WEBVTT 1 00:00:00.300 --> 00:00:01.230 Hi, everyone. 2 00:00:01.230 --> 00:00:03.420 In this lecture, we'll be discussing the epidemiology 3 00:00:03.420 --> 00:00:06.690 of gastric cancer, or stomach cancer. 4 00:00:06.690 --> 00:00:07.830 Our goals for this lecture 5 00:00:07.830 --> 00:00:10.230 are to review the anatomy and function of the stomach, 6 00:00:10.230 --> 00:00:12.660 to describe the global burden of stomach cancer, 7 00:00:12.660 --> 00:00:15.270 and identify high risk populations. 8 00:00:15.270 --> 00:00:17.040 To describe the declining trends 9 00:00:17.040 --> 00:00:19.380 in stomach cancer mortality, 10 00:00:19.380 --> 00:00:21.120 and to discuss genetic factors 11 00:00:21.120 --> 00:00:24.033 and the prevention and control of stomach cancer. 12 00:00:25.350 --> 00:00:26.310 So to begin with, 13 00:00:26.310 --> 00:00:29.310 and looking at the anatomy of the stomach, 14 00:00:29.310 --> 00:00:31.320 we see that it's a hollow muscular organ 15 00:00:31.320 --> 00:00:34.230 juxtaposed between the esophagus and the duodenum. 16 00:00:34.230 --> 00:00:35.700 With a resting volume ranging 17 00:00:35.700 --> 00:00:39.720 from 45 to 75 milliliters in the human adult. 18 00:00:39.720 --> 00:00:42.120 The stomach is lined by a specialized epithelium 19 00:00:42.120 --> 00:00:44.280 that secretes proteases, 20 00:00:44.280 --> 00:00:46.500 which are enzymes that digest protein, 21 00:00:46.500 --> 00:00:48.690 and hydrochloric acid. 22 00:00:48.690 --> 00:00:51.510 The acidic nature of the stomach inhibits bacterial growth 23 00:00:51.510 --> 00:00:53.700 and facilitates the correct acid environment 24 00:00:53.700 --> 00:00:55.650 for activation of the enzymes 25 00:00:55.650 --> 00:00:57.933 secreted by the gastric epithelium. 26 00:00:58.830 --> 00:01:01.650 The stomach lining is folded into rugae 27 00:01:01.650 --> 00:01:03.723 to allow expression and contraction. 28 00:01:04.650 --> 00:01:07.200 The bolus, which is the masticator 29 00:01:07.200 --> 00:01:09.460 chewed food that enters the stomach 30 00:01:10.410 --> 00:01:13.350 comes in at the gastro esophageal sphincter 31 00:01:13.350 --> 00:01:16.593 and is turned by muscular contractions of the stomach wall. 32 00:01:17.970 --> 00:01:22.200 Chyme, or partially digested food passes from the stomach 33 00:01:22.200 --> 00:01:23.880 through the pyloric sphincter 34 00:01:23.880 --> 00:01:26.250 into the duodenum of the small intestine 35 00:01:26.250 --> 00:01:28.533 where the extraction of nutrients begins. 36 00:01:30.390 --> 00:01:32.670 When we look at the incidence rates 37 00:01:32.670 --> 00:01:34.860 of stomach cancer globally 38 00:01:34.860 --> 00:01:37.320 we see that gastro cancer remains one of the most common 39 00:01:37.320 --> 00:01:39.570 forms of cancer worldwide. 40 00:01:39.570 --> 00:01:44.570 In 2012, 951,594 cases were diagnosed 41 00:01:44.730 --> 00:01:48.543 and 723,027 deaths occurred. 42 00:01:49.560 --> 00:01:53.790 Gastric cancer was in about 9.9% of new cancers in 2012 43 00:01:53.790 --> 00:01:56.670 and about 70% of the cases in deaths 44 00:01:56.670 --> 00:01:59.520 occurred in low and middle income countries. 45 00:01:59.520 --> 00:02:01.470 The incidents in mortality rates are highest 46 00:02:01.470 --> 00:02:05.730 in China and Mongolia, Eastern Asia, the Indian regions 47 00:02:05.730 --> 00:02:08.725 of South America, Eastern Europe, and Mali 48 00:02:08.725 --> 00:02:10.593 and Zaire in Africa. 49 00:02:11.430 --> 00:02:14.010 Gastric cancer used to be the leading cause of cancer deaths 50 00:02:14.010 --> 00:02:15.690 in the world until the 1980s 51 00:02:15.690 --> 00:02:17.583 when it was overtaken by lung cancer. 52 00:02:20.520 --> 00:02:23.490 So, as previously discussed, when we're looking at 53 00:02:23.490 --> 00:02:26.100 mortality rates of stomach cancer globally 54 00:02:26.100 --> 00:02:29.040 we see high rates in South America, 55 00:02:29.040 --> 00:02:30.630 in different parts of Asia 56 00:02:30.630 --> 00:02:33.423 and in some African countries like Mali. 57 00:02:35.100 --> 00:02:37.140 When we're looking at stomach cancer mortality rates 58 00:02:37.140 --> 00:02:42.140 in the US, we see that they've declined significantly 59 00:02:42.300 --> 00:02:45.120 since 1930 in both men and women, 60 00:02:45.120 --> 00:02:48.720 and this mirrors is a declining cases globally. 61 00:02:48.720 --> 00:02:51.300 In the US, death rates from stomach cancer have declined 62 00:02:51.300 --> 00:02:54.663 by nearly 90% in men and women since 1930. 63 00:02:57.510 --> 00:02:59.910 A similar pattern of declining mortality has emerged 64 00:02:59.910 --> 00:03:02.820 in Japan, and Japan importantly is the nation 65 00:03:02.820 --> 00:03:05.580 with the highest stomach cancer mortality in the world. 66 00:03:05.580 --> 00:03:08.760 In 1950, when nearly a hundred deaths were occurring 67 00:03:08.760 --> 00:03:11.190 per 100,000 in men. 68 00:03:11.190 --> 00:03:12.600 Since then, mortality rates 69 00:03:12.600 --> 00:03:15.180 from stomach cancer have declined by nearly 70% 70 00:03:15.180 --> 00:03:18.093 in Japanese men and 90% in Japanese women. 71 00:03:19.380 --> 00:03:23.760 In 2020 in the US, the age standardized incidence 72 00:03:23.760 --> 00:03:27.960 of gastric cancer was 11.1 per 100,000 overall 73 00:03:27.960 --> 00:03:32.960 but 15.8 per 100,000 men and 7 per 100,000 women. 74 00:03:33.210 --> 00:03:37.020 The mortality was 7.7 per 100,000 75 00:03:37.020 --> 00:03:41.283 or 11 per 100,000 men and 4.9 per 100,000 women. 76 00:03:42.600 --> 00:03:46.593 So why has gastric carcinoma declined? 77 00:03:47.820 --> 00:03:50.100 So we can call this an unplanned triumph 78 00:03:50.100 --> 00:03:52.080 of epidemiology that's resulted 79 00:03:52.080 --> 00:03:54.273 in changing balance of risk factors. 80 00:03:55.140 --> 00:03:57.060 So the major reason for the decline 81 00:03:57.060 --> 00:04:00.960 in stomach cancer in high income countries is the rapid 82 00:04:00.960 --> 00:04:05.370 and widespread escalation of refrigeration since 1900. 83 00:04:05.370 --> 00:04:08.670 The expansion of industrial refrigeration has meant 84 00:04:08.670 --> 00:04:11.700 fresher produce for the consumer and in turn has resulted 85 00:04:11.700 --> 00:04:15.630 in higher per capita intake of vitamins A, C, and E 86 00:04:15.630 --> 00:04:18.093 which protect against gastric carcinogenesis. 87 00:04:18.960 --> 00:04:21.960 Furthermore, the increase in refrigeration has reduced 88 00:04:21.960 --> 00:04:25.110 the need for salting and pickling, two traditional means 89 00:04:25.110 --> 00:04:26.520 of food preservation associated 90 00:04:26.520 --> 00:04:29.673 with increased gastric cancer risk. 91 00:04:30.570 --> 00:04:32.100 Improved food sanitation 92 00:04:32.100 --> 00:04:34.080 through better techniques of processing, handling, 93 00:04:34.080 --> 00:04:36.630 and refrigeration has reduced exposure 94 00:04:36.630 --> 00:04:40.620 to the infectious microbe helicobacter pylori 95 00:04:40.620 --> 00:04:42.990 particularly among children. 96 00:04:42.990 --> 00:04:44.460 This bacterium is known to cause 97 00:04:44.460 --> 00:04:47.190 chronic stomach inflammation and bacterial infiltrates 98 00:04:47.190 --> 00:04:49.380 of the organism are commonly found associated 99 00:04:49.380 --> 00:04:53.193 with gastric adenocarcinoma and its precursor lesions. 100 00:04:54.690 --> 00:04:56.640 Studies combining methods of epidemiology 101 00:04:56.640 --> 00:04:58.830 and microbiology clearly suggest 102 00:04:58.830 --> 00:05:01.470 that helicobacter pylori should be considered 103 00:05:01.470 --> 00:05:04.203 to be a major causal factor of gastric carcinoma. 104 00:05:09.210 --> 00:05:12.780 So to give a little bit more background on H-pylori, 105 00:05:12.780 --> 00:05:16.260 it's a gram negative microaerophilic bacterium found 106 00:05:16.260 --> 00:05:17.310 in the stomach. 107 00:05:17.310 --> 00:05:20.760 It was identified in 1982 when it was found present 108 00:05:20.760 --> 00:05:23.853 in patients with chronic gastritis and gastric ulcers. 109 00:05:25.050 --> 00:05:25.890 It's also been linked 110 00:05:25.890 --> 00:05:29.430 to the development of duodenal ulcers and stomach cancer. 111 00:05:29.430 --> 00:05:31.890 However, over 80% of the individuals infected 112 00:05:31.890 --> 00:05:33.990 with the bacterium are asymptomatic 113 00:05:33.990 --> 00:05:36.600 and it's been postulated that it may play an important role 114 00:05:36.600 --> 00:05:38.643 in the natural stomach ecology. 115 00:05:39.570 --> 00:05:42.770 More than 50% of the world's population harbor H-pylori 116 00:05:42.770 --> 00:05:44.850 in the upper gastrointestinal tract 117 00:05:44.850 --> 00:05:46.590 and infection is more prevalent 118 00:05:46.590 --> 00:05:49.020 in low and middle income countries 119 00:05:49.020 --> 00:05:52.383 and incidences decreasing in high income countries. 120 00:05:54.450 --> 00:05:57.660 To colonize the stomach, H-pylori must survive the acidic pH 121 00:05:57.660 --> 00:06:00.030 of the lumen and uses flagella to burrow 122 00:06:00.030 --> 00:06:03.720 into the mucus to reach its habitat 123 00:06:03.720 --> 00:06:07.620 or its niche close to the stomach's epithelial cell layer. 124 00:06:07.620 --> 00:06:09.810 Many bacteria can be found deep in the mucus 125 00:06:09.810 --> 00:06:11.520 which is continuously secreted 126 00:06:11.520 --> 00:06:13.950 by mucus secreting cells and removed 127 00:06:13.950 --> 00:06:15.750 on the luminal side. 128 00:06:15.750 --> 00:06:17.550 To avoid being carried into the lumen 129 00:06:17.550 --> 00:06:20.910 H-pylori senses the pH gradient within the mucus layer 130 00:06:20.910 --> 00:06:23.790 by chemotaxis and swims away from the acidic contents 131 00:06:23.790 --> 00:06:26.850 of the lumen towards the more neutral pH environment 132 00:06:26.850 --> 00:06:29.043 of the epithelial cell surface. 133 00:06:30.630 --> 00:06:32.700 H-pylori also produces large amounts 134 00:06:32.700 --> 00:06:36.480 of the enzyme urease, which breaks down urea 135 00:06:36.480 --> 00:06:38.790 which is normally secreted into the stomach. 136 00:06:38.790 --> 00:06:41.190 It breaks it down to carbon dioxide and ammonia. 137 00:06:42.240 --> 00:06:44.070 Ammonia is converted to ammonium 138 00:06:44.070 --> 00:06:45.903 which neutralizes gastric acid. 139 00:06:47.310 --> 00:06:49.680 This neutralization of gastric acid allows 140 00:06:49.680 --> 00:06:53.220 for the survival of H-pylori in the acidic stomach. 141 00:06:53.220 --> 00:06:56.100 The ammonia produced is toxic to the gastric epithelium 142 00:06:56.100 --> 00:06:58.953 and causes damage and neoplastic transformation. 143 00:07:00.570 --> 00:07:04.650 We see that key stomach cancer risk factors are again 144 00:07:04.650 --> 00:07:07.740 cigarette smoking and other forms of tobacco addiction. 145 00:07:07.740 --> 00:07:10.050 A recent comprehensive review in meta-analysis 146 00:07:10.050 --> 00:07:12.120 of the available data found a twofold increase 147 00:07:12.120 --> 00:07:16.170 in the risk of stomach cancer among male chronic smokers. 148 00:07:16.170 --> 00:07:18.990 There's also consistent evidence that tobacco addiction 149 00:07:18.990 --> 00:07:21.480 in combination with chronic alcohol consumption 150 00:07:21.480 --> 00:07:24.333 synergistically heightens the risk by fivefold. 151 00:07:26.430 --> 00:07:29.550 More than 90% of gastric cancers are adenocarcinomas 152 00:07:29.550 --> 00:07:31.110 which are divisible pathologically 153 00:07:31.110 --> 00:07:33.780 and anatomically into two subtypes. 154 00:07:33.780 --> 00:07:36.660 The first is poorly differentiated or diffuse 155 00:07:36.660 --> 00:07:39.540 adenocarcinomas arising near the cardia, 156 00:07:39.540 --> 00:07:42.930 just distal to the gastro esophageal junction. 157 00:07:42.930 --> 00:07:45.870 There's also well differentiated or intestinal 158 00:07:45.870 --> 00:07:47.370 adenocarcinomas that arise elsewhere 159 00:07:47.370 --> 00:07:52.370 in the corpus of the stomach or non-cardia adenocarcinomas. 160 00:07:52.470 --> 00:07:54.480 Well differentiated or intestinal 161 00:07:54.480 --> 00:07:57.060 non-cardia adenocarcinomas of the stomach 162 00:07:57.060 --> 00:07:58.950 develop primarily as a consequence 163 00:07:58.950 --> 00:08:02.940 of environmental factors like chronic H-pylorus infection 164 00:08:02.940 --> 00:08:06.600 particularly due to Cag-A positive strains 165 00:08:06.600 --> 00:08:09.300 resulting in chronic severe atrophic gastritis 166 00:08:09.300 --> 00:08:12.090 that progresses to invasive cancer. 167 00:08:12.090 --> 00:08:14.460 Synergism of H-pylorus infection 168 00:08:14.460 --> 00:08:16.410 with other environmental factors 169 00:08:16.410 --> 00:08:19.290 including high salt diets, nutritional deficits, 170 00:08:19.290 --> 00:08:23.580 and chronic tobacco and alcohol exposure can increase risk. 171 00:08:23.580 --> 00:08:25.740 The non-cardia intestinal subtype 172 00:08:25.740 --> 00:08:27.330 of gastric cancer predominates 173 00:08:27.330 --> 00:08:29.550 in high risk regions of the world 174 00:08:29.550 --> 00:08:32.130 and rates of this subtype have declined dramatically 175 00:08:32.130 --> 00:08:33.600 in many developed nations 176 00:08:33.600 --> 00:08:35.069 primarily due to refrigeration 177 00:08:35.069 --> 00:08:38.160 replacing salt preservation efficient meat, 178 00:08:38.160 --> 00:08:40.410 better access to fresh fruits and vegetables, 179 00:08:40.410 --> 00:08:43.920 improved sanitation, reduces in tobacco and alcohol use, 180 00:08:43.920 --> 00:08:47.193 and effective antibiotic therapy for H-pylorus infection. 181 00:08:48.030 --> 00:08:49.500 In contrast to the decline 182 00:08:49.500 --> 00:08:52.350 in non-cardia intestinal gastric cancer, 183 00:08:52.350 --> 00:08:55.170 the rates of diffuse gastric adenocarcinomas arising 184 00:08:55.170 --> 00:08:57.300 near the cardia are increasing 185 00:08:57.300 --> 00:08:58.830 in many high income countries 186 00:08:58.830 --> 00:09:01.950 particularly among Caucasian males. 187 00:09:01.950 --> 00:09:04.230 The increasing incidence of the diffuse type 188 00:09:04.230 --> 00:09:07.200 of a adenocarcinomas arising near the cardia of the stomach 189 00:09:07.200 --> 00:09:10.710 is related to obesity and other conditions that predispose 190 00:09:10.710 --> 00:09:12.990 to gastro esophageal reflex disease, 191 00:09:12.990 --> 00:09:15.243 or GERD and Barrett's esophagus. 192 00:09:16.200 --> 00:09:18.900 It's been hypothesized that ablation of colonization 193 00:09:18.900 --> 00:09:21.810 of the stomach by H-pylorus has accentuated the development 194 00:09:21.810 --> 00:09:24.633 of these conditions in some developed populations. 195 00:09:26.190 --> 00:09:29.970 There's also key genetic factors that can predispose 196 00:09:29.970 --> 00:09:33.450 for stomach cancer, so case control and cohort analyses 197 00:09:33.450 --> 00:09:35.610 of gastro cancer patients have shown that the risk 198 00:09:35.610 --> 00:09:37.590 of gastric cancer in first degree relatives 199 00:09:37.590 --> 00:09:42.090 of index cases is increased two to three fold 200 00:09:42.090 --> 00:09:46.740 and familial clusters of hereditary diffuse 201 00:09:46.740 --> 00:09:49.470 gastric carcinoma have been discovered. 202 00:09:49.470 --> 00:09:52.410 Such families manifest key germline mutations 203 00:09:52.410 --> 00:09:57.000 in the CDH1 gene that encodes E-Cadherin 204 00:09:57.000 --> 00:10:00.600 an important calcium dependent cell adhesion molecule. 205 00:10:00.600 --> 00:10:03.270 Excess cases of gastric cancer have also been observed 206 00:10:03.270 --> 00:10:07.470 in families with the adenomatous polyposis coli gene 207 00:10:07.470 --> 00:10:12.470 that predisposes to familial adenomatous polyposis, or FAP. 208 00:10:13.530 --> 00:10:15.990 And in families with hereditary non-polyposis 209 00:10:15.990 --> 00:10:18.270 colorectal cancer or lynch syndrome 210 00:10:18.270 --> 00:10:21.333 which is due to mutated mismatched DNA repair genes. 211 00:10:22.170 --> 00:10:24.450 Blood group A has been reported to be more prevalent 212 00:10:24.450 --> 00:10:27.300 among gastric cancer cases than among controls 213 00:10:27.300 --> 00:10:28.500 and appears to be associated 214 00:10:28.500 --> 00:10:31.650 with the development of the diffuse type of disease. 215 00:10:31.650 --> 00:10:34.230 Finally, patients with pernicious anemia are also 216 00:10:34.230 --> 00:10:37.410 at increased risk for the development of gastric cancer. 217 00:10:37.410 --> 00:10:39.180 Pernicious anemia is due to the lack 218 00:10:39.180 --> 00:10:42.333 of intrinsic factor and failure to observe vitamin B12. 219 00:10:43.890 --> 00:10:48.060 Finally, to briefly discuss the prevention of stomach cancer 220 00:10:48.060 --> 00:10:49.800 we see that stomach cancer is caused 221 00:10:49.800 --> 00:10:51.540 by interactions between carcinogens 222 00:10:51.540 --> 00:10:56.160 and inflammatory factors derived from various sources. 223 00:10:56.160 --> 00:10:59.370 Salt restriction are less than six grams per day. 224 00:10:59.370 --> 00:11:02.460 The avoidance of processed meat, absence from tobacco 225 00:11:02.460 --> 00:11:04.800 and limitation of alcohol intake are all important 226 00:11:04.800 --> 00:11:07.623 for prevention and control of stomach cancer.