> 00:45:58,689 nothing beyond local anesthesia even, 963 00:45:58,689 --> 00:46:01,065 put a needle in and draw out a core of cells 964 00:46:01,065 --> 00:46:02,043 and get those 965 00:46:02,043 --> 00:46:05,399 under the microscope 966 00:46:05,399 --> 00:46:07,032 and the extreme of this 967 00:46:07,032 --> 00:46:09,041 is putting in, and this can be done 968 00:46:09,041 --> 00:46:12,409 you know with CT guidance into internal organs 969 00:46:12,409 --> 00:46:14,929 put a very fine skinny needle in there 970 00:46:14,929 --> 00:46:16,969 suck out some juice 971 00:46:16,969 --> 00:46:18,003 from the 972 00:46:18,003 --> 00:46:19,519 lump 973 00:46:19,519 --> 00:46:22,057 and that juice will usually contain a few floating cells 974 00:46:22,057 --> 00:46:26,002 and the trained cytopathologist could look at the degree of anaplasia and so forth 975 00:46:26,002 --> 00:46:29,089 in those cells and make a diagnosis. 976 00:46:29,089 --> 00:46:32,038 So, this is 977 00:46:32,038 --> 00:46:37,079 always, almost always, what we do before undertaking treatment. 978 00:46:37,079 --> 00:46:38,579 And 979 00:46:38,579 --> 00:46:40,069 980 00:46:40,069 --> 00:46:43,749 just to tell you, in conclusion, that this visual exam 981 00:46:43,749 --> 00:46:49,099 under the scope is frequently augmented by other things. 982 00:46:49,099 --> 00:46:51,859 Someone asked me, for instance, 983 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 984 00:46:54,829 --> 00:46:56,159 primary. 985 00:46:56,159 --> 00:46:59,279 My answer was no, unfortunately 986 00:46:59,279 --> 00:47:02,309 many different glandular neoplasms 987 00:47:02,309 --> 00:47:04,269 look the same under the microscope, 988 00:47:04,269 --> 00:47:06,199 989 00:47:06,199 --> 00:47:10,499 so all we can say is this came from a glandular tissue. Sometimes we can use 990 00:47:10,499 --> 00:47:13,099 immuno histochemical techniques, 991 00:47:13,099 --> 00:47:18,209 in other words, there maybe certain proteins on the surface of certain cells 992 00:47:18,209 --> 00:47:21,539 that identify them 993 00:47:21,539 --> 00:47:26,589 we have a library of of antibodies directed against these various proteins 994 00:47:26,589 --> 00:47:29,709 and they're labeled in a certain way and we can 995 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 996 00:47:35,016 --> 00:47:37,339 we know that protein is represented, and to 997 00:47:37,339 --> 00:47:41,599 give you a concrete example, suppose we had a lymph node that had a glandular cancer 998 00:47:41,599 --> 00:47:43,269 and one of the possibilities 999 00:47:43,269 --> 00:47:47,489 would be from the prostate 1000 00:47:47,489 --> 00:47:52,229 we could take an antibiotic to PSA (prostate specific antigen) 1001 00:47:52,229 --> 00:47:54,041 stain that tissue, and if it lit up, 1002 00:47:54,041 --> 00:47:57,149 those cancer cells had the prostate antigen, easy! 1003 00:47:57,149 --> 00:47:58,599 this came from prostate. 1004 00:47:58,599 --> 00:48:01,067 So we use those sorts of things 1005 00:48:01,067 --> 00:48:08,119 we've gotten into molecular methods of identifying this or that molecule and 1006 00:48:08,119 --> 00:48:12,039 in the cell population that augments what we can do visually and the ultimate 1007 00:48:12,039 --> 00:48:13,579 1008 00:48:13,579 --> 00:48:18,349 is something you're going to hear a lot more about and that is subjecting 1009 00:48:18,349 --> 00:48:23,092 the tumor to analysis with what we call microarrays which are the system 1010 00:48:23,092 --> 00:48:28,769 whereby you can screen for thousands of genes and see which ones 1011 00:48:28,769 --> 00:48:30,159 are activated 1012 00:48:30,159 --> 00:48:32,479 and we're beginning to 1013 00:48:32,479 --> 00:48:33,709 ''beginning'' 1014 00:48:33,709 --> 00:48:38,949 to be able to say well with this, this, this, these genes activated 1015 00:48:38,949 --> 00:48:42,559 this neoplasm is more likely to do this, and with this, this, this set of genes 1016 00:48:42,559 --> 00:48:48,989 activated it's more likely to do that. That's where it is all going. 1017 00:48:48,989 --> 99:59:59,999 Okay we'll continue this on Wednesday and feed you the rest.