WEBVTT 1 00:00:00.660 --> 00:00:01.530 Hi all. 2 00:00:01.530 --> 00:00:03.720 In this lecture, we'll be discussing the epidemiology 3 00:00:03.720 --> 00:00:06.093 of urinary bladder cancer. 4 00:00:06.093 --> 00:00:07.890 The goals of this lecture 5 00:00:07.890 --> 00:00:10.950 are to define the histological forms of bladder cancer, 6 00:00:10.950 --> 00:00:13.051 describe the global burden of bladder cancer, 7 00:00:13.051 --> 00:00:16.470 to review studies of tobacco and bladder cancer, 8 00:00:16.470 --> 00:00:20.850 and to look at the different kinds of bladder cancer cells. 9 00:00:20.850 --> 00:00:24.034 We're also going to look at schistosomiasis 10 00:00:24.034 --> 00:00:27.420 and the related burden of bladder cancer in Egypt, 11 00:00:27.420 --> 00:00:30.495 as well as other environmental risk factors. 12 00:00:30.495 --> 00:00:34.320 So to begin with, to give a brief overview 13 00:00:34.320 --> 00:00:36.180 of the anatomy of the bladder, 14 00:00:36.180 --> 00:00:38.040 we see that urine manufactured by the kidneys 15 00:00:38.040 --> 00:00:40.050 travels to the bladder through the ureters 16 00:00:40.050 --> 00:00:42.360 for storage prior to excretion. 17 00:00:42.360 --> 00:00:43.697 In normal adults, the urinary bladder holds 18 00:00:43.697 --> 00:00:46.575 300 to 600 milliliters of urine, 19 00:00:46.575 --> 00:00:49.050 and the urinary bladder is lined by multiple layers 20 00:00:49.050 --> 00:00:51.780 of transitional epithelium called urothelium, 21 00:00:51.780 --> 00:00:53.010 which expands or contracts 22 00:00:53.010 --> 00:00:55.160 depending on the volume of urine contained. 23 00:00:59.433 --> 00:01:00.873 During 2012, 24 00:01:00.873 --> 00:01:05.873 429,793 new cases were diagnosed in the world population, 25 00:01:06.090 --> 00:01:10.020 and 165,068 died from bladder cancer. 26 00:01:10.020 --> 00:01:14.797 Of these, 77% occurred, 27 00:01:14.797 --> 00:01:19.129 of the cases, and 75% of deaths occurred in men. 28 00:01:19.129 --> 00:01:21.960 The annual age-adjusted incidence rate in men 29 00:01:21.960 --> 00:01:24.240 was nine cases per 100,000, 30 00:01:24.240 --> 00:01:26.820 compared to 2.2 per 100,000 in women, 31 00:01:26.820 --> 00:01:29.940 and the mortality rate was 3.2 deaths per 100,000 in men, 32 00:01:29.940 --> 00:01:33.206 compared to 0.9 per 100,000 in women. 33 00:01:33.206 --> 00:01:35.730 Thus, bladder cancer develops three to four times 34 00:01:35.730 --> 00:01:37.503 more frequently in men than women. 35 00:01:39.840 --> 00:01:42.120 Bladder cancer rates are highest in African nations 36 00:01:42.120 --> 00:01:45.150 and eastern Mediterranean regions, particularly Egypt, 37 00:01:45.150 --> 00:01:46.740 where squama cell bladder cancer arises 38 00:01:46.740 --> 00:01:49.389 due to chronic infection by the parasitic worm, 39 00:01:49.389 --> 00:01:51.450 Schistosoma haematobium. 40 00:01:51.450 --> 00:01:53.070 Rates of transitional cell carcinoma 41 00:01:53.070 --> 00:01:55.380 of the bladder urothelium are highest in Western Europe 42 00:01:55.380 --> 00:01:58.200 and other countries where the prevalence of smoking is high, 43 00:01:58.200 --> 00:01:59.853 particularly among men. 44 00:02:01.081 --> 00:02:04.320 In 2020, the age-standardized incidence of bladder cancer 45 00:02:04.320 --> 00:02:07.092 was 5.6 per 100,000 people overall, 46 00:02:07.092 --> 00:02:10.553 but the rate was 9.5 per 100,000 in men 47 00:02:10.553 --> 00:02:13.440 and 2.4 per 100,000 in women. 48 00:02:13.440 --> 00:02:16.170 Similarly, the mortality is higher in men, 49 00:02:16.170 --> 00:02:20.450 with a 1.9 per 100,000 mortality overall, 50 00:02:20.450 --> 00:02:24.600 though men were dying at a rate of 3.3 per 100,000 51 00:02:24.600 --> 00:02:28.353 while women were dying at rate 0.86 per 100,000 women. 52 00:02:30.452 --> 00:02:31.980 In high income countries 53 00:02:31.980 --> 00:02:33.600 in North America, Europe, and Australia, 54 00:02:33.600 --> 00:02:36.219 most bladder cancers, or approximately 95%, 55 00:02:36.219 --> 00:02:39.420 are transitional cell carcinomas 56 00:02:39.420 --> 00:02:41.610 that arise from the epithelial cell lining 57 00:02:41.610 --> 00:02:43.931 of the bladder or the urothelium. 58 00:02:43.931 --> 00:02:46.440 The urothelium undergoes a stepwise process of changes 59 00:02:46.440 --> 00:02:49.080 from mild to severe dysplasia that result in the formation 60 00:02:49.080 --> 00:02:51.321 of non-invasive papillary carcinoma in situ, 61 00:02:51.321 --> 00:02:53.550 and ultimately, invasive cancer 62 00:02:53.550 --> 00:02:55.890 that penetrates the basement membrane. 63 00:02:55.890 --> 00:02:58.110 Transitional cell carcinomas of the urinary bladder 64 00:02:58.110 --> 00:03:00.960 often show multiple cancerous foci at the time of diagnosis, 65 00:03:00.960 --> 00:03:03.060 a phenomenon known as field cancerization. 66 00:03:04.410 --> 00:03:05.970 In low- and middle-income countries 67 00:03:05.970 --> 00:03:07.500 of Africa and Southern Asia, 68 00:03:07.500 --> 00:03:09.660 the predominant histological type of bladder cancer 69 00:03:09.660 --> 00:03:11.010 is squamous cell carcinoma, 70 00:03:11.010 --> 00:03:14.512 which arises due to chronic infection by the parasitic worm, 71 00:03:14.512 --> 00:03:17.220 Schistosoma haematobium. 72 00:03:17.220 --> 00:03:20.100 Chronic infection of the bladder by these parasites 73 00:03:20.100 --> 00:03:22.440 causes sustained local inflammation, irritation 74 00:03:22.440 --> 00:03:24.082 and subsequent reparative hyperplasia 75 00:03:24.082 --> 00:03:25.980 and squamous metaplasia, 76 00:03:25.980 --> 00:03:27.780 in which the normal urothelial cells 77 00:03:27.780 --> 00:03:30.180 are replaced by squamous cells. 78 00:03:30.180 --> 00:03:31.860 These changes in the bladder mucosa 79 00:03:31.860 --> 00:03:34.263 eventually progress to squamous cell carcinoma. 80 00:03:35.910 --> 00:03:37.080 The dominant risk factor 81 00:03:37.080 --> 00:03:39.000 for transitional cell urinary bladder cancer 82 00:03:39.000 --> 00:03:40.620 is cigarette smoking. 83 00:03:40.620 --> 00:03:42.990 Tobacco use accounts for about two thirds of new cases 84 00:03:42.990 --> 00:03:45.900 in men and about one third of new cases in women. 85 00:03:45.900 --> 00:03:48.000 Epidemiologic cohort and case control studies 86 00:03:48.000 --> 00:03:50.370 have consistently observed two to threefold increases 87 00:03:50.370 --> 00:03:51.780 in the relative risk of developing 88 00:03:51.780 --> 00:03:54.990 transitional cell bladder cancer among chronic smokers, 89 00:03:54.990 --> 00:03:56.670 compared to non-smokers, 90 00:03:56.670 --> 00:03:58.590 as well as dose-response relationships 91 00:03:58.590 --> 00:04:02.100 with the number of cigarette smoked and duration of smoking. 92 00:04:02.100 --> 00:04:04.650 Cigarette smoking shows similar effects for men and women, 93 00:04:04.650 --> 00:04:05.730 as well as for individuals 94 00:04:05.730 --> 00:04:07.980 with different ethnic backgrounds. 95 00:04:07.980 --> 00:04:10.530 Urinary bladder carcinogenesis associated with smoking 96 00:04:10.530 --> 00:04:14.130 is primarily the result of aromatic amines and arylamines 97 00:04:14.130 --> 00:04:16.560 present in cigarette smoke that reach to the bladder mucosa, 98 00:04:16.560 --> 00:04:19.350 such as benzidine, 4-aminobiphenyl, 99 00:04:19.350 --> 00:04:24.350 2-naphthylamine, and 4-chloro-orthotoluidine. 100 00:04:26.490 --> 00:04:28.590 Molecular investigations show that these compounds 101 00:04:28.590 --> 00:04:30.930 are ultimately bio-transformed or activated 102 00:04:30.930 --> 00:04:32.310 in the acidic environment of the bladder 103 00:04:32.310 --> 00:04:35.523 to form potent DNA-reactive carcinogens. 104 00:04:37.124 --> 00:04:39.750 The common practice of smoking black tobacco 105 00:04:39.750 --> 00:04:41.821 may thus explain the high rates of bladder cancer 106 00:04:41.821 --> 00:04:44.155 observed among men in Spain, Italy, 107 00:04:44.155 --> 00:04:46.503 the Netherlands, and Uruguay. 108 00:04:49.500 --> 00:04:52.260 Squamous cell carcinoma of the bladder frequently develop 109 00:04:52.260 --> 00:04:56.070 due to chronic infection by the Schistosoma haematobium. 110 00:04:56.070 --> 00:04:57.960 The parasite is endemic to the Nile River, 111 00:04:57.960 --> 00:04:59.460 but is also found throughout Africa, 112 00:04:59.460 --> 00:05:01.350 in some parts of Southeast Asia, 113 00:05:01.350 --> 00:05:04.710 and on the islands of Cyprus and southern Portugal. 114 00:05:04.710 --> 00:05:07.110 It has been estimated that 85% of Egyptians 115 00:05:07.110 --> 00:05:08.970 become infected with the parasite in their lifetimes, 116 00:05:08.970 --> 00:05:10.290 which accounts for the astounding fact 117 00:05:10.290 --> 00:05:11.910 that bladder cancer accounts for 30% 118 00:05:11.910 --> 00:05:14.784 of all malignant neoplasms in Egypt. 119 00:05:14.784 --> 00:05:16.650 Schistosome worms mature in the liver 120 00:05:16.650 --> 00:05:18.480 and migrate to the plexus of blood vessels, 121 00:05:18.480 --> 00:05:21.750 which nourish nourish the bladder and pelvic organs. 122 00:05:21.750 --> 00:05:25.560 Female worms deposit their eggs in the walls of the bladder, 123 00:05:25.560 --> 00:05:28.860 uterus, prostate, or other pelvic organs. 124 00:05:28.860 --> 00:05:31.350 Chronic parasitic infection produces chronic inflammation 125 00:05:31.350 --> 00:05:32.940 of the bladder urothelium, 126 00:05:32.940 --> 00:05:34.230 which may ultimately transform 127 00:05:34.230 --> 00:05:38.398 into squamous metaplasia and carcinoma. 128 00:05:38.398 --> 00:05:40.830 Schistosomes are dioecious, and the two sexes 129 00:05:40.830 --> 00:05:43.260 mature and reproduce in the vascular system. 130 00:05:43.260 --> 00:05:44.850 The eggs are laid in small blood vessels 131 00:05:44.850 --> 00:05:47.010 and then liberated into the lumen of the intestines 132 00:05:47.010 --> 00:05:48.183 or the urinary bladder. 133 00:05:49.260 --> 00:05:50.910 Schistosome eggs hatch when they reach fresh water, 134 00:05:50.910 --> 00:05:52.234 and the newborn form of the worm 135 00:05:52.234 --> 00:05:55.590 swims in search of an appropriate snail host. 136 00:05:55.590 --> 00:05:57.750 After getting into the snail, 137 00:05:57.750 --> 00:06:01.680 the parasite develops into another form called cercariae, 138 00:06:01.680 --> 00:06:03.283 which is liberated into the fresh water again 139 00:06:03.283 --> 00:06:05.460 and penetrates the swimmers, 140 00:06:05.460 --> 00:06:08.040 the skin of swimmers and bathers. 141 00:06:08.040 --> 00:06:09.450 Upon entering the human, 142 00:06:09.450 --> 00:06:11.430 the parasite reaches the circulation in the liver 143 00:06:11.430 --> 00:06:12.880 and the cycle repeats itself. 144 00:06:15.180 --> 00:06:17.700 The disease caused by infectious schistosomes 145 00:06:17.700 --> 00:06:19.226 is called schistosomiasis, 146 00:06:19.226 --> 00:06:21.814 and it is a neglected tropical disease, 147 00:06:21.814 --> 00:06:24.723 meaning that the, 148 00:06:26.010 --> 00:06:28.728 it primarily infects individuals living in tropical regions 149 00:06:28.728 --> 00:06:30.960 and low- and middle-income countries. 150 00:06:30.960 --> 00:06:34.180 Consequently, there's little funding 151 00:06:34.180 --> 00:06:39.180 devoted to combating schistosomiasis and finding solutions 152 00:06:40.674 --> 00:06:44.677 or vaccinations against infection with schistosomes. 153 00:06:46.166 --> 00:06:48.877 A large number of environmental and occupational factors 154 00:06:48.877 --> 00:06:51.350 increase the risk of bladder cancer. 155 00:06:51.350 --> 00:06:54.698 These include occupational exposure to arylamines, 156 00:06:54.698 --> 00:06:57.000 such as those listed on the slide, 157 00:06:57.000 --> 00:06:59.420 and other compounds and intermediates in the synthesis 158 00:06:59.420 --> 00:07:02.460 of azo-dyes and pigments used in the textile, 159 00:07:02.460 --> 00:07:05.790 printing, plastic, rubber and cable industries. 160 00:07:05.790 --> 00:07:07.500 Long-term exposure to these compounds 161 00:07:07.500 --> 00:07:08.910 among workers in these industries 162 00:07:08.910 --> 00:07:12.450 increases the risk of bladder cancer by about 50%. 163 00:07:12.450 --> 00:07:14.627 Workers in aluminum production, 164 00:07:14.627 --> 00:07:17.100 yellow and magenta dye manufacturing 165 00:07:17.100 --> 00:07:19.650 and coal gasification may also be an increased risk 166 00:07:19.650 --> 00:07:21.330 because of sustained exposure to a variety 167 00:07:21.330 --> 00:07:23.460 of chemicals that reach to the bladder mucosa, 168 00:07:23.460 --> 00:07:26.010 including polycyclic aromatic hydrocarbons, 169 00:07:26.010 --> 00:07:30.090 polychlorinated biphenyls, formaldehyde and solvents. 170 00:07:30.090 --> 00:07:31.830 The uncertainties surrounding the hazards 171 00:07:31.830 --> 00:07:34.350 posed by these occupations is partly attributable 172 00:07:34.350 --> 00:07:36.330 to the difficulty of measuring past exposure 173 00:07:36.330 --> 00:07:38.103 to specific chemical agents. 174 00:07:39.768 --> 00:07:43.140 The analgesic medication, phenacetin, 175 00:07:43.140 --> 00:07:46.230 was once widely used in European nations 176 00:07:46.230 --> 00:07:47.550 until the drug was linked to cancers 177 00:07:47.550 --> 00:07:50.400 of the renal pelvis and urinary bladder. 178 00:07:50.400 --> 00:07:52.020 A case control investigation found 179 00:07:52.020 --> 00:07:53.280 more than a sixfold increase 180 00:07:53.280 --> 00:07:55.080 in the risk of bladder cancer development 181 00:07:55.080 --> 00:07:57.591 due to heavy use among women. 182 00:07:57.591 --> 00:08:00.780 These compounds were removed from the US market in 1983, 183 00:08:00.780 --> 00:08:03.505 and have now been discontinued worldwide, 184 00:08:03.505 --> 00:08:06.120 but certainly, chemotherapeutic agents 185 00:08:06.120 --> 00:08:08.220 used in cancer therapy can increase the risk 186 00:08:08.220 --> 00:08:09.624 of developing bladder cancer. 187 00:08:09.624 --> 00:08:12.723 For example, cyclophosphamide, 188 00:08:14.240 --> 00:08:17.070 an alkylating agent used to treat advanced malignancies, 189 00:08:17.070 --> 00:08:19.620 has been linked to bladder cancer development. 190 00:08:19.620 --> 00:08:21.333 This agent has strong immunosuppressive events 191 00:08:21.333 --> 00:08:23.070 and sometimes causes a disease 192 00:08:23.070 --> 00:08:26.250 known as hemorrhagic cystitis. 193 00:08:26.250 --> 00:08:29.460 The condition is associated with a tenfold increase 194 00:08:29.460 --> 00:08:31.710 in the risk of developing transitional cell carcinoma 195 00:08:31.710 --> 00:08:32.883 of the urinary bladder. 196 00:08:34.029 --> 00:08:37.650 A 50-year longitudinal study documented marked increases 197 00:08:37.650 --> 00:08:39.210 in bladder and lung cancer mortality 198 00:08:39.210 --> 00:08:41.941 related to ingestion of arsenic-contaminated drinking water 199 00:08:41.941 --> 00:08:44.703 by a population residing in northern Chile. 200 00:08:45.630 --> 00:08:47.910 Observed cancer rates were highest 10 to 20 years 201 00:08:47.910 --> 00:08:49.888 after peak concentrations of arsenic 202 00:08:49.888 --> 00:08:51.720 were detected in the drinking water, 203 00:08:51.720 --> 00:08:53.591 suggesting a long latency period, 204 00:08:53.591 --> 00:08:56.250 and peak rates of bladder cancer were elevated 205 00:08:56.250 --> 00:09:00.139 by sixfold in men and nearly 14-fold in women. 206 00:09:00.139 --> 00:09:02.220 There are also genetic factors 207 00:09:02.220 --> 00:09:05.010 related to the development of urinary bladder cancer. 208 00:09:05.010 --> 00:09:06.857 So the relative risk of bladder cancer is influenced 209 00:09:06.857 --> 00:09:08.070 by the smoking habit, 210 00:09:08.070 --> 00:09:09.780 as well as genetically determined enzymes 211 00:09:09.780 --> 00:09:13.590 that either activate or detoxify smoking contaminates 212 00:09:13.590 --> 00:09:15.780 that enter the human system. 213 00:09:15.780 --> 00:09:17.910 First degree relatives of patients with bladder cancer 214 00:09:17.910 --> 00:09:20.340 have a twofold increased risk of developing the disease, 215 00:09:20.340 --> 00:09:22.090 compared to the general population. 216 00:09:23.010 --> 00:09:24.840 By comparison, there's a fivefold increase 217 00:09:24.840 --> 00:09:27.570 in the risk for individuals with a positive family history 218 00:09:27.570 --> 00:09:29.193 who are also chronic smokers. 219 00:09:30.270 --> 00:09:32.334 Exposure to aryl amines from tobacco smoke 220 00:09:32.334 --> 00:09:34.200 or environmental contaminants 221 00:09:34.200 --> 00:09:36.750 increases the risk of bladder cancer. 222 00:09:36.750 --> 00:09:38.580 The metabolism of arylamines occurs 223 00:09:38.580 --> 00:09:39.990 in the liver and the urinary bladder 224 00:09:39.990 --> 00:09:42.830 through specific enzymatic reactions. 225 00:09:42.830 --> 00:09:44.910 The first step takes place in the liver, 226 00:09:44.910 --> 00:09:46.620 where nitrous oxidation of arylamines 227 00:09:46.620 --> 00:09:49.593 is catalyzed by enzymes of the P450 system. 228 00:09:50.727 --> 00:09:52.980 Various enzymes help to detoxify 229 00:09:52.980 --> 00:09:54.330 various bladder carcinogens, 230 00:09:54.330 --> 00:09:56.793 including carcinogenic arylamines. 231 00:09:57.840 --> 00:10:01.710 However, a specific mutation in the gene, 232 00:10:01.710 --> 00:10:03.630 or one of the genes controlling one of these enzymes, 233 00:10:03.630 --> 00:10:05.359 results in slow metabolism for arylamines 234 00:10:05.359 --> 00:10:08.913 and an increased risk of bladder cancer development. 235 00:10:10.652 --> 00:10:14.220 In the US, the annual instance of bladder cancer 236 00:10:14.220 --> 00:10:17.640 is twice as high in white men as in African American men, 237 00:10:17.640 --> 00:10:22.640 and 24% higher in white women than African American women. 238 00:10:24.240 --> 00:10:26.580 These ethnic differences, which have persisted for decades, 239 00:10:26.580 --> 00:10:28.380 are likely related to genetic differences 240 00:10:28.380 --> 00:10:29.940 in the metabolism of arylamines 241 00:10:29.940 --> 00:10:32.283 from cigarette smoking or other sources.