WEBVTT 1 00:00:00.450 --> 00:00:03.293 Hi everyone, and welcome to this lecture 2 00:00:03.293 --> 00:00:06.870 on the Epidemiology of Vaginal, Vulvar, and Anal Cancer. 3 00:00:06.870 --> 00:00:08.760 In this lecture, we have several goals. 4 00:00:08.760 --> 00:00:10.530 We'll begin by describing the global burden 5 00:00:10.530 --> 00:00:12.840 of vaginal, vulvar, and anal cancer. 6 00:00:12.840 --> 00:00:15.090 We'll look at high risk populations. 7 00:00:15.090 --> 00:00:16.990 We'll discuss diethylstilbestrol 8 00:00:18.240 --> 00:00:22.560 and clear cell vaginal cancer, squamous cell carcinomas, 9 00:00:22.560 --> 00:00:24.660 and prevention and control. 10 00:00:24.660 --> 00:00:26.280 Finally, we'll circle back to looking 11 00:00:26.280 --> 00:00:28.383 at HPV vaccination strategies. 12 00:00:31.200 --> 00:00:33.630 So epidemiological features of vaginal, 13 00:00:33.630 --> 00:00:36.150 vulvar, and anal cancer are similar to cervical cancer 14 00:00:36.150 --> 00:00:38.130 since all are etiologically linked 15 00:00:38.130 --> 00:00:40.080 to infection of the respective tissues 16 00:00:40.080 --> 00:00:44.310 by oncogenic strains of human papillomavirus, or HPV. 17 00:00:44.310 --> 00:00:46.410 However, the global burden of cervical cancer 18 00:00:46.410 --> 00:00:49.410 is nearly tenfold higher than the combined impact 19 00:00:49.410 --> 00:00:52.530 of malignancies of the vagina, vulva, and anus. 20 00:00:52.530 --> 00:00:55.140 During 2012 cancers of the vagina, 21 00:00:55.140 --> 00:00:56.700 vulva, and anus were diagnosed in 22 00:00:56.700 --> 00:00:59.643 about 56,000 women and caused 31,000 deaths. 23 00:01:00.480 --> 00:01:03.480 Anal cancer also afflicts about 14,000 men each year 24 00:01:03.480 --> 00:01:06.453 causing an additional 8,000 deaths in the male population. 25 00:01:09.150 --> 00:01:12.210 Molecular studies have documented the presence of HPV DNA 26 00:01:12.210 --> 00:01:15.480 in a high proportion of other anogenital carcinomas, 27 00:01:15.480 --> 00:01:18.090 as well as their precursor lesions. 28 00:01:18.090 --> 00:01:20.370 And chronic anogenital infections 29 00:01:20.370 --> 00:01:23.709 due to oncogenic HPV strains, again HPV 16 30 00:01:23.709 --> 00:01:26.880 and 18 are those oncogenic strains, are estimated 31 00:01:26.880 --> 00:01:30.330 to cause approximately 88% of anal cancers, 32 00:01:30.330 --> 00:01:35.193 70% of vaginal cancers, and 43% of vulvar cancers. 33 00:01:36.840 --> 00:01:40.980 Cancer develops when the DNA from oncogenic HPV strains 34 00:01:40.980 --> 00:01:44.160 and integrate with the DNA of host cells in the cervix, 35 00:01:44.160 --> 00:01:46.800 vagina, vulva, anus, and other tissues. 36 00:01:46.800 --> 00:01:48.930 Integration of viral genes into the genome 37 00:01:48.930 --> 00:01:51.300 of the invaded epithelial cells leads 38 00:01:51.300 --> 00:01:53.730 to the over expression of certain viral genes, 39 00:01:53.730 --> 00:01:57.870 like E6 and E7, that inactivate tumor suppressor genes, 40 00:01:57.870 --> 00:02:02.870 like p53 and Rb, or upregulate protooncogenic genes, 41 00:02:04.350 --> 00:02:06.483 such as ras and telomerase. 42 00:02:08.010 --> 00:02:10.380 Potential co-factors include chronic exposure 43 00:02:10.380 --> 00:02:12.150 to tobacco carcinogens, 44 00:02:12.150 --> 00:02:15.420 systematic HIV-related immunosuppression, and co-infection 45 00:02:15.420 --> 00:02:20.013 by other genital viruses like HSV2, and bacteria. 46 00:02:21.240 --> 00:02:23.250 Key steps in this process are illustrated 47 00:02:23.250 --> 00:02:24.753 in the figure on the slide. 48 00:02:26.070 --> 00:02:29.100 The global distribution of HPV infections 49 00:02:29.100 --> 00:02:31.410 is shown on this slide, the prevalence 50 00:02:31.410 --> 00:02:34.680 of HPV infection in cervical tissues is high. 51 00:02:34.680 --> 00:02:37.500 And over 20% among asymptomatic women living 52 00:02:37.500 --> 00:02:39.990 in sub-Saharan Africa, Central America, 53 00:02:39.990 --> 00:02:42.150 South America, and Southeast Asia. 54 00:02:42.150 --> 00:02:44.910 And low or less than 10% in those living 55 00:02:44.910 --> 00:02:49.650 in North America, Western Europe, Scandinavia, and Oceania. 56 00:02:49.650 --> 00:02:51.060 The pattern is a virtual image 57 00:02:51.060 --> 00:02:53.070 of the distribution of cervical cancer incidence, 58 00:02:53.070 --> 00:02:54.720 and approximates the global pattern 59 00:02:54.720 --> 00:02:57.243 of vaginal, vulvar, and anal carcinoma. 60 00:02:58.890 --> 00:03:01.050 So, as we discussed previously, 61 00:03:01.050 --> 00:03:04.680 there's two different pathways that HPV infection 62 00:03:04.680 --> 00:03:07.230 can go depending on whether one is infected 63 00:03:07.230 --> 00:03:10.053 with low risk strains or high risk strains. 64 00:03:11.880 --> 00:03:14.430 We also see that chronic HIV infection increases 65 00:03:14.430 --> 00:03:16.560 the risk of developing multiple other cancers, 66 00:03:16.560 --> 00:03:19.410 including those related to HPV infection. 67 00:03:19.410 --> 00:03:23.190 Among patients with HIV/AIDS, all HPV associated cancers 68 00:03:23.190 --> 00:03:25.260 occurred in significant excess 69 00:03:25.260 --> 00:03:28.290 of the excess rates in the general population. 70 00:03:28.290 --> 00:03:30.150 Invasive malignancies of the cervix, 71 00:03:30.150 --> 00:03:31.950 vagina, vulva, and anus were increased 72 00:03:31.950 --> 00:03:34.920 more than fivefold among HIV-infected women. 73 00:03:34.920 --> 00:03:37.440 And malignancies of the anus and penis were increased 74 00:03:37.440 --> 00:03:41.043 by 38 fold, and fourfold among HIV-infected men. 75 00:03:44.340 --> 00:03:47.850 In 2020, the age-standardized incidence 76 00:03:47.850 --> 00:03:51.390 of vaginal cancer was 0.36/100,000 77 00:03:51.390 --> 00:03:56.130 and the mortality was 0.16/100,000. 78 00:03:56.130 --> 00:03:58.140 Vaginal cancer is an uncommon malignancy 79 00:03:58.140 --> 00:04:01.290 accounting for less than 0.3% of all female cancers 80 00:04:01.290 --> 00:04:03.480 and about 1 to 2% of malignancies 81 00:04:03.480 --> 00:04:05.640 of the female genital tract. 82 00:04:05.640 --> 00:04:08.550 During 2008, approximately 13,000 new cases 83 00:04:08.550 --> 00:04:11.250 of vaginal cancer were diagnosed in the world. 84 00:04:11.250 --> 00:04:14.100 And of these, 8,000 occurred in women living in low, 85 00:04:14.100 --> 00:04:15.500 and middle income countries. 86 00:04:18.420 --> 00:04:20.490 In 2020, the age-standardized incidence 87 00:04:20.490 --> 00:04:23.250 of vulvar cancer was 0.85/100,000 women 88 00:04:23.250 --> 00:04:26.850 and the mortality was 0.30/100,000 women. 89 00:04:26.850 --> 00:04:29.160 This carcinoma accounts for about 1 to 2% 90 00:04:29.160 --> 00:04:31.680 of all malignancies of the female genitalia. 91 00:04:31.680 --> 00:04:35.220 And worldwide vulvar cancer was diagnosed in 27,000 women 92 00:04:35.220 --> 00:04:39.180 during 2008 and caused nearly 15,000 deaths. 93 00:04:39.180 --> 00:04:40.980 Vulvar cancer rarely manifests 94 00:04:40.980 --> 00:04:43.620 in a woman under the age of 60 years. 95 00:04:43.620 --> 00:04:46.020 It is preceded by pre-malignant lesions 96 00:04:46.020 --> 00:04:49.233 called vulgar intraepithelial neoplasia. 97 00:04:51.060 --> 00:04:53.160 Anal cancer in 2020 exhibited 98 00:04:53.160 --> 00:04:57.930 an overall age-standardized incidence of 0.54/100,000 99 00:04:57.930 --> 00:05:01.230 with a slightly higher incidence rate among women. 100 00:05:01.230 --> 00:05:05.460 The mortality rate was 0.20/100,000 people 101 00:05:05.460 --> 00:05:07.920 with an approximately equal mortality rate 102 00:05:07.920 --> 00:05:09.660 between men and women. 103 00:05:09.660 --> 00:05:11.790 Anal cancer is also relatively uncommon, 104 00:05:11.790 --> 00:05:13.530 and it comprises only 2 to 3% 105 00:05:13.530 --> 00:05:15.723 of all gastrointestinal malignancies. 106 00:05:17.250 --> 00:05:19.260 And more than 90% of anal malignancies 107 00:05:19.260 --> 00:05:21.690 are squamous cell carcinomas, and the remainder 108 00:05:21.690 --> 00:05:23.390 are predominantly adenocarcinomas. 109 00:05:24.244 --> 00:05:27.060 Sarcomas and malignant melanomas very rarely develop 110 00:05:27.060 --> 00:05:29.283 from tissues of the anal canal. 111 00:05:30.120 --> 00:05:32.010 The incidence of anal cancer has more than doubled 112 00:05:32.010 --> 00:05:33.510 in some populations in recent years 113 00:05:33.510 --> 00:05:35.970 in association with increasing risks 114 00:05:35.970 --> 00:05:40.443 of STIs like HPV, HSV2 and HIV. 115 00:05:41.580 --> 00:05:42.960 Other significant risk factors 116 00:05:42.960 --> 00:05:44.760 include receptive anal intercourse, 117 00:05:44.760 --> 00:05:48.603 history of genital warts, and chronic cigarette smoking. 118 00:05:50.190 --> 00:05:53.160 Most vaginal malignancies, 90 to 95%, 119 00:05:53.160 --> 00:05:54.930 are squamous cell carcinomas that arise 120 00:05:54.930 --> 00:05:56.340 from the vaginal epithelium 121 00:05:56.340 --> 00:05:59.010 distal to the opening of the cervix. 122 00:05:59.010 --> 00:06:01.320 The other prominent cell type of vaginal cancer 123 00:06:01.320 --> 00:06:02.820 is clear cell adenocarcinoma 124 00:06:02.820 --> 00:06:06.960 which is caused by in-utero exposure to diethylstilbestrol, 125 00:06:06.960 --> 00:06:10.083 or DES, which is a synthetic form of estrogen. 126 00:06:11.190 --> 00:06:14.490 The onset of vaginal cancer differs markedly 127 00:06:14.490 --> 00:06:16.560 according to histologic cell type. 128 00:06:16.560 --> 00:06:18.330 For example, squamous cell carcinomas 129 00:06:18.330 --> 00:06:21.600 of the vagina are predominantly diagnosed in adult women 130 00:06:21.600 --> 00:06:25.470 whereas clear cell adenocarcinomas are found in young girls. 131 00:06:25.470 --> 00:06:26.970 Squamous cell carcinomas are linked 132 00:06:26.970 --> 00:06:29.010 to exposure to oncogenic HPV strains 133 00:06:29.010 --> 00:06:31.590 through sexual activity with multiple partners, 134 00:06:31.590 --> 00:06:35.520 co-infection by HIV, and chronic cigarette smoking. 135 00:06:35.520 --> 00:06:38.100 While in contrast, clear cell adenocarcinomas 136 00:06:38.100 --> 00:06:42.450 arise due to in-utero exposure to carcinogenic agent DES, 137 00:06:42.450 --> 00:06:44.253 or that synthetic estrogen. 138 00:06:46.140 --> 00:06:49.899 Clear cell... So clear cell adenocarcinomas result 139 00:06:49.899 --> 00:06:52.743 from exposure in-utero to DES. 140 00:06:54.698 --> 00:06:57.750 A routine practice in the US and throughout Europe 141 00:06:57.750 --> 00:07:00.960 during 1940 to 1971 was to administer DES 142 00:07:00.960 --> 00:07:03.630 to pregnant women with first trimester bleeding 143 00:07:03.630 --> 00:07:05.880 in order to prevent miscarriage, 144 00:07:05.880 --> 00:07:08.190 and premature labor and delivery. 145 00:07:08.190 --> 00:07:10.170 It's estimated that during this time 146 00:07:10.170 --> 00:07:12.480 DES was prescribed to 5 to 10 million women 147 00:07:12.480 --> 00:07:14.823 in the US, and millions more in Europe. 148 00:07:15.780 --> 00:07:17.580 It was soon discovered that daughters 149 00:07:17.580 --> 00:07:19.823 of women treated with DES developed clear cell 150 00:07:19.823 --> 00:07:22.623 adenocarcinomas at an exceptionally high rate, 151 00:07:23.460 --> 00:07:25.680 and this tumor's extraordinarily rare. 152 00:07:25.680 --> 00:07:27.630 And unlike other forms of vaginal cancer 153 00:07:27.630 --> 00:07:30.030 that are usually diagnosed late in life, 154 00:07:30.030 --> 00:07:32.580 clear cell vaginal adenocarcinomas stimulated 155 00:07:32.580 --> 00:07:35.850 by in-utero DES exposure are more often diagnosed 156 00:07:35.850 --> 00:07:36.963 during adolescence. 157 00:07:37.860 --> 00:07:41.100 As we see from this chart in 1981, 400 cases 158 00:07:41.100 --> 00:07:42.660 of clear cell adenocarcinomas in the vagina 159 00:07:42.660 --> 00:07:47.660 had been diagnosed among young women born after 1940. 160 00:07:48.510 --> 00:07:51.930 The number of cases peaked in the US in 1975, 161 00:07:51.930 --> 00:07:56.730 and has since declined, and use of DES was discontinued 162 00:07:56.730 --> 00:08:01.083 in 1972, but it continued in Europe until 1978. 163 00:08:03.540 --> 00:08:06.120 Squamous cell carcinoma arises from a web of causation 164 00:08:06.120 --> 00:08:08.340 that includes multiple risk factors. 165 00:08:08.340 --> 00:08:10.680 These risk factors include early sexual activity 166 00:08:10.680 --> 00:08:12.690 with several partners leading to chronic infection 167 00:08:12.690 --> 00:08:16.770 of the cervical, anal, and vaginal epithelium by HPV 16, 168 00:08:16.770 --> 00:08:21.770 HPV 18, and/or genital Herpes Simplex Virus 2, or HSV2. 169 00:08:22.920 --> 00:08:25.290 Coupled with chronic cigarette smoking. 170 00:08:25.290 --> 00:08:27.660 Immunosuppression due to HIV/AIDS infection 171 00:08:27.660 --> 00:08:29.673 also markedly increases the risk. 172 00:08:32.340 --> 00:08:34.890 So, as mentioned before, more than 90% 173 00:08:34.890 --> 00:08:37.890 of vulvar malignancies are squamous cell carcinomas. 174 00:08:37.890 --> 00:08:40.800 There are two types of squamous cell carcinoma. 175 00:08:40.800 --> 00:08:44.130 The first classic, warty, or bowenoid SCC 176 00:08:44.130 --> 00:08:46.110 is predominantly associated with chronic infection 177 00:08:46.110 --> 00:08:50.160 by HPV 16, 18, or 33, and is often found 178 00:08:50.160 --> 00:08:52.680 in younger women prior to menopause. 179 00:08:52.680 --> 00:08:54.990 Factors associated with malignant transformation 180 00:08:54.990 --> 00:08:57.420 of the vulvar mucosa in HPV infected women 181 00:08:57.420 --> 00:08:59.760 included early age at first intercourse, 182 00:08:59.760 --> 00:09:03.060 multiple sexual partners, HIV infection, 183 00:09:03.060 --> 00:09:05.463 HSV2 infection, and cigarette smoking. 184 00:09:06.660 --> 00:09:10.140 Keratinizing, differentiated, or simple SCC occurs 185 00:09:10.140 --> 00:09:11.820 in older postmenopausal women, 186 00:09:11.820 --> 00:09:14.253 and is not related to HPV infection. 187 00:09:15.600 --> 00:09:17.970 This carcinoma is associated with inflammatory 188 00:09:17.970 --> 00:09:21.780 vulvar distrophies such as lichen sclerosis, 189 00:09:21.780 --> 00:09:25.770 and chronic venereal granulomatous disease. 190 00:09:25.770 --> 00:09:28.230 Vulvar lichen sclerosis is a sinuous 191 00:09:28.230 --> 00:09:30.240 inflammatory condition most commonly found 192 00:09:30.240 --> 00:09:33.903 in older postmenopausal women and girls prior to menarche. 193 00:09:36.480 --> 00:09:39.000 Compared to the general population, the incidence rates 194 00:09:39.000 --> 00:09:42.540 of invasive and in situ anal cancers are increased 195 00:09:42.540 --> 00:09:44.700 more than 100 fold in AIDS afflicted men, 196 00:09:44.700 --> 00:09:47.040 and women less than 30 years of age. 197 00:09:47.040 --> 00:09:48.660 Compared to the general population, 198 00:09:48.660 --> 00:09:50.030 the incidence of invasive carcinoma 199 00:09:50.030 --> 00:09:53.640 of the anus is increased sevenfold among HIV-infected women, 200 00:09:53.640 --> 00:09:56.433 and 38 fold among HIV-infected men. 201 00:09:57.390 --> 00:09:59.550 The incidence of anal cancer increases 202 00:09:59.550 --> 00:10:03.030 with increasing prevalence of men who have sex with men. 203 00:10:03.030 --> 00:10:05.610 Based on linear projections, the incidence of anal cancer 204 00:10:05.610 --> 00:10:07.770 increases more than fivefold when the prevalence 205 00:10:07.770 --> 00:10:10.793 of men who have sex with men exceeds 70%. 206 00:10:12.510 --> 00:10:14.820 So to discuss primary and secondary prevention 207 00:10:14.820 --> 00:10:19.820 of these types of cancer, we see that a key step 208 00:10:20.160 --> 00:10:21.930 for primary prevention, as was discussed 209 00:10:21.930 --> 00:10:24.900 for cervical cancer, is effective use 210 00:10:24.900 --> 00:10:29.900 of the HPV vaccines like Gardasil. 211 00:10:31.710 --> 00:10:34.290 Results of randomized clinical trials have shown up 212 00:10:34.290 --> 00:10:36.360 to 100% efficacy in preventing infection 213 00:10:36.360 --> 00:10:39.420 by oncogenic strains of HPV and reducing 214 00:10:39.420 --> 00:10:40.800 the risk of pre-cancerous lesions 215 00:10:40.800 --> 00:10:43.740 of the cervical, vaginal, and vulvar epithelium 216 00:10:43.740 --> 00:10:45.240 among young women who received 217 00:10:45.240 --> 00:10:47.223 the vaccine prior to infection. 218 00:10:48.660 --> 00:10:51.030 In the absence of symptoms, or major risk factors, 219 00:10:51.030 --> 00:10:53.340 the Pap test is not routinely used for screening 220 00:10:53.340 --> 00:10:55.980 the vagina of the female genital tract. 221 00:10:55.980 --> 00:10:58.530 However, if symptoms are present like bleeding, 222 00:10:58.530 --> 00:11:00.630 pelvic pain, or a palpable mass 223 00:11:00.630 --> 00:11:02.880 the Pap test is an effective diagnostic tool 224 00:11:02.880 --> 00:11:05.220 for the detection of dysplastic epithelial lesions 225 00:11:05.220 --> 00:11:06.813 of the vagina, vulva, and anus. 226 00:11:07.680 --> 00:11:09.300 Such pre-malignant lesions are called 227 00:11:09.300 --> 00:11:11.804 vaginal intraepithelial neoplasia, 228 00:11:11.804 --> 00:11:13.860 vulvar intraepithelial neoplasia, 229 00:11:13.860 --> 00:11:15.840 or anal intraepithelial neoplasia, 230 00:11:15.840 --> 00:11:17.763 and similar to cervical dysplasia. 231 00:11:21.930 --> 00:11:25.950 Finally, this chart depicts some of the names 232 00:11:25.950 --> 00:11:29.460 of common pre-malignant lesions of the urogenital tract, 233 00:11:29.460 --> 00:11:32.460 their classification and their description. 234 00:11:32.460 --> 00:11:35.310 This slide is less important, but I wanted to include it 235 00:11:35.310 --> 00:11:37.770 just in case you wanted more information 236 00:11:37.770 --> 00:11:42.060 about different kinds of pre-malignant lesions 237 00:11:42.060 --> 00:11:44.733 that could lead to malignancies.