WEBVTT 1 00:00:00.330 --> 00:00:03.060 Hi everyone, and welcome to today's lecture 2 00:00:03.060 --> 00:00:05.493 on the epidemiology of malignant melanoma. 3 00:00:06.418 --> 00:00:09.270 In this lecture, we have several goals. 4 00:00:09.270 --> 00:00:11.850 We'll begin by looking at the global pattern of melanoma 5 00:00:11.850 --> 00:00:14.160 and high and low risk populations 6 00:00:14.160 --> 00:00:16.680 as well as trends in melanoma risk. 7 00:00:16.680 --> 00:00:18.930 We'll also look at the pathogenesis of melanoma, 8 00:00:18.930 --> 00:00:23.490 risk factors, and studies of genetic predisposition. 9 00:00:23.490 --> 00:00:26.310 We'll also look at studies of tanning beds and melanoma 10 00:00:26.310 --> 00:00:29.580 and some prevention and treatment strategies. 11 00:00:29.580 --> 00:00:33.180 So to begin with, when we look at the global trends 12 00:00:33.180 --> 00:00:36.750 of malignant melanoma from 2000 to 2012, 13 00:00:36.750 --> 00:00:40.800 we see that case numbers are on the rise. 14 00:00:40.800 --> 00:00:44.220 During 2012, malignant melanoma of the skin was diagnosed 15 00:00:44.220 --> 00:00:46.920 in over 200,000 individuals worldwide 16 00:00:46.920 --> 00:00:49.710 and caused more than 50,000 deaths. 17 00:00:49.710 --> 00:00:52.050 This potentially fatal form of skin cancer 18 00:00:52.050 --> 00:00:55.470 was detected slightly more frequently in men than in women, 19 00:00:55.470 --> 00:00:58.440 and the deaths from melanoma in men exceeded deaths in women 20 00:00:58.440 --> 00:01:00.600 by more than 30%. 21 00:01:00.600 --> 00:01:03.210 The global burden of melanoma has increased dramatically 22 00:01:03.210 --> 00:01:08.010 in the last decade, and during this 2000 to 2012 time period 23 00:01:08.010 --> 00:01:11.280 the annual number of cases increased by 45%, 24 00:01:11.280 --> 00:01:15.874 and the annual deaths from melanoma increased by 49%. 25 00:01:15.874 --> 00:01:18.120 Incidence rates are markedly higher 26 00:01:18.120 --> 00:01:19.950 in high income countries 27 00:01:19.950 --> 00:01:21.930 than in low and middle income countries. 28 00:01:21.930 --> 00:01:25.080 For example, the incidence in American and Canadian women 29 00:01:25.080 --> 00:01:27.180 which is 20 per 100,000 30 00:01:27.180 --> 00:01:30.666 is 10 to 20 times higher than the incidence rates 31 00:01:30.666 --> 00:01:32.670 among women living in India and sub-Saharan Africa 32 00:01:32.670 --> 00:01:35.910 where rates are only one to two per 100,000. 33 00:01:35.910 --> 00:01:38.430 In contrast, mortality rates of thyroid cancer 34 00:01:38.430 --> 00:01:42.480 are markedly higher in low and middle income countries, 35 00:01:42.480 --> 00:01:44.550 and for example mortality rates range 36 00:01:44.550 --> 00:01:47.040 from one to three deaths per 100,000 among women 37 00:01:47.040 --> 00:01:48.840 in sub-Saharan Africa compared 38 00:01:48.840 --> 00:01:51.420 to only about 0.3 deaths per 100,000 39 00:01:51.420 --> 00:01:53.673 among women in Canada and the United States. 40 00:01:56.280 --> 00:01:59.400 Survival from malignant melanoma is nearly 100% 41 00:01:59.400 --> 00:02:01.620 if diagnosed prior to invasion of the dermis 42 00:02:01.620 --> 00:02:03.570 and metastatic spread. 43 00:02:03.570 --> 00:02:07.110 Overall, five year survival is 91% in the US 44 00:02:07.110 --> 00:02:08.850 and 81% in Europe. 45 00:02:08.850 --> 00:02:11.730 The survival in low and middle income countries 46 00:02:11.730 --> 00:02:14.640 is relatively poor, approximately 40% 47 00:02:14.640 --> 00:02:16.620 in large part due to late diagnosis 48 00:02:16.620 --> 00:02:18.273 and limited access to therapy, 49 00:02:19.491 --> 00:02:20.520 but also because melanomas often develop 50 00:02:20.520 --> 00:02:22.800 on the soles of the feet and thus go undetected 51 00:02:22.800 --> 00:02:27.513 until invasion and metastasis has occurred. 52 00:02:29.220 --> 00:02:33.030 When we look at the data of malignant melanoma incidence 53 00:02:33.030 --> 00:02:34.440 and mortality in 2020, 54 00:02:34.440 --> 00:02:36.210 we see that the age standardized incidence 55 00:02:36.210 --> 00:02:39.636 was 3.44 per 100,000 overall 56 00:02:39.636 --> 00:02:43.770 with a slightly higher rate in men than in women. 57 00:02:43.770 --> 00:02:44.940 When we look at mortality, 58 00:02:44.940 --> 00:02:46.470 we see that the overall rate 59 00:02:46.470 --> 00:02:49.370 is 0.56 per 100,000 people globally. 60 00:02:49.370 --> 00:02:54.370 While for men it's 0.70 per 100,000, 61 00:02:56.370 --> 00:02:59.133 and for women it's 0.45 per 100,000. 62 00:03:01.080 --> 00:03:03.060 Rapid increases in incidence and mortality 63 00:03:03.060 --> 00:03:06.840 have recently been observed in both sexes in many countries, 64 00:03:06.840 --> 00:03:08.250 even where rates, 65 00:03:08.250 --> 00:03:11.550 even in those where rates were formerly low like Japan. 66 00:03:11.550 --> 00:03:14.430 In the Nordic countries, for example, the rate of increase 67 00:03:14.430 --> 00:03:19.020 since 1980 has averaged approximately 30% every five years. 68 00:03:19.020 --> 00:03:21.660 Similar increases are evident in the US population 69 00:03:21.660 --> 00:03:23.280 where the incidence of malignant melanoma 70 00:03:23.280 --> 00:03:25.080 has more than tripled in men and women 71 00:03:25.080 --> 00:03:26.763 during the last three decades. 72 00:03:28.110 --> 00:03:30.090 The cell of origin of malignant melanoma 73 00:03:30.090 --> 00:03:31.200 is the melanocyte 74 00:03:31.200 --> 00:03:35.700 which resides in the basal layer of the epidermis. 75 00:03:35.700 --> 00:03:37.920 In this location, melanocytes are in contact 76 00:03:37.920 --> 00:03:40.023 with keratinocytes of the epidermis. 77 00:03:41.400 --> 00:03:43.320 Melanocytes synthesize melanin, 78 00:03:43.320 --> 00:03:44.610 a brownish black pigment 79 00:03:44.610 --> 00:03:47.863 that is distributed to surrounding keratinocytes 80 00:03:47.863 --> 00:03:51.000 through dendritic projections. 81 00:03:51.000 --> 00:03:54.093 Here we see the melanocytes synthesizing melanin. 82 00:03:55.967 --> 00:03:56.970 The melanocyte population 83 00:03:56.970 --> 00:03:59.643 rests upon a fibrous basement membrane 84 00:03:59.643 --> 00:04:01.740 that separates the epidermis from the dermis. 85 00:04:01.740 --> 00:04:03.930 When malignant melanoma first develops, 86 00:04:03.930 --> 00:04:05.880 the basement membrane forms a protective barrier 87 00:04:05.880 --> 00:04:09.480 that keeps the tumor cells confined in situ. 88 00:04:09.480 --> 00:04:11.970 However, malignant melanocytes are unusual 89 00:04:11.970 --> 00:04:14.100 in their ability to breach the basement membrane 90 00:04:14.100 --> 00:04:16.650 and invade the underlying dermis. 91 00:04:16.650 --> 00:04:18.960 The high metastatic potential of malignant melanoma 92 00:04:18.960 --> 00:04:21.030 is responsible for its significant impact 93 00:04:21.030 --> 00:04:22.233 on cancer mortality. 94 00:04:23.850 --> 00:04:26.490 Damage to melanocytes caused by ultraviolet radiation 95 00:04:26.490 --> 00:04:29.670 is central to the pathogenesis of malignant melanoma. 96 00:04:29.670 --> 00:04:32.640 For example, patients with xenoderma pigmentosum 97 00:04:32.640 --> 00:04:34.200 have a genetically inherited defect 98 00:04:34.200 --> 00:04:36.450 in the repair of DNA photo products 99 00:04:36.450 --> 00:04:39.000 induced by ultraviolet radiation. 100 00:04:39.000 --> 00:04:40.440 Individuals with this condition 101 00:04:40.440 --> 00:04:42.090 are at greatly increased risk 102 00:04:42.090 --> 00:04:43.560 of developing malignant melanoma, 103 00:04:43.560 --> 00:04:45.870 as well as squamous cell and basal cell carcinomas 104 00:04:45.870 --> 00:04:47.400 of the skin. 105 00:04:47.400 --> 00:04:50.651 Both ultraviolet A and ultraviolet B radiation 106 00:04:50.651 --> 00:04:54.653 have deleterious effects on the DNA of melanocytes 107 00:04:54.653 --> 00:04:55.890 and other cells of the skin. 108 00:04:55.890 --> 00:04:58.680 Ultraviolet B radiation induces the formation 109 00:04:58.680 --> 00:05:01.530 of pyrimidine dimers that are incorrectly repaired 110 00:05:01.530 --> 00:05:03.870 cause DNA mutations. 111 00:05:03.870 --> 00:05:06.600 Ultraviolet A radiation causes oxidative damage 112 00:05:06.600 --> 00:05:09.003 to DNA that is also potentially metagenic. 113 00:05:09.930 --> 00:05:12.810 Melanin serves photo protective functions in the skin. 114 00:05:12.810 --> 00:05:15.300 It absorbs ultraviolet protons 115 00:05:15.300 --> 00:05:17.430 in reactive oxygen species generated 116 00:05:17.430 --> 00:05:20.100 by the interaction of photons with cell membrane lipids 117 00:05:20.100 --> 00:05:22.203 and other cellular components. 118 00:05:23.040 --> 00:05:26.670 Within cells, melanin forms a super nuclear protective cap 119 00:05:26.670 --> 00:05:29.220 around the nucleus, thereby shielding the nuclear DNA 120 00:05:29.220 --> 00:05:31.113 from damaging ultraviolet radiation. 121 00:05:32.010 --> 00:05:33.810 The photo protective property of melanin 122 00:05:33.810 --> 00:05:36.472 is illustrated by the phenomenon of tanning 123 00:05:36.472 --> 00:05:37.920 in response to ultraviolet radiation. 124 00:05:37.920 --> 00:05:41.250 Tanning is due to enhanced proliferation of melanocytes 125 00:05:41.250 --> 00:05:44.220 accompanied by increased synthesis and transfer of melanin 126 00:05:44.220 --> 00:05:45.873 to surrounding keratinocytes. 127 00:05:47.273 --> 00:05:48.840 The primary risk factor 128 00:05:48.840 --> 00:05:50.400 for the development of malignant melanoma 129 00:05:50.400 --> 00:05:53.580 is excessive exposure to ultraviolet rays from the sun. 130 00:05:53.580 --> 00:05:56.310 Many epidemiologic investigations have also demonstrated 131 00:05:56.310 --> 00:05:58.350 that the risk increases with lighter pigmentation 132 00:05:58.350 --> 00:06:00.150 of the skin by melanin. 133 00:06:00.150 --> 00:06:01.890 Individuals with lightly pigmented skin 134 00:06:01.890 --> 00:06:03.000 are at the highest risk. 135 00:06:03.000 --> 00:06:04.740 Individuals with darkly pigmented skin 136 00:06:04.740 --> 00:06:06.510 are at the lowest risk. 137 00:06:06.510 --> 00:06:08.970 Other phenotypic factors also increase the risk 138 00:06:08.970 --> 00:06:12.270 including inability to tan, light eye color, red hair, 139 00:06:12.270 --> 00:06:13.470 and extensive freckling. 140 00:06:14.490 --> 00:06:16.290 Furthermore, the risk increases 141 00:06:16.290 --> 00:06:18.770 with the number of pigmented nevi. 142 00:06:18.770 --> 00:06:22.530 The risk of malignant melanoma development is clearly linked 143 00:06:22.530 --> 00:06:24.870 to cumulative exposure to the sun. 144 00:06:24.870 --> 00:06:27.450 The risk is heightened by intense intermittent exposure 145 00:06:27.450 --> 00:06:29.040 causing multiple sunburns, 146 00:06:29.040 --> 00:06:31.536 particularly during childhood and adolescence. 147 00:06:31.536 --> 00:06:34.290 Malignant melanoma frequently occurs 148 00:06:34.290 --> 00:06:35.130 in areas of the body 149 00:06:35.130 --> 00:06:37.440 that are in intermittently exposed to the sun 150 00:06:37.440 --> 00:06:40.200 such as the back in men and lower legs in women 151 00:06:40.200 --> 00:06:42.900 with relative sparing of more frequently exposed sites 152 00:06:42.900 --> 00:06:45.033 like the face, hands, and forearms. 153 00:06:45.990 --> 00:06:47.670 It's more likely to develop in persons 154 00:06:47.670 --> 00:06:49.410 with predominantly indoor occupations 155 00:06:49.410 --> 00:06:51.255 whose exposure to the sun 156 00:06:51.255 --> 00:06:52.380 is limited to weekends and vacations, 157 00:06:52.380 --> 00:06:53.610 and the marked increase 158 00:06:53.610 --> 00:06:55.830 in the incidence of malignant melanoma in recent decades 159 00:06:55.830 --> 00:06:59.040 may reflect the effects of intense intermittent exposure 160 00:06:59.040 --> 00:07:01.500 in individuals who vacation in sunny climates 161 00:07:01.500 --> 00:07:02.793 during the winter months. 162 00:07:04.253 --> 00:07:07.080 A history of five or more sunburns during adolescence 163 00:07:07.080 --> 00:07:09.530 more than doubles the risk of malignant melanoma. 164 00:07:11.248 --> 00:07:14.550 As pointed out in a review of melanoma epidemiology, 165 00:07:14.550 --> 00:07:17.130 there are two broad categories of pigmented nevi, 166 00:07:17.130 --> 00:07:18.870 common and dysplastic 167 00:07:18.870 --> 00:07:22.080 which carry different risks of melanoma development. 168 00:07:22.080 --> 00:07:24.810 Dysplastic nevi, which carry a far greater risk 169 00:07:24.810 --> 00:07:27.480 are characterized by size greater than five millimeters 170 00:07:27.480 --> 00:07:30.220 at largest diameter, a flat surface, 171 00:07:30.220 --> 00:07:34.230 irregular asymmetric shapes, indiscriminate borders 172 00:07:34.230 --> 00:07:37.147 and variability in the degree of pigmentation. 173 00:07:37.147 --> 00:07:40.290 In a meta-analysis of 46 epidemiologic studies, 174 00:07:40.290 --> 00:07:43.770 dose responses were examined in melanoma risk 175 00:07:43.770 --> 00:07:47.190 associated with the number of common or dysplastic nevi. 176 00:07:47.190 --> 00:07:49.560 Individuals with more than 100 common nevi 177 00:07:49.560 --> 00:07:51.186 have a relative risk of 6.4 178 00:07:51.186 --> 00:07:55.413 compared to individuals with less than 15 common nevi. 179 00:07:58.830 --> 00:08:02.130 Approximately 10% of melanoma cases diagnosed in the US 180 00:08:02.130 --> 00:08:06.000 report that one or more relatives are also affected. 181 00:08:06.000 --> 00:08:07.140 In case control studies, 182 00:08:07.140 --> 00:08:08.760 individuals with a positive family history 183 00:08:08.760 --> 00:08:10.440 have roughly a twofold increased risk 184 00:08:10.440 --> 00:08:12.790 compared to individuals with no family history. 185 00:08:13.680 --> 00:08:16.890 The family atypical mole and melanoma or FAMM syndrome 186 00:08:16.890 --> 00:08:18.210 is a rare genetic disorder 187 00:08:18.210 --> 00:08:20.710 giving rise to multiple dysplastic pigmented moles 188 00:08:22.209 --> 00:08:24.353 of the skin that invariably progress to malignant melanoma. 189 00:08:25.260 --> 00:08:27.720 Genetic linkage studies of members of families 190 00:08:27.720 --> 00:08:28.710 with the FAMM syndrome 191 00:08:28.710 --> 00:08:31.500 have identified two major susceptibility genes, 192 00:08:31.500 --> 00:08:35.220 CDKN2A and CDK4, both of which are inherited 193 00:08:35.220 --> 00:08:37.710 in an autosomal dominant pattern. 194 00:08:37.710 --> 00:08:40.230 Carriers of either mutant gene are at 100% risk 195 00:08:40.230 --> 00:08:43.860 at developing malignant melanoma during their lifetimes. 196 00:08:43.860 --> 00:08:45.450 One form of the FAMM syndrome 197 00:08:45.450 --> 00:08:50.430 is caused by mutation in CDKN2A, the gene that encodes P16, 198 00:08:50.430 --> 00:08:53.580 an important cell cycle regulating protein. 199 00:08:53.580 --> 00:08:56.871 The CDKN2A gene is located on the short arm 200 00:08:56.871 --> 00:08:59.250 of chromosome nine, and this gene normally codes 201 00:08:59.250 --> 00:09:02.190 for the tumor suppressor protein P16, which is essential 202 00:09:02.190 --> 00:09:04.680 for the regulation of cell division. 203 00:09:04.680 --> 00:09:08.790 Mutant forms of CDKN2A encode dysfunctional P16 protein 204 00:09:08.790 --> 00:09:10.980 that leads to a loss of control of cell division 205 00:09:10.980 --> 00:09:14.007 and enhanced proliferation of melanocytes. 206 00:09:14.007 --> 00:09:16.140 A second form of the FAMM syndrome 207 00:09:16.140 --> 00:09:18.660 is caused by mutation in the CDK4 gene 208 00:09:18.660 --> 00:09:21.720 which maps to the long arm of chromosome 12. 209 00:09:21.720 --> 00:09:24.030 This gene also codes for an oncogenic protein 210 00:09:24.030 --> 00:09:26.190 that is important for the regulation of cell division 211 00:09:26.190 --> 00:09:27.840 of melanocytes. 212 00:09:27.840 --> 00:09:29.820 Mutations in this gene are very rare 213 00:09:29.820 --> 00:09:33.243 and have been detected only in a few families. 214 00:09:36.120 --> 00:09:39.570 In 2009, the International Agency for Research on Cancer 215 00:09:39.570 --> 00:09:42.690 or IARC released a report that categorized tanning beds 216 00:09:42.690 --> 00:09:44.880 as carcinogenic to humans. 217 00:09:44.880 --> 00:09:47.100 This classification is based upon analysis 218 00:09:47.100 --> 00:09:49.020 of more than 20 epidemiological studies 219 00:09:49.020 --> 00:09:51.510 indicating that people who begin using tanning devices 220 00:09:51.510 --> 00:09:56.510 before age 30 are 75% more likely to develop melanoma. 221 00:09:59.670 --> 00:10:01.230 The stratospheric ozone layer 222 00:10:01.230 --> 00:10:03.210 resides 10 to 30 miles above the earth 223 00:10:03.210 --> 00:10:04.620 and acts as a protective shield 224 00:10:04.620 --> 00:10:07.080 against the sun's harmful ultraviolet rays, 225 00:10:07.080 --> 00:10:09.930 particularly UVB rays. 226 00:10:09.930 --> 00:10:12.300 The natural ozone shield has been gradually depleted 227 00:10:12.300 --> 00:10:14.850 by the atmospheric release of manmade chemicals 228 00:10:14.850 --> 00:10:17.340 like chlorofluorocarbons or freons 229 00:10:17.340 --> 00:10:19.950 and Bromofluorocarbons or halons 230 00:10:19.950 --> 00:10:24.420 that spark the catalytic destruction of ozone. 231 00:10:24.420 --> 00:10:27.570 Ozone destruction is most prominent around the polar regions 232 00:10:27.570 --> 00:10:29.400 of the earth leading to ozone holes 233 00:10:29.400 --> 00:10:33.060 and penetration of the earth's atmosphere by UVB rays. 234 00:10:33.060 --> 00:10:35.100 Excessive exposure to UVB rays 235 00:10:35.100 --> 00:10:38.103 is linked to the development of malignant melanoma 236 00:10:38.103 --> 00:10:39.930 as well as other conditions like cataracts. 237 00:10:39.930 --> 00:10:42.930 Such windows of UVB exposure appear to coincide roughly 238 00:10:42.930 --> 00:10:45.702 with the high mortality rates of malignant melanoma 239 00:10:45.702 --> 00:10:48.240 in the southern hemispheres of the world. 240 00:10:48.240 --> 00:10:50.220 Finally, let's briefly discuss prevention 241 00:10:50.220 --> 00:10:52.020 of malignant melanoma. 242 00:10:52.020 --> 00:10:55.170 So as noted, a key risk factor from malignant melanoma 243 00:10:55.170 --> 00:10:58.530 is ultraviolet ray exposure. 244 00:10:58.530 --> 00:11:01.350 So naturally, the primary prevention of malignant melanoma 245 00:11:01.350 --> 00:11:03.090 is dependent upon minimizing exposure 246 00:11:03.090 --> 00:11:05.700 to intensive ultraviolet radiation from the sun, 247 00:11:05.700 --> 00:11:07.684 tanning beds and other sources of radiation. 248 00:11:07.684 --> 00:11:10.320 Avoidance of intense sun exposure 249 00:11:10.320 --> 00:11:11.970 during peak times of the day, 250 00:11:11.970 --> 00:11:14.520 wearing protective clothing and using sunscreen lotions 251 00:11:14.520 --> 00:11:15.693 can offer protection. 252 00:11:16.770 --> 00:11:19.170 National and community programs of secondary prevention 253 00:11:19.170 --> 00:11:21.480 have also proven to be highly effective. 254 00:11:21.480 --> 00:11:23.190 The American Academy of Dermatology 255 00:11:23.190 --> 00:11:24.900 recommends annual inspection of the skin 256 00:11:24.900 --> 00:11:26.910 by a certified dermatologist for the detection 257 00:11:26.910 --> 00:11:30.000 and surgical removal of dysplastic pigmented nevi 258 00:11:30.000 --> 00:11:31.320 and other suspicious lesions 259 00:11:31.320 --> 00:11:33.370 prior to their progression to malignancy. 260 00:11:34.380 --> 00:11:37.380 Finally, a special surgical technique called Mohs surgery 261 00:11:37.380 --> 00:11:39.480 where repeated circumferential sections 262 00:11:39.480 --> 00:11:42.300 of tumor are removed and microscopically examined 263 00:11:42.300 --> 00:11:44.250 until cancer-free margins are evident 264 00:11:44.250 --> 00:11:45.480 has been shown to be effective 265 00:11:45.480 --> 00:11:48.813 in treating in situ cutaneous malignant melanomas.