WEBVTT 1 00:00:00.540 --> 00:00:01.373 Hi, all, 2 00:00:01.373 --> 00:00:02.610 and welcome to today's lecture 3 00:00:02.610 --> 00:00:05.067 on the "Epidemiology of Uterine Cancer". 4 00:00:06.750 --> 00:00:09.727 In this lecture, we have several goals. 5 00:00:09.727 --> 00:00:10.560 We're going to review the anatomy 6 00:00:10.560 --> 00:00:11.820 of the corpus uteri 7 00:00:11.820 --> 00:00:14.700 to discuss the global burden of corpus uterine cancer, 8 00:00:14.700 --> 00:00:18.000 contrast trends in endometrial and cervical cancer, 9 00:00:18.000 --> 00:00:20.520 discuss risk factors for endometrial cancer, 10 00:00:20.520 --> 00:00:23.730 and discuss preventive factors for endometrial cancer. 11 00:00:23.730 --> 00:00:24.780 We'll conclude by looking 12 00:00:24.780 --> 00:00:26.733 at prevention and control strategies. 13 00:00:27.780 --> 00:00:31.722 So, first, looking at incidence rates 14 00:00:31.722 --> 00:00:34.203 of cancer of the corpus uteri, or uterine cancer, 15 00:00:35.070 --> 00:00:39.000 cancer was diagnosed in 319,605 women 16 00:00:39.000 --> 00:00:43.650 and caused 76,155 deaths in 2012. 17 00:00:43.650 --> 00:00:46.380 Annual incidence rates are highest in developed countries 18 00:00:46.380 --> 00:00:50.370 of North America, Russia, Europe, and Scandinavia. 19 00:00:50.370 --> 00:00:51.600 All of those places have rates 20 00:00:51.600 --> 00:00:54.667 higher than 15 cases per 100,000, 21 00:00:55.692 --> 00:00:56.700 and lowest in underdeveloped countries 22 00:00:56.700 --> 00:00:58.906 of Southeast Asia and Africa, 23 00:00:58.906 --> 00:01:00.780 which all have cases numbering less than three 24 00:01:00.780 --> 00:01:03.360 per 100,000 per year. 25 00:01:03.360 --> 00:01:06.252 Due to shared risk factors at heighten exposure 26 00:01:06.252 --> 00:01:08.340 to both endogenous and exogenous estrogens, 27 00:01:08.340 --> 00:01:11.129 the global pattern of corpus uteri cancer 28 00:01:11.129 --> 00:01:12.929 is similar to that of breast cancer. 29 00:01:14.760 --> 00:01:17.670 The trends of mortality generally follow the trends 30 00:01:17.670 --> 00:01:20.313 and incidence for corpus uterine cancer as well. 31 00:01:22.140 --> 00:01:24.718 So, we see that the global burden of cancer 32 00:01:24.718 --> 00:01:26.580 of the corpus uteri has increased sharply 33 00:01:26.580 --> 00:01:28.230 in the 21st century unfortunately. 34 00:01:28.230 --> 00:01:30.660 And, during the time span from 2012, 35 00:01:30.660 --> 00:01:33.600 reported numbers of new cases and deaths have increased 36 00:01:33.600 --> 00:01:37.683 by 69% and 70% respectively. 37 00:01:39.210 --> 00:01:41.463 When we look at uterine cancer in 2020, 38 00:01:42.359 --> 00:01:43.383 we see that there's age... 39 00:01:43.383 --> 00:01:44.921 An age-standardized incidence rate 40 00:01:44.921 --> 00:01:47.160 of 8.7 per 100,000 women globally, 41 00:01:47.160 --> 00:01:48.870 and an age-standardized mortality 42 00:01:48.870 --> 00:01:52.473 of 1.8 per 100,000 women globally. 43 00:01:54.420 --> 00:01:58.280 So, next, let's turn to the anatomy of the... 44 00:01:59.340 --> 00:02:02.370 Of the uterine corpus. 45 00:02:02.370 --> 00:02:05.410 So, we'll note that endometrial carcinomas 46 00:02:06.298 --> 00:02:09.098 account for 92% of malignant tumors of the corpus uteri. 47 00:02:10.460 --> 00:02:11.880 These tumors arise from the epithelial lining 48 00:02:11.880 --> 00:02:16.083 of the endometrium as we see here. 49 00:02:18.030 --> 00:02:19.980 Histologically, endometrial carcinomas 50 00:02:19.980 --> 00:02:22.890 are adenocarcinomas that show glandular characteristics 51 00:02:22.890 --> 00:02:23.943 under the microscope. 52 00:02:25.440 --> 00:02:27.540 In addition to the endometrial carcinomas, 53 00:02:27.540 --> 00:02:31.230 sarcomas derived from connective tissues of the uterus 54 00:02:31.230 --> 00:02:34.530 account for only 3% of uterine cancers. 55 00:02:34.530 --> 00:02:37.440 There are two subtypes of corpus uterine cancer, 56 00:02:37.440 --> 00:02:41.100 carcinosarcomas and mixed malignant malarian tumors. 57 00:02:41.100 --> 00:02:44.940 Those account for the final 5% of uterine cancers. 58 00:02:44.940 --> 00:02:47.130 These tumors consist of a mix 59 00:02:47.130 --> 00:02:48.930 of glandular and connective tissues. 60 00:02:49.830 --> 00:02:54.420 Finally, the very rare final type of cancer 61 00:02:54.420 --> 00:02:58.917 of the corpus uteri is choriocarcinoma, 62 00:02:58.917 --> 00:03:00.900 and that's a rare type of uterine malignancy 63 00:03:00.900 --> 00:03:02.903 that occasionally develops during pregnancy. 64 00:03:06.000 --> 00:03:07.950 So, endometrial cancer accounts 65 00:03:07.950 --> 00:03:10.500 for about 10% of female cancers, 66 00:03:10.500 --> 00:03:14.730 and 80 to 90% of cases are diagnosed after menopause. 67 00:03:14.730 --> 00:03:17.460 There's the peak incidence at 55 to 65 years 68 00:03:17.460 --> 00:03:19.992 of 60 per 100,000, 69 00:03:19.992 --> 00:03:23.070 and 40,320 new endometrial cancers were... 70 00:03:23.070 --> 00:03:25.890 Are diagnosed in the US annually. 71 00:03:25.890 --> 00:03:29.133 There's also a little over 7,000 deaths 72 00:03:29.133 --> 00:03:31.283 from endometrial cancer in the US annually. 73 00:03:33.080 --> 00:03:33.913 In high income countries, 74 00:03:33.913 --> 00:03:36.510 endometrial cancer has surpassed cervical cancer 75 00:03:36.510 --> 00:03:39.093 as the leading gynecological malignancy in women. 76 00:03:40.484 --> 00:03:41.970 Annual incidence rates of endometrial cancer 77 00:03:41.970 --> 00:03:43.758 among American women 78 00:03:43.758 --> 00:03:45.450 have trended upwards since 2000, 79 00:03:45.450 --> 00:03:47.280 and are now three to four times higher 80 00:03:47.280 --> 00:03:49.594 than cervical cancer rates, 81 00:03:49.594 --> 00:03:50.813 which continue to decline. 82 00:03:52.186 --> 00:03:54.922 Recent increases in the incidence of endometrial cancer 83 00:03:54.922 --> 00:03:55.830 and declining rates of cervical cancer 84 00:03:55.830 --> 00:03:58.500 are also evident in Great Britain, Western Europe, 85 00:03:58.500 --> 00:04:00.303 Scandinavia, and Australia. 86 00:04:02.340 --> 00:04:04.680 So, when we look at endometrial cancer risk factors, 87 00:04:04.680 --> 00:04:06.030 we see some similarities 88 00:04:06.030 --> 00:04:10.410 to those of cervical cancer and breast cancer. 89 00:04:10.410 --> 00:04:13.380 So, namely, we see the early menarche, late first pregnancy, 90 00:04:13.380 --> 00:04:16.290 and late menopause are all play a role 91 00:04:16.290 --> 00:04:18.930 in the development of endometrial cancer. 92 00:04:18.930 --> 00:04:21.000 Others, factors include infertility, 93 00:04:21.000 --> 00:04:24.792 obesity and hypertension, familial history, 94 00:04:24.792 --> 00:04:26.760 cancer family syndrome, diabetes, 95 00:04:26.760 --> 00:04:28.996 estrogen replacement therapy, 96 00:04:28.996 --> 00:04:31.146 and selective estrogen receptor modulation. 97 00:04:32.490 --> 00:04:34.500 So, as mentioned previously, 98 00:04:34.500 --> 00:04:36.600 the majority of endometrial cancer cases 99 00:04:36.600 --> 00:04:38.520 or plurality of endometrial cancer cases 100 00:04:38.520 --> 00:04:41.733 are diagnosed between 55 to 64 years of age. 101 00:04:43.560 --> 00:04:44.580 It's also important to note 102 00:04:44.580 --> 00:04:47.830 that there are type one and type two cancers 103 00:04:48.690 --> 00:04:51.240 when we discuss endometrial cancer. 104 00:04:51.240 --> 00:04:55.066 These are differentiated according to the dependence 105 00:04:55.066 --> 00:04:55.899 or lack of dependence on estrogen 106 00:04:55.899 --> 00:04:57.330 for growth and development. 107 00:04:57.330 --> 00:04:59.774 Essentially, type one cancers, 108 00:04:59.774 --> 00:05:01.530 which make up a 90% of endometrial cancers 109 00:05:01.530 --> 00:05:02.920 are estrogen dependent 110 00:05:03.918 --> 00:05:05.520 and contain estrogen receptor... 111 00:05:05.520 --> 00:05:08.580 Estrogen receptors or they're ER positive. 112 00:05:08.580 --> 00:05:10.623 On the other hand, type two cancers, 113 00:05:11.520 --> 00:05:13.980 which are 10% of endometrial cancers, 114 00:05:13.980 --> 00:05:15.630 are non estrogen dependent, 115 00:05:15.630 --> 00:05:17.223 and are ER negative. 116 00:05:20.460 --> 00:05:22.620 So, here we'll look a little bit more 117 00:05:22.620 --> 00:05:27.133 at the pathology and carcinogenesis of endometrial cancer 118 00:05:29.130 --> 00:05:32.820 by looking at the endometrial or menstrual cycle. 119 00:05:32.820 --> 00:05:33.810 So, we see, 120 00:05:33.810 --> 00:05:35.964 as we've discussed in the breast 121 00:05:35.964 --> 00:05:37.096 and cervical cancer lectures, 122 00:05:37.096 --> 00:05:39.057 a sustained exposure to estrogen, 123 00:05:39.057 --> 00:05:40.440 particularly in the absence of progesterone 124 00:05:40.440 --> 00:05:42.033 or unopposed estrogen, 125 00:05:43.029 --> 00:05:44.806 may increase the mitotic rate 126 00:05:44.806 --> 00:05:47.770 and cause atypical hyperplasia of the mammary epithelium 127 00:05:47.770 --> 00:05:48.810 or endometrial epithelium, 128 00:05:48.810 --> 00:05:51.540 which increases the chance of cancer development. 129 00:05:51.540 --> 00:05:53.850 That is when there are high levels of estrogen 130 00:05:53.850 --> 00:05:55.860 and low levels of progesterone, 131 00:05:55.860 --> 00:05:57.870 cells are dividing more frequently, 132 00:05:57.870 --> 00:06:01.143 leading to possibly a higher risk of cancer. 133 00:06:03.390 --> 00:06:06.120 The chronic repetitive inflammatory process of menstruation 134 00:06:06.120 --> 00:06:07.500 may also play an important role 135 00:06:07.500 --> 00:06:10.260 in the genesis of endometrial cancer. 136 00:06:10.260 --> 00:06:11.550 As we've discussed before, 137 00:06:11.550 --> 00:06:14.973 inflammation is closely tied to cancer development. 138 00:06:18.540 --> 00:06:21.000 As we've discussed before as well, 139 00:06:21.000 --> 00:06:22.950 polycystic ovary syndrome, 140 00:06:22.950 --> 00:06:25.213 where in women of reproductive age 141 00:06:25.213 --> 00:06:26.370 develop bilateral ovarian cysts 142 00:06:26.370 --> 00:06:29.463 in association with prolonged anovulation, infertility, 143 00:06:29.463 --> 00:06:32.700 excess ovarian secretion of androgens, 144 00:06:32.700 --> 00:06:37.700 and endometriosis may be related to endometrial cancer. 145 00:06:39.450 --> 00:06:41.610 And, in fact, results of some studies have shown 146 00:06:41.610 --> 00:06:44.220 that women with this syndrome have a fourfold increase 147 00:06:44.220 --> 00:06:47.120 in risk of endometrial cancer as opposed to healthy women. 148 00:06:48.612 --> 00:06:50.656 One mechanism underlying this association 149 00:06:50.656 --> 00:06:52.140 is during an anovulatory menstrual cycle, 150 00:06:52.140 --> 00:06:54.870 there's increased exposure of the endometrium to estrogens, 151 00:06:54.870 --> 00:06:56.403 unopposed by progesterone. 152 00:06:58.020 --> 00:07:00.540 Granulosis cell ovarian tumors 153 00:07:00.540 --> 00:07:03.757 occasionally develop an association with menstrual cell... 154 00:07:03.757 --> 00:07:06.082 Menstrual cycle irregularities, infertility, 155 00:07:06.082 --> 00:07:07.170 and vaginal bleeding. 156 00:07:07.170 --> 00:07:10.200 Human ovarian granulosis cells secret excess estrogen, 157 00:07:10.200 --> 00:07:13.205 which in turn stimulates estrogen receptors 158 00:07:13.205 --> 00:07:14.351 and other tissues 159 00:07:14.351 --> 00:07:16.142 and in the endometry... 160 00:07:16.142 --> 00:07:16.975 In the endometrium. 161 00:07:18.208 --> 00:07:20.280 And, due to hyperestrogenism and hormonal imbalance, 162 00:07:20.280 --> 00:07:23.505 endometrial cancers develop in about 10% of women 163 00:07:23.505 --> 00:07:26.100 with ovarian granulosis cell tumors. 164 00:07:26.100 --> 00:07:28.710 Finally, endometriosis or the abnormal presence 165 00:07:28.710 --> 00:07:29.940 of endometrial glands 166 00:07:29.940 --> 00:07:33.450 in the myometrium or muscle tissues, 167 00:07:33.450 --> 00:07:36.600 ovaries, uterine ligaments, vagina, et cetera, 168 00:07:36.600 --> 00:07:39.300 can lead to significant symptoms, 169 00:07:39.300 --> 00:07:42.330 including bleeding, inflammation, cystic formation, 170 00:07:42.330 --> 00:07:43.473 and fibrosis. 171 00:07:45.180 --> 00:07:48.330 And, this can be diagnosed with colonoscopy or pathology, 172 00:07:48.330 --> 00:07:50.670 and it increases the risk of ovarian cancer, 173 00:07:50.670 --> 00:07:53.013 but has not been linked to endometrial cancer. 174 00:07:55.200 --> 00:07:59.130 Obesity is a significant risk factor of endometrial cancer 175 00:07:59.130 --> 00:08:01.500 due to higher endogenous estrogen levels 176 00:08:01.500 --> 00:08:03.588 in obese individuals 177 00:08:03.588 --> 00:08:05.070 and reduced levels of sex hormone, blighting, 178 00:08:05.070 --> 00:08:07.863 binding globulins, or a type of protein. 179 00:08:09.484 --> 00:08:11.640 Diabetes also plays a role 180 00:08:11.640 --> 00:08:13.650 in the development of endometrial cancer. 181 00:08:13.650 --> 00:08:15.540 And, for type two diabetics, 182 00:08:15.540 --> 00:08:17.040 there's a twofold risk increase 183 00:08:17.040 --> 00:08:19.170 in the development of endometrial cancer. 184 00:08:19.170 --> 00:08:22.653 There's a threefold risk increase for type one diabetics. 185 00:08:26.640 --> 00:08:29.040 Next, we see that in the early 1970s, 186 00:08:29.040 --> 00:08:32.447 the incidence of endometrial cancer abruptly doubled 187 00:08:32.447 --> 00:08:34.223 among many Caucasian women in the US. 188 00:08:35.223 --> 00:08:36.060 This phenomenon was observed shortly 189 00:08:36.060 --> 00:08:39.030 after a marked increase in estrogen replacement therapy 190 00:08:39.030 --> 00:08:40.590 or equine estrogens, 191 00:08:40.590 --> 00:08:43.320 for the treatment of hot flashes at the time of menopause 192 00:08:43.320 --> 00:08:44.583 in some American women. 193 00:08:45.600 --> 00:08:47.340 Subsequent epidemiologic studies 194 00:08:47.340 --> 00:08:49.350 consistently revealed significant increases 195 00:08:49.350 --> 00:08:52.637 in the risk of developing endometrial cancer among women 196 00:08:52.637 --> 00:08:54.960 who received estrogen replacement therapy. 197 00:08:54.960 --> 00:08:57.960 And, this risk persisted for more than 10 years 198 00:08:57.960 --> 00:09:01.740 after discontinuation of use of hormone replacement therapy. 199 00:09:01.740 --> 00:09:04.770 However, again, I'll point out that it's important 200 00:09:04.770 --> 00:09:08.130 to view the New York Times Magazine article 201 00:09:08.130 --> 00:09:10.770 in the American Dissected Podcast, 202 00:09:10.770 --> 00:09:12.420 which discusses some recent revelations 203 00:09:12.420 --> 00:09:16.110 about the use of hormone replacement therapy 204 00:09:16.110 --> 00:09:18.600 in relation to the development of cancer, 205 00:09:18.600 --> 00:09:21.900 including some ways in which the data of that study 206 00:09:21.900 --> 00:09:26.110 may have been interpreted 207 00:09:27.180 --> 00:09:30.903 in less than completely accurate fashion. 208 00:09:33.090 --> 00:09:35.220 The decline in the incidence of endometrial cancer 209 00:09:35.220 --> 00:09:38.250 to pre-1970 levels during the 1980s 210 00:09:38.250 --> 00:09:40.470 is ascribed to the introduction of progesterones 211 00:09:40.470 --> 00:09:42.993 as part of the hormonal replacement regimen. 212 00:09:45.300 --> 00:09:48.540 So, there's several key steps that can be taken 213 00:09:48.540 --> 00:09:51.543 to reduce one's risk of endometrial cancer. 214 00:09:52.607 --> 00:09:55.230 These include oral contraceptive use, regular exercise, 215 00:09:55.230 --> 00:09:58.504 the use of aspirin, consuming coffee... 216 00:09:58.504 --> 00:10:01.473 Or, consuming coffee, 217 00:10:02.430 --> 00:10:05.550 lowering one's rate of chronic smoking, 218 00:10:05.550 --> 00:10:07.113 and undergoing hysterectomy. 219 00:10:09.420 --> 00:10:11.370 So, the use of oral contraceptives 220 00:10:11.370 --> 00:10:12.840 has been sure to decrease the risk 221 00:10:12.840 --> 00:10:14.673 of developing endometrial cancer. 222 00:10:15.546 --> 00:10:16.620 In a meta-analysis of 11 studies, 223 00:10:16.620 --> 00:10:19.713 duration of use was found to be inversely related to risk. 224 00:10:20.732 --> 00:10:22.350 That is, the longer one uses contraceptives, 225 00:10:22.350 --> 00:10:25.290 the greater they decrease their risk of... 226 00:10:25.290 --> 00:10:28.353 Or, of developing ovarian or endometrial cancer rather. 227 00:10:29.310 --> 00:10:30.900 Compared to women with no exposure, 228 00:10:30.900 --> 00:10:32.790 12 years of using oral contraceptive 229 00:10:32.790 --> 00:10:35.981 reduced the risk by 72%, 230 00:10:35.981 --> 00:10:36.814 and this effect persisted 231 00:10:36.814 --> 00:10:39.723 for 20 years after discontinuation. 232 00:10:41.867 --> 00:10:44.160 When we look at the genetics of endometrial cancer 233 00:10:44.160 --> 00:10:47.250 to discuss familial inheritance briefly, 234 00:10:47.250 --> 00:10:48.990 we see that type one tumors, 235 00:10:48.990 --> 00:10:51.870 or the estrogen dependent ones, 236 00:10:51.870 --> 00:10:55.380 are related to PTEN mutations and Cowden's Disease. 237 00:10:55.380 --> 00:10:57.300 We also see the type two tumors 238 00:10:57.300 --> 00:10:59.550 are those that are estrogen independent, 239 00:10:59.550 --> 00:11:03.630 are related to familial passage of P53 mutations 240 00:11:03.630 --> 00:11:05.163 and Lynch Syndromes. 241 00:11:06.150 --> 00:11:10.440 Next, we see that there are other key tumors of this system, 242 00:11:10.440 --> 00:11:14.643 though they are much rarer than endometrial tumors. 243 00:11:15.690 --> 00:11:18.570 So, leiomyomas, or fibroid tumors, 244 00:11:18.570 --> 00:11:20.970 are benign tumors with smooth muscle 245 00:11:20.970 --> 00:11:24.720 occurring in 25% of women during reproductive years. 246 00:11:24.720 --> 00:11:27.000 So, these tumors are benign, 247 00:11:27.000 --> 00:11:29.837 and they cause discomfort and bleeding, 248 00:11:29.837 --> 00:11:33.240 and are similar to endometrial cancer 249 00:11:33.240 --> 00:11:35.670 in regard to their risk factors. 250 00:11:35.670 --> 00:11:37.670 They're oftentimes treated with surgery. 251 00:11:38.730 --> 00:11:41.520 Leiomyosarcoma is a rare malignancy 252 00:11:41.520 --> 00:11:44.580 that arises from smooth muscle, or the myometrium, 253 00:11:44.580 --> 00:11:47.594 or connective tissues of the uterus. 254 00:11:47.594 --> 00:11:48.427 The... 255 00:11:48.427 --> 00:11:51.810 Whether they're derived from preexisting benign leiomyomas 256 00:11:51.810 --> 00:11:54.660 remains a highly controversial issue. 257 00:11:54.660 --> 00:11:56.790 Choriocarcinomas are rare tumors 258 00:11:56.790 --> 00:11:59.580 that develop from trophoblastic cells 259 00:11:59.580 --> 00:12:02.820 that ordinarily form the chorionic membranes 260 00:12:02.820 --> 00:12:04.740 of the placenta. 261 00:12:04.740 --> 00:12:08.043 These are malignancies that occur during pregnancy. 262 00:12:09.344 --> 00:12:10.500 The majority of these choriocarcinomas 263 00:12:10.500 --> 00:12:12.640 develop in the endometrium, 264 00:12:12.640 --> 00:12:14.100 though they can also rise in extra uterine sites, 265 00:12:14.100 --> 00:12:15.960 like the ovaries or fallopian tubes 266 00:12:15.960 --> 00:12:18.243 in association with ectopic pregnancy. 267 00:12:19.080 --> 00:12:21.270 Approximately 50% of choriocarcinomas 268 00:12:21.270 --> 00:12:25.260 develop from hydatidiform moles 269 00:12:25.260 --> 00:12:26.970 and 20% are in association 270 00:12:26.970 --> 00:12:29.490 with spontaneous abortions and miscarriages, 271 00:12:29.490 --> 00:12:31.530 20 to 30% in normal pregnancies, 272 00:12:31.530 --> 00:12:34.053 and two to 3% in ectopic pregnancies. 273 00:12:36.810 --> 00:12:40.050 Since these tissues with choriocarcinomas 274 00:12:40.050 --> 00:12:45.050 secrete human chorionic gonadotropin, or HCG, 275 00:12:45.240 --> 00:12:48.120 a marked elevation in the blood tissue of this hormone 276 00:12:48.120 --> 00:12:50.550 serves as an early biomarker of tumor development 277 00:12:50.550 --> 00:12:54.605 and a good tool to be leveraged when screening 278 00:12:54.605 --> 00:12:55.830 for choriocarcinomas. 279 00:12:55.830 --> 00:12:57.573 Again, I'll note that these, 280 00:12:58.680 --> 00:13:01.950 these tissues and compounds 281 00:13:01.950 --> 00:13:03.030 that are not listed on the slide 282 00:13:03.030 --> 00:13:05.039 are in the slide notes below, 283 00:13:05.039 --> 00:13:07.283 so I'd encourage you to check those out if you haven't yet.