WEBVTT 1 00:00:00.720 --> 00:00:03.360 Hi everyone, and welcome to today's lecture 2 00:00:03.360 --> 00:00:06.450 on epidemiology of esophageal cancer. 3 00:00:06.450 --> 00:00:08.250 In this lecture, we will begin 4 00:00:08.250 --> 00:00:10.860 by reviewing the anatomy and function of the esophagus, 5 00:00:10.860 --> 00:00:14.190 describing the global burden of esophageal cancer, 6 00:00:14.190 --> 00:00:17.790 with a particular focus on the esophageal cancer belt. 7 00:00:17.790 --> 00:00:21.540 We'll also describe squamous cell carcinoma 8 00:00:21.540 --> 00:00:24.510 and adenocarcinoma of the esophagus. 9 00:00:24.510 --> 00:00:27.450 And describe risk factors for esophageal cancer, 10 00:00:27.450 --> 00:00:29.340 progression of Barrett's esophagus, 11 00:00:29.340 --> 00:00:32.913 and prevention of esophageal cancer, so let's jump in. 12 00:00:34.170 --> 00:00:37.230 So to talk about the anatomy of the esophagus, 13 00:00:37.230 --> 00:00:38.640 it's important to note that the esophagus 14 00:00:38.640 --> 00:00:41.100 is a muscular tube that transports saliva, 15 00:00:41.100 --> 00:00:43.350 food, and liquids from the mouth to the stomach. 16 00:00:43.350 --> 00:00:45.660 In the human adult, the esophagus 17 00:00:45.660 --> 00:00:48.660 is about 20 centimeters, or eight inches long, 18 00:00:48.660 --> 00:00:53.010 and it's lined by stratified squamous epithelium. 19 00:00:53.010 --> 00:00:54.660 The upper esophageal sphincter, 20 00:00:54.660 --> 00:00:56.490 which is located just below the pharynx, 21 00:00:56.490 --> 00:00:59.700 allows passage of food and liquids during swallowing. 22 00:00:59.700 --> 00:01:01.470 The lower esophageal sphincter, located 23 00:01:01.470 --> 00:01:04.140 at the junction of the lower esophagus with the stomach, 24 00:01:04.140 --> 00:01:07.770 regulates the passage of food and liquids into the stomach. 25 00:01:07.770 --> 00:01:09.150 Just before entering the stomach, 26 00:01:09.150 --> 00:01:11.300 the esophagus passes through the diaphragm. 27 00:01:13.800 --> 00:01:15.660 This figure shows the incidence 28 00:01:15.660 --> 00:01:19.083 of esophageal cancer across both sexes. 29 00:01:20.010 --> 00:01:22.710 So approximately 5% of all cancer deaths 30 00:01:22.710 --> 00:01:24.510 are due to esophageal cancer, making it 31 00:01:24.510 --> 00:01:27.273 the sixth leading cause of death from cancer. 32 00:01:28.170 --> 00:01:29.670 The incidence of esophageal cancer 33 00:01:29.670 --> 00:01:32.340 shows marked international variability. 34 00:01:32.340 --> 00:01:35.250 We see that some countries have much higher rates 35 00:01:35.250 --> 00:01:39.900 of esophageal cancer incidence than others. 36 00:01:39.900 --> 00:01:41.310 For example, the annual incidence 37 00:01:41.310 --> 00:01:43.770 in North America and Western Europe ranges 38 00:01:43.770 --> 00:01:47.280 from 3 to 5 cases per 100,000. 39 00:01:47.280 --> 00:01:48.720 While the annual incidence is more 40 00:01:48.720 --> 00:01:52.173 than 100 per 100,000 in Iran, and some parts of China. 41 00:01:53.520 --> 00:01:55.113 In the US approximately 15,000 new cases 42 00:01:55.113 --> 00:01:58.080 of esophageal cancer are diagnosed annually, 43 00:01:58.080 --> 00:02:01.170 and 14,000 people die from the disease. 44 00:02:01.170 --> 00:02:03.330 Approximately 50% of cases presented 45 00:02:03.330 --> 00:02:05.100 with incurable advanced disease, 46 00:02:05.100 --> 00:02:06.390 and the five-year survival rate 47 00:02:06.390 --> 00:02:09.420 of patients with resectable esophageal cancer 48 00:02:09.420 --> 00:02:13.133 is low, ranging from 20 to 30%. 49 00:02:14.430 --> 00:02:18.150 When we look at the mortality of... 50 00:02:18.150 --> 00:02:20.160 mortality rates for esophageal cancer 51 00:02:20.160 --> 00:02:25.160 we see that they largely follow incidence rates 52 00:02:25.230 --> 00:02:27.630 in different parts of the world. 53 00:02:27.630 --> 00:02:30.510 In 2020 in the US the age standardized incidence 54 00:02:30.510 --> 00:02:33.640 of esophageal cancer was 6.3 per 100,000 55 00:02:34.620 --> 00:02:37.230 with esophageal cancer occurring 56 00:02:37.230 --> 00:02:41.730 about three times higher in men than in women. 57 00:02:41.730 --> 00:02:44.670 The age standardized mortality of esophageal cancer in 2020 58 00:02:44.670 --> 00:02:49.470 in the US was 5.6 deaths per 100,000 people, 59 00:02:49.470 --> 00:02:54.470 or 8.3 deaths per 100,000 men, and 3.2 per 100,000 women. 60 00:02:56.190 --> 00:03:00.990 The esophageal cancer belt extends from northeast China 61 00:03:00.990 --> 00:03:05.160 to parts of the Middle East, or southwest Asia. 62 00:03:05.160 --> 00:03:07.680 The cumulative lifetime risk of esophageal cancer 63 00:03:07.680 --> 00:03:08.940 in certain Chinese provinces, 64 00:03:08.940 --> 00:03:12.330 and Northern Iran approaches 25%. 65 00:03:12.330 --> 00:03:14.640 Cancer of the esophagus was a common condition 66 00:03:14.640 --> 00:03:17.310 in the centuries past in both China and Iran, 67 00:03:17.310 --> 00:03:21.270 suggesting the longstanding presence of major risk factors. 68 00:03:21.270 --> 00:03:24.360 These risk factors may include drinking super hot tea, 69 00:03:24.360 --> 00:03:28.320 or other beverages, exposure to alpha toxins 70 00:03:28.320 --> 00:03:32.820 and other mycotoxins, exposure to excess nitrous ambience, 71 00:03:32.820 --> 00:03:35.910 exposure to certain minerals like arsenic, 72 00:03:35.910 --> 00:03:40.170 HPV and other viruses, nutritional deficiencies, 73 00:03:40.170 --> 00:03:43.890 especially vitamins A, B, C, and E, 74 00:03:43.890 --> 00:03:45.723 and tobacco, and alcohol use. 75 00:03:48.600 --> 00:03:51.390 When we look at esophageal cancer epidemiology 76 00:03:51.390 --> 00:03:53.130 it's important to compare the differences 77 00:03:53.130 --> 00:03:57.270 between squamous cell carcinoma and adenocarcinoma. 78 00:03:57.270 --> 00:03:59.730 So squamous cell carcinomas develop 79 00:03:59.730 --> 00:04:02.070 in the middle and upper third of the esophagus 80 00:04:02.070 --> 00:04:05.490 while adenocarcinomas arise in the lower esophagus 81 00:04:05.490 --> 00:04:08.430 near the gastroesophageal junction. 82 00:04:08.430 --> 00:04:11.820 And these risk factors differ by histology. 83 00:04:11.820 --> 00:04:15.810 And we can see, you know, some of those major risk factors 84 00:04:15.810 --> 00:04:18.870 in this chart here, as well as differences in age 85 00:04:18.870 --> 00:04:22.743 when these different carcinomas occur. 86 00:04:24.060 --> 00:04:27.060 So when we think about the pathogenesis of esophageal cancer 87 00:04:28.170 --> 00:04:29.430 it's important to know that there has been 88 00:04:29.430 --> 00:04:32.070 a marked increase in the incidence of adenocarcinomas 89 00:04:32.070 --> 00:04:35.400 of the lower esophagus near the gastroesophageal junction, 90 00:04:35.400 --> 00:04:38.280 particularly among men of the US, UK, 91 00:04:38.280 --> 00:04:40.893 and other high income countries in recent decades. 92 00:04:41.973 --> 00:04:44.550 Adenocarcinomas of the lower esophagus arise 93 00:04:44.550 --> 00:04:47.490 by a sequence of metaplastic and dysplastic changes 94 00:04:47.490 --> 00:04:52.020 in the esophageal epithelium known as Barrett's esophagus. 95 00:04:52.020 --> 00:04:55.530 Such changes arise due to chronic gastroesophageal reflux 96 00:04:55.530 --> 00:04:58.260 of acidic stomach fluid into the normally basic environment 97 00:04:58.260 --> 00:04:59.583 of the lower esophagus. 98 00:05:00.450 --> 00:05:02.790 Barrett's esophagus is a pre-malignant lesion 99 00:05:02.790 --> 00:05:04.530 that must be aggressively treated to halt 100 00:05:04.530 --> 00:05:07.440 its progression to invasive esophageal cancer, 101 00:05:07.440 --> 00:05:09.840 a condition that is life-threatening. 102 00:05:09.840 --> 00:05:12.540 And effective screening strategies have been proposed 103 00:05:12.540 --> 00:05:15.000 for high-risk populations using endoscopy 104 00:05:15.000 --> 00:05:17.400 with mucosal iodine staining, and biopsy 105 00:05:17.400 --> 00:05:20.640 to identify severe dysplastic lesions and carcinomas 106 00:05:20.640 --> 00:05:25.310 in situ that are curable by... or by radical mucosectomy 107 00:05:28.770 --> 00:05:31.050 and adenocarcinomas of the lower esophagus 108 00:05:31.050 --> 00:05:35.163 are now more common than squamous cell carcinomas in the US. 109 00:05:36.960 --> 00:05:41.960 So the progression to squamous cell carcinoma occurs 110 00:05:42.300 --> 00:05:44.640 when high high-grade dysplastic lesions transform 111 00:05:44.640 --> 00:05:48.780 to carcinoma in situ and eventually to invasive cancer. 112 00:05:48.780 --> 00:05:51.450 There's two major metrics that are used 113 00:05:51.450 --> 00:05:54.660 when looking at the staging of esophageal dysplasia, 114 00:05:54.660 --> 00:05:57.600 or squamous cell carcinoma, that would would be 115 00:05:57.600 --> 00:06:00.840 whether the cancer has invaded contiguous tissues 116 00:06:00.840 --> 00:06:02.553 and that's denoted with a T, 117 00:06:03.420 --> 00:06:06.360 and whether the cancer has invaded lymph nodes, 118 00:06:06.360 --> 00:06:08.820 and that's denoted with an N. 119 00:06:08.820 --> 00:06:11.490 Key risk factors for squamous cell carcinoma 120 00:06:11.490 --> 00:06:16.110 are tobacco, alcohol, betel quid, mycotic infection, 121 00:06:16.110 --> 00:06:18.963 steaming hot beverages, and nutritional deficits. 122 00:06:21.420 --> 00:06:23.820 Other risk factors for esophageal cancer 123 00:06:23.820 --> 00:06:26.070 differ according to histologic subtype, 124 00:06:26.070 --> 00:06:30.063 and anatomic location in the esophagus as we've noted. 125 00:06:31.290 --> 00:06:33.900 We see that among the environmental risk factors 126 00:06:33.900 --> 00:06:37.140 for both histologic types, chronic alcoholism 127 00:06:37.140 --> 00:06:39.120 and cigarette smoking contribute most heavily 128 00:06:39.120 --> 00:06:41.460 to the development of esophageal cancer. 129 00:06:41.460 --> 00:06:44.970 And esophageal cancer is 25 times more common 130 00:06:44.970 --> 00:06:48.600 among heavy drinkers than among controls. 131 00:06:48.600 --> 00:06:51.030 Similarly, habitual smokers of cigarettes have 132 00:06:51.030 --> 00:06:54.570 a six to sevenfold increased frequency of esophageal cancer 133 00:06:54.570 --> 00:06:57.003 after adjustment for alcohol consumption. 134 00:07:00.000 --> 00:07:03.030 So when we discussed adenocarcinoma before 135 00:07:03.030 --> 00:07:05.220 we mentioned Barrett's esophagus. 136 00:07:05.220 --> 00:07:08.100 And Barrett's esophagus is the term describing 137 00:07:08.100 --> 00:07:10.620 a sequence of metaplastic and dysplastic changes 138 00:07:10.620 --> 00:07:14.940 in the esophageal epithelium, so cellular changes arise due 139 00:07:14.940 --> 00:07:17.190 to that chronic gastroesophageal reflux 140 00:07:17.190 --> 00:07:20.370 of acidic stomach fluid into the lower esophagus, 141 00:07:20.370 --> 00:07:21.633 as we mentioned before. 142 00:07:22.830 --> 00:07:25.410 Barrett's esophagus is the pre-malignant lesion 143 00:07:25.410 --> 00:07:28.560 of this lower esophageal area, 144 00:07:28.560 --> 00:07:30.810 or a gastrointestinal junction. 145 00:07:30.810 --> 00:07:33.360 Barrett's esophagus is likely related 146 00:07:33.360 --> 00:07:35.253 to chronic GERD and obesity. 147 00:07:36.480 --> 00:07:40.590 We also see that the COX-2 inflammatory pathway plays a role 148 00:07:40.590 --> 00:07:45.360 in the progression to a malignant neoplasm, 149 00:07:45.360 --> 00:07:47.940 and that Barrett's esophagus patients have 150 00:07:47.940 --> 00:07:52.940 a 30 to 125 increase in relative risk of adenocarcinoma. 151 00:07:54.750 --> 00:07:57.570 Unfortunately, there's no known effective screening tool 152 00:07:57.570 --> 00:07:59.253 for Barrett's esophagus. 153 00:08:01.050 --> 00:08:03.261 So as I just mentioned, COX-2, 154 00:08:03.261 --> 00:08:07.740 or the cyclooxygenase enzyme plays a role 155 00:08:07.740 --> 00:08:12.740 in the development of cancer from Barrett's esophagus. 156 00:08:15.600 --> 00:08:20.600 So this COX-2 gene becomes markedly over expressed 157 00:08:21.630 --> 00:08:23.640 throughout the progression of Barrett's esophagus 158 00:08:23.640 --> 00:08:25.263 to esophageal cancer. 159 00:08:30.780 --> 00:08:33.330 When we're discussing esophageal adenocarcinomas 160 00:08:33.330 --> 00:08:37.560 and Barrett's esophagus, we see 161 00:08:37.560 --> 00:08:38.820 that there have been associations 162 00:08:38.820 --> 00:08:41.670 between increases in these carcinomas 163 00:08:41.670 --> 00:08:44.370 in developed nations like the US and Great Britain. 164 00:08:44.370 --> 00:08:47.160 And these increases have occurred 165 00:08:47.160 --> 00:08:49.800 at the same time as increasing obesity 166 00:08:49.800 --> 00:08:53.070 and gastroesophageal reflex disease or GERD, 167 00:08:53.070 --> 00:08:55.620 and reduced rates of gastric infection 168 00:08:55.620 --> 00:09:00.620 by helicobacter pylorus, so this seesaw diagram here, 169 00:09:02.910 --> 00:09:05.670 really depicts the ways that people can be protected, 170 00:09:05.670 --> 00:09:07.350 or communities can be protected 171 00:09:07.350 --> 00:09:11.670 from esophageal adenocarcinoma, and the risk factors, 172 00:09:11.670 --> 00:09:15.570 and how for any individual, they're going to have 173 00:09:15.570 --> 00:09:17.550 some combination of these risk factors 174 00:09:17.550 --> 00:09:19.710 and protective factors that's going to determine 175 00:09:19.710 --> 00:09:24.273 their overall risk for developing esophageal adenocarcinoma. 176 00:09:25.980 --> 00:09:28.530 So even though H. pylori infections 177 00:09:28.530 --> 00:09:29.940 of the gastric mucosa heighten 178 00:09:29.940 --> 00:09:32.760 the risk of developing stomach cancer. 179 00:09:32.760 --> 00:09:35.790 This microbe appears to protect against the development 180 00:09:35.790 --> 00:09:38.823 of Barrett's esophagus in esophageal adenocarcinoma. 181 00:09:43.110 --> 00:09:46.200 H, pylori also produces ammonia, 182 00:09:46.200 --> 00:09:48.810 which neutralizes gastric acid. 183 00:09:48.810 --> 00:09:50.670 So when this gastric acid is coming 184 00:09:50.670 --> 00:09:54.510 into the lower esophagus, it's possible 185 00:09:54.510 --> 00:09:57.480 that it's being neutralized by the ammonia produced 186 00:09:57.480 --> 00:10:00.540 by H. Pylori which then is not causing 187 00:10:00.540 --> 00:10:03.840 as much cellular damage and inflammation 188 00:10:03.840 --> 00:10:05.343 as it might be otherwise. 189 00:10:09.930 --> 00:10:13.170 When we look at genetic risk factors for esophageal cancer 190 00:10:13.170 --> 00:10:17.550 we see that there are various conditions, or syndromes, 191 00:10:17.550 --> 00:10:20.700 as well as tumor suppressor genes that play a role 192 00:10:20.700 --> 00:10:23.940 in one's risk for esophageal cancer. 193 00:10:23.940 --> 00:10:27.810 So for example, achalasia, which is due to a dysfunction 194 00:10:27.810 --> 00:10:30.390 of the gastrointestinal sphincter, interrupts 195 00:10:30.390 --> 00:10:33.360 the passage of food from the esophagus into the stomach 196 00:10:33.360 --> 00:10:36.543 and increases the risk of esophageal cancer by 15 fold. 197 00:10:37.590 --> 00:10:40.969 The Plummer-Vinson syndrome consists of iron deficiency, 198 00:10:40.969 --> 00:10:44.670 anemia coupled with muscle atrophy, dysphagia, 199 00:10:44.670 --> 00:10:46.380 and the formation of esophageal rings, 200 00:10:46.380 --> 00:10:48.750 or webs in the upper esophagus. 201 00:10:48.750 --> 00:10:50.700 The syndrome is associated with the development 202 00:10:50.700 --> 00:10:52.650 of squamous cell carcinomas proximal 203 00:10:52.650 --> 00:10:54.303 to the upper esophageal webs. 204 00:10:56.010 --> 00:10:58.860 Genetic polymorphisms of certain tumor suppressor genes 205 00:10:58.860 --> 00:11:01.320 that modulate cell division may also contribute 206 00:11:01.320 --> 00:11:03.543 to the genesis of esophageal cancer. 207 00:11:04.710 --> 00:11:08.186 Scientists found genetic polymorphisms in cyclin D1 208 00:11:08.186 --> 00:11:12.870 and P53 that increased the risk of esophageal cancer 209 00:11:12.870 --> 00:11:15.453 by sixfold and threefold respectively. 210 00:11:17.970 --> 00:11:20.800 So, as I just mentioned, there's increases 211 00:11:21.750 --> 00:11:26.750 in the risk for esophageal cancer, 212 00:11:27.840 --> 00:11:30.990 specifically Barrett's esophagus and adenocarcinoma 213 00:11:30.990 --> 00:11:33.510 when we look at individuals 214 00:11:33.510 --> 00:11:38.167 with certain genetic polymorphisms, like cyclin D1 and P53. 215 00:11:39.090 --> 00:11:43.680 Finally, the prevention of esophageal cancer 216 00:11:43.680 --> 00:11:46.320 can occur on many different fronts. 217 00:11:46.320 --> 00:11:48.360 So to begin with, it's important to avoid exposure 218 00:11:48.360 --> 00:11:51.360 to alcohol, tobacco, boiling hot beverages, 219 00:11:51.360 --> 00:11:53.760 and other caustic substances 220 00:11:53.760 --> 00:11:56.010 that can cause inflammation in the esophagus. 221 00:11:56.880 --> 00:11:59.730 In low and middle income countries, avoiding intake 222 00:11:59.730 --> 00:12:02.280 of multigrains and other foods or beverages fermented 223 00:12:02.280 --> 00:12:06.790 from multigrain can decrease one's risk of esophageal cancer 224 00:12:07.890 --> 00:12:09.930 And international efforts are now being directed 225 00:12:09.930 --> 00:12:12.000 to the obesity pandemic in order to reduce 226 00:12:12.000 --> 00:12:15.513 the burden of GERD and other obesity related diseases. 227 00:12:16.620 --> 00:12:18.780 Multiple epidemiologic studies have examined 228 00:12:18.780 --> 00:12:20.250 the potential role of aspirin, 229 00:12:20.250 --> 00:12:23.370 and other non-steroidal anti-inflammatory drugs, 230 00:12:23.370 --> 00:12:27.450 or NSAIDs, in the prevention of esophageal cancer. 231 00:12:27.450 --> 00:12:31.740 In a recent meta-analysis of these studies that took place 232 00:12:31.740 --> 00:12:34.620 in 2003 it was determined that regular use 233 00:12:34.620 --> 00:12:37.290 of NSAIDs was associated with a 40% reduction 234 00:12:37.290 --> 00:12:39.033 in the risk of esophageal cancer. 235 00:12:40.230 --> 00:12:41.820 NSAIDs are known to reduce inflammation 236 00:12:41.820 --> 00:12:44.820 by inhibiting the cyclooxygenase enzymes, COX-1 237 00:12:44.820 --> 00:12:47.970 and COX-2 that are responsible 238 00:12:47.970 --> 00:12:51.063 for aspects of the inflammatory cascade. 239 00:12:52.800 --> 00:12:57.090 In high-risk populations, endoscopic screening 240 00:12:57.090 --> 00:12:59.490 for Barrett's esophagus, or other dysplastic changes 241 00:12:59.490 --> 00:13:02.580 in the esophageal mucosa, coupled with ablative treatment 242 00:13:02.580 --> 00:13:04.020 have proven effective in preventing 243 00:13:04.020 --> 00:13:05.913 the development of esophageal cancer. 244 00:13:06.840 --> 00:13:09.090 Treatments found effective, include administration 245 00:13:09.090 --> 00:13:10.470 of proton pump inhibitors, 246 00:13:10.470 --> 00:13:12.813 and ablation by radiofrequency energy. 247 00:13:13.830 --> 00:13:15.510 Patients with Barrett's esophagus 248 00:13:15.510 --> 00:13:17.250 or other pre-malignant lesions should 249 00:13:17.250 --> 00:13:18.450 thus seek immediate treatment 250 00:13:18.450 --> 00:13:22.440 to prevent progression to esophageal cancer. 251 00:13:22.440 --> 00:13:24.930 And over the counter chemo preventive medications 252 00:13:24.930 --> 00:13:26.370 include proton pump inhibitors, 253 00:13:26.370 --> 00:13:29.703 antacids, and histamine 2 receptor antagonists. 254 00:13:30.780 --> 00:13:34.290 Finally, and just to circle back to this point, aspirin 255 00:13:34.290 --> 00:13:39.290 and other NSAIDs reduce the risk through COX-2 inhibition 256 00:13:39.990 --> 00:13:42.630 and thus, can prove to be important tools 257 00:13:42.630 --> 00:13:45.063 in lowering one's risk for esophageal cancer.