WEBVTT 1 00:00:00.660 --> 00:00:02.880 Hi everyone, and welcome to today's lecture 2 00:00:02.880 --> 00:00:05.343 on the epidemiology of cervical cancer. 3 00:00:06.390 --> 00:00:09.122 In this lecture, we have several goals. 4 00:00:09.122 --> 00:00:10.080 We'll begin by describing the global burden 5 00:00:10.080 --> 00:00:11.640 of cervical cancer. 6 00:00:11.640 --> 00:00:13.650 We will look at high risk populations 7 00:00:13.650 --> 00:00:16.350 and discuss the impact of the Pap test. 8 00:00:16.350 --> 00:00:19.620 We'll also look at carcinogenesis by HPV strains. 9 00:00:19.620 --> 00:00:23.400 Look at the synergism of HPV and tobacco carcinogens, 10 00:00:23.400 --> 00:00:28.140 and discuss HIV and HPV co-infection. 11 00:00:28.140 --> 00:00:30.820 Finally, we'll consider cervical cancer prevention 12 00:00:31.774 --> 00:00:34.350 by looking at HPV vaccination strategies. 13 00:00:34.350 --> 00:00:36.630 So to begin with, cancer of uterine cervix 14 00:00:36.630 --> 00:00:38.550 is the third most common cancer diagnosed 15 00:00:38.550 --> 00:00:41.130 among women worldwide behind only breast cancer 16 00:00:41.130 --> 00:00:42.960 and colorectal cancer. 17 00:00:42.960 --> 00:00:47.960 During 2012, 527,624 new cases were diagnosed 18 00:00:48.420 --> 00:00:52.743 and 265,653 women died from cervical cancer. 19 00:00:53.580 --> 00:00:58.580 Nearly 85% of the new cases or 444,546 cases were diagnosed 20 00:01:00.270 --> 00:01:03.090 in women living in low and middle income countries 21 00:01:03.090 --> 00:01:05.100 where cervical cancer was the third leading cause 22 00:01:05.100 --> 00:01:06.360 of cancer deaths, 23 00:01:06.360 --> 00:01:09.630 ranking only behind breast cancer and lung cancer. 24 00:01:09.630 --> 00:01:11.610 Cervical cancer was much less common 25 00:01:11.610 --> 00:01:13.710 in high income countries 26 00:01:13.710 --> 00:01:16.953 where it afflicted only 83,078 women. 27 00:01:18.240 --> 00:01:21.598 The highest incidents and mortality rates were observed 28 00:01:21.598 --> 00:01:24.458 in Sub-Saharan Africa, Melanesia, Latin America, 29 00:01:24.458 --> 00:01:26.880 and the Caribbean, south central Asia, India, 30 00:01:26.880 --> 00:01:29.400 certain nations of South America like Bolivian Guyana 31 00:01:29.400 --> 00:01:31.260 and Southeast Asia. 32 00:01:31.260 --> 00:01:34.079 The public health burden due to cervical cancer 33 00:01:34.079 --> 00:01:35.250 in these nations reflects the virtual absence 34 00:01:35.250 --> 00:01:36.810 of screening programs for the detection 35 00:01:36.810 --> 00:01:38.490 and treatment of pre-cancerous lesions 36 00:01:38.490 --> 00:01:39.723 of the uterine cervix. 37 00:01:40.680 --> 00:01:43.890 For example, in India where screening for cervical cancer 38 00:01:43.890 --> 00:01:46.620 was still largely absent in 2012, 39 00:01:46.620 --> 00:01:50.970 approximately 122,844 women were diagnosed 40 00:01:50.970 --> 00:01:55.890 and 67,477 women died from cervical cancer in 2012. 41 00:01:57.150 --> 00:01:58.980 The woman of most high income countries 42 00:01:58.980 --> 00:02:01.920 and other nations like China have relatively low rates 43 00:02:01.920 --> 00:02:04.830 of cervical cancer, and the incidence and mortality rates 44 00:02:04.830 --> 00:02:07.320 of cervical cancer have declined dramatically among women 45 00:02:07.320 --> 00:02:09.690 of high income countries since the introduction 46 00:02:09.690 --> 00:02:12.330 and widespread use of screening for cervical dysplasia 47 00:02:12.330 --> 00:02:13.953 in the mid 20th century. 48 00:02:15.450 --> 00:02:19.610 As noted, the mortality rates of cervical cancer are high 49 00:02:19.610 --> 00:02:22.473 primarily in low and middle income countries. 50 00:02:23.370 --> 00:02:26.880 In 2020, cervical cancer had an age standardized incidence 51 00:02:26.880 --> 00:02:29.150 of 13.3 per 100,000 women, 52 00:02:29.150 --> 00:02:33.246 and a mortality of 7.3 per 100,000 women. 53 00:02:33.246 --> 00:02:36.840 When we look at the early detection of cervical dysplasia, 54 00:02:36.840 --> 00:02:40.392 we see lots of successes in high income countries. 55 00:02:40.392 --> 00:02:42.900 In the early decades of the 20th century 56 00:02:42.900 --> 00:02:44.610 cancer of the cervix was the leading cause 57 00:02:44.610 --> 00:02:47.340 of cancer mortality among American women. 58 00:02:47.340 --> 00:02:50.310 But since 1955, mortality due to cervical cancer 59 00:02:50.310 --> 00:02:52.680 has declined by 74%. 60 00:02:52.680 --> 00:02:55.150 Today, cancer of the cervix ranks 14th 61 00:02:56.410 --> 00:02:58.110 in female cancer mortality accounting for approximately 62 00:02:58.974 --> 00:03:00.990 4,000 deaths per year in the US. 63 00:03:00.990 --> 00:03:02.790 The dramatic reduction in cervical cancer 64 00:03:02.790 --> 00:03:05.240 among women have developed nations is due largely 65 00:03:06.114 --> 00:03:07.490 to the effectiveness of 66 00:03:07.490 --> 00:03:10.200 the Papanicolaou-Traut Cytological test. 67 00:03:10.200 --> 00:03:13.140 The Pap test, as it's also known, was introduced in the US 68 00:03:13.140 --> 00:03:16.230 around 1950, and it provides a quick, safe, affordable, 69 00:03:16.230 --> 00:03:19.380 and accurate means of detecting pre-cancerous lesions 70 00:03:19.380 --> 00:03:21.300 of the cervix that can be cured 71 00:03:21.300 --> 00:03:24.150 by simple surgery or other techniques. 72 00:03:24.150 --> 00:03:27.110 It's important to note that in situ cervical cancer 73 00:03:27.110 --> 00:03:28.443 is a hundred percent curable 74 00:03:28.443 --> 00:03:30.960 by appropriate surgical techniques. 75 00:03:30.960 --> 00:03:33.780 Advanced stage cervical cancer, which has not spread beyond 76 00:03:33.780 --> 00:03:37.560 the cervix is 80 to 90% curable by surgery. 77 00:03:37.560 --> 00:03:39.510 And the importance of cervical cancer screening 78 00:03:39.510 --> 00:03:41.520 coupled with appropriate therapy is underscored 79 00:03:41.520 --> 00:03:43.670 by differences in cervical cancer mortality 80 00:03:44.595 --> 00:03:47.460 in populations with high versus low screening rates. 81 00:03:47.460 --> 00:03:50.100 Public health programs to inform and educate the population 82 00:03:50.100 --> 00:03:52.100 as to the efficacy of cervical screening 83 00:03:53.279 --> 00:03:55.015 by appropriate implementation of Papanicolaou 84 00:03:55.015 --> 00:03:58.560 cytological testing in early age are therefore imperative. 85 00:03:58.560 --> 00:04:00.960 Evaluation of the pap smear has also resulted 86 00:04:00.960 --> 00:04:03.390 in critical information regarding carcinogens, 87 00:04:03.390 --> 00:04:06.030 and in fact more is known about the natural history 88 00:04:06.030 --> 00:04:08.493 of cervical cancer than any other malignancy. 89 00:04:10.260 --> 00:04:12.540 Though the Pap test has produced substantial declines 90 00:04:12.540 --> 00:04:14.970 in cervical cancer incidents and mortality, 91 00:04:14.970 --> 00:04:18.020 it's noteworthy that marked disparities persist 92 00:04:18.020 --> 00:04:19.350 among the subpopulations with certain nations 93 00:04:19.350 --> 00:04:22.838 perhaps due to excess risk, lack of screening, 94 00:04:22.838 --> 00:04:24.600 and limited healthcare access. 95 00:04:24.600 --> 00:04:27.719 This point really emphasizes that access to healthcare 96 00:04:27.719 --> 00:04:31.710 or health outcomes are really driven by social 97 00:04:31.710 --> 00:04:33.783 and structural determinants of health, 98 00:04:34.837 --> 00:04:37.560 and that healthcare access to the Pap test is a key factor 99 00:04:37.560 --> 00:04:41.460 in decreasing the rates of cervical cancer. 100 00:04:41.460 --> 00:04:44.520 So for example, as this chart shows among US women, 101 00:04:44.520 --> 00:04:47.480 the mortality rate for African Americans is still 102 00:04:47.480 --> 00:04:49.080 nearly twice that of Caucasians. 103 00:04:53.640 --> 00:04:56.160 Cancer of the uterine cervix almost always originates 104 00:04:56.160 --> 00:04:59.160 at the squamocolumnar junction of the cervical os, 105 00:04:59.160 --> 00:05:02.460 in the transitional area between the cervix and the vagina. 106 00:05:02.460 --> 00:05:05.310 It's at this border that the columnar epithelium 107 00:05:05.310 --> 00:05:08.190 of the cervix transforms into the squamous cell epithelium 108 00:05:08.190 --> 00:05:10.680 of the vagina, and the vast majority, 109 00:05:10.680 --> 00:05:15.390 or 95% of cervical cancers are of the squamous cell variety. 110 00:05:15.390 --> 00:05:17.730 However, a few adenous carcinomas evolve 111 00:05:17.730 --> 00:05:18.930 from the cervical glands, 112 00:05:18.930 --> 00:05:21.090 and in fact some of the cervical malignancies 113 00:05:21.090 --> 00:05:22.473 are of the mixed variety. 114 00:05:23.340 --> 00:05:25.860 Carcinoma of the cervix arises from a series 115 00:05:25.860 --> 00:05:28.950 of stepwise epithelial changes ranging from progressively 116 00:05:28.950 --> 00:05:31.680 more severe dysplasia to carcinoma in situ 117 00:05:31.680 --> 00:05:34.560 and ultimately invasive carcinoma. 118 00:05:34.560 --> 00:05:37.500 And that's depicted in this figure that shows a progression 119 00:05:37.500 --> 00:05:41.518 of cancer development in the cervix. 120 00:05:41.518 --> 00:05:44.850 While carcinoma of the cervix may occur at any age 121 00:05:44.850 --> 00:05:47.130 following puberty, the peak incidence is about 30 122 00:05:47.130 --> 00:05:49.320 to 40 years of age for in situ lesions 123 00:05:49.320 --> 00:05:51.993 and 40 to 50 years of age for invasive cancer. 124 00:05:53.658 --> 00:05:57.690 There's several risk factors for cervical cancer. 125 00:05:57.690 --> 00:06:01.023 These include early age at first intercourse, 126 00:06:01.023 --> 00:06:03.173 a high parity or a high number of children, 127 00:06:04.099 --> 00:06:05.748 multiple sexual partners, 128 00:06:05.748 --> 00:06:07.080 contact with high risk sexual partners, 129 00:06:07.080 --> 00:06:11.553 cigarette smoking, and human papilloma virus or HPV. 130 00:06:13.920 --> 00:06:18.920 There's a couple different pathways that can occur 131 00:06:20.070 --> 00:06:23.910 when one is infected with HPV, so it's important to note 132 00:06:23.910 --> 00:06:27.120 that with HPV there's low and high risk strains as depicted 133 00:06:27.120 --> 00:06:32.120 on this chart, and we see that the high risk strains, 134 00:06:35.114 --> 00:06:37.993 16, 18, and 31 are really those that are important 135 00:06:37.993 --> 00:06:39.870 for driving cancer development. 136 00:06:39.870 --> 00:06:43.860 There's a number of steps involved in this pathway 137 00:06:43.860 --> 00:06:46.997 from HPV infection to cervical cancer, 138 00:06:46.997 --> 00:06:51.180 but it's key that they lead to an increase 139 00:06:51.180 --> 00:06:53.850 in cell proliferation, no maturation, 140 00:06:53.850 --> 00:06:56.760 and clonal selection for cancerous cells. 141 00:06:56.760 --> 00:07:01.590 We also see that co carcinogens play a role like HIV 142 00:07:01.590 --> 00:07:05.190 and nitrous amines that can promote 143 00:07:05.190 --> 00:07:06.490 the development of cancer. 144 00:07:08.220 --> 00:07:12.870 We also see that there's a synergistic effect 145 00:07:12.870 --> 00:07:16.590 between smoking and infection with HPV 16. 146 00:07:16.590 --> 00:07:19.350 So molecular studies show that HPV infection 147 00:07:19.350 --> 00:07:22.419 coupled with low dose nitrosamines, 148 00:07:22.419 --> 00:07:24.600 are resulting from cigarette smoke and the cervical mucosa 149 00:07:24.600 --> 00:07:25.980 of cigarette smokers, 150 00:07:25.980 --> 00:07:30.630 synergistically promote carcinogenesis. 151 00:07:30.630 --> 00:07:32.207 That's because HPV strain 16 152 00:07:32.207 --> 00:07:35.340 and 18 interact with the ras gene 153 00:07:35.340 --> 00:07:38.160 in causing transformed tumorigenic foci 154 00:07:38.160 --> 00:07:40.620 in cultured cervical cells. 155 00:07:40.620 --> 00:07:43.380 Male partners of women with cervical cancer develop lesions 156 00:07:43.380 --> 00:07:45.780 of their genitalia harboring HPV 16 157 00:07:45.780 --> 00:07:50.382 and HPV 18 from which they spread to women. 158 00:07:50.382 --> 00:07:55.382 These strains of HPV also are thought to play key risk roles 159 00:07:56.250 --> 00:07:59.310 in other squamous cell tumors or proliferation of lesions 160 00:07:59.310 --> 00:08:01.203 of the skin and mucus membranes. 161 00:08:02.370 --> 00:08:06.870 Other risk factors include HIV/AIDS and immunosuppression. 162 00:08:06.870 --> 00:08:10.258 That is when immunosuppression takes place, 163 00:08:10.258 --> 00:08:14.670 there is a synergistic interaction between HIV 164 00:08:14.670 --> 00:08:17.250 and oncogenic HPV strains, 165 00:08:17.250 --> 00:08:20.253 which can lead to development of cervical cancer. 166 00:08:21.330 --> 00:08:24.420 As noted previously, chronic inflammation is also 167 00:08:24.420 --> 00:08:28.830 a key driver of cancer development as related to expression 168 00:08:28.830 --> 00:08:31.803 of the cyclooxygenase-2 or COX-2 gene. 169 00:08:34.350 --> 00:08:37.380 Finally, some key steps for cervical cancer prevention 170 00:08:37.380 --> 00:08:40.470 and control include abstinence from sexual contact, 171 00:08:40.470 --> 00:08:43.770 monogamy, condom use, avoidance of tobacco, 172 00:08:43.770 --> 00:08:46.121 regular screening by Papanicolaou cytological testing, 173 00:08:46.121 --> 00:08:50.880 and vaccination against high risk HPV strains. 174 00:08:50.880 --> 00:08:54.930 And to dig a little bit deeper into that vaccination step, 175 00:08:54.930 --> 00:08:57.360 there's two key effective vaccines 176 00:08:57.360 --> 00:09:01.680 for use against human papillomavirus. 177 00:09:01.680 --> 00:09:05.400 The first, Gardasil, is produced by Merck 178 00:09:05.400 --> 00:09:08.737 and it prevents the infection by HPV type six, 179 00:09:08.737 --> 00:09:10.140 11, 16, and 18. 180 00:09:10.140 --> 00:09:14.101 And the second, Cervarix, produced by GlaxoSmithKline 181 00:09:14.101 --> 00:09:19.101 or GSK prevented infections by HPV strains 16 and 18. 182 00:09:19.110 --> 00:09:21.210 These vaccines are high cost 183 00:09:21.210 --> 00:09:24.570 which can prevent their utility in being administered 184 00:09:24.570 --> 00:09:26.790 in low income countries. 185 00:09:26.790 --> 00:09:31.440 And really their utility is limited 186 00:09:31.440 --> 00:09:34.740 in broad scale vaccination campaigns 187 00:09:34.740 --> 00:09:37.650 or prevention of cervical cancer campaigns. 188 00:09:37.650 --> 00:09:41.040 They also need to be administered for exposure to HPV 189 00:09:41.040 --> 00:09:43.740 and they should be used in conjunction with screening.