WEBVTT 1 00:00:00.360 --> 00:00:02.040 Hi all and welcome to this lecture 2 00:00:02.040 --> 00:00:05.141 on the epidemiology of testicular cancer. 3 00:00:05.141 --> 00:00:06.871 In this lecture, we have several goals. 4 00:00:06.871 --> 00:00:09.390 We'll review the anatomy of the testis. 5 00:00:09.390 --> 00:00:11.340 We'll review spermatogenesis. 6 00:00:11.340 --> 00:00:13.560 Look at the global burden of testicular cancer, 7 00:00:13.560 --> 00:00:15.592 and trends in testicular cancer. 8 00:00:15.592 --> 00:00:17.478 We also will discuss risk factors, 9 00:00:17.478 --> 00:00:20.490 and prevention in therapy. 10 00:00:20.490 --> 00:00:23.730 So to begin with, we'll give a brief overview 11 00:00:23.730 --> 00:00:27.630 of the anatomy of the testis. 12 00:00:27.630 --> 00:00:28.800 So each testis consists 13 00:00:28.800 --> 00:00:32.760 of approximately 250 lobules separated by fibrous strands. 14 00:00:32.760 --> 00:00:35.850 Each lobule consists of loose connective tissue, 15 00:00:35.850 --> 00:00:39.000 and a network of tubules called seminiferous tubules. 16 00:00:39.000 --> 00:00:41.820 Each seminiferous tubule is lined by a basement membrane 17 00:00:41.820 --> 00:00:44.430 that supports the germinal epithelium. 18 00:00:44.430 --> 00:00:46.020 The germinal epithelium is made 19 00:00:46.020 --> 00:00:49.800 up of primordial germ cells or spermatogonia, 20 00:00:49.800 --> 00:00:52.080 from which sperm arise. 21 00:00:52.080 --> 00:00:54.543 Spermatogonia are sperms, or stem cells, 22 00:00:54.543 --> 00:00:57.810 which proliferate by mitosis. 23 00:00:57.810 --> 00:01:00.630 As spermatogonia move away from the basement membrane, 24 00:01:00.630 --> 00:01:02.220 they undergo miosis 25 00:01:02.220 --> 00:01:05.700 to form immature sperm called spermatids. 26 00:01:05.700 --> 00:01:10.290 Two important cell types, sertoli cells, and leydig cells, 27 00:01:10.290 --> 00:01:12.990 stimulate and regulate the process of spermatogenesis. 28 00:01:14.003 --> 00:01:16.950 Sertoli cells are nurse cells, and secrete estrogen 29 00:01:16.950 --> 00:01:19.735 and other hormones in response to the pituitary hormone, 30 00:01:19.735 --> 00:01:23.280 follicular stimulating hormone, or FSH. 31 00:01:23.280 --> 00:01:25.530 Leydig cells secrete testosterone, 32 00:01:25.530 --> 00:01:28.530 in response to the pituitary hormone, luteinizing hormone, 33 00:01:28.530 --> 00:01:30.697 or LH. 34 00:01:30.697 --> 00:01:33.207 Spermatic angiogenesis involves both mitotic, 35 00:01:33.207 --> 00:01:36.300 and myotic divisions of germinal epithelial cells 36 00:01:36.300 --> 00:01:39.213 under the influence of testosterone and estrogen. 37 00:01:40.434 --> 00:01:45.245 So 95% of all tumors of the testis are germ cell neoplasms. 38 00:01:45.245 --> 00:01:48.480 There are four specific types of germ cell tumors. 39 00:01:48.480 --> 00:01:53.480 Seminomas, embryonal carcinomas, malignant teratomas, 40 00:01:53.760 --> 00:01:56.190 and choriocarcinomas. 41 00:01:56.190 --> 00:01:57.450 These lesions can be combined 42 00:01:57.450 --> 00:02:02.117 into two histologic groups, seminomas and non-seminomas. 43 00:02:02.117 --> 00:02:06.597 So seminomas arise from sertoli or leydig cells, 44 00:02:06.597 --> 00:02:09.810 and they're predominantly occur in young adults. 45 00:02:09.810 --> 00:02:12.660 They're rare during infancy, and they're radio-sensitive. 46 00:02:13.500 --> 00:02:16.110 These have a monotonous histology. 47 00:02:16.110 --> 00:02:18.810 Non-seminomas arise from embryonic cells, 48 00:02:18.810 --> 00:02:20.700 and they're common in infants. 49 00:02:20.700 --> 00:02:22.470 They're not radio-sensitive, 50 00:02:22.470 --> 00:02:24.843 and they have a variable histology. 51 00:02:26.790 --> 00:02:30.383 Embryonal carcinomas have a high AFP, 52 00:02:30.383 --> 00:02:33.030 while malignant teratomas are characterized 53 00:02:33.030 --> 00:02:34.980 by bizarre histology. 54 00:02:34.980 --> 00:02:39.980 Choriocarcinomas are characterized by high HCG values. 55 00:02:42.240 --> 00:02:45.480 50% of all germ cell tumors are seminomas, 56 00:02:45.480 --> 00:02:47.910 and 50% are non-seminomas. 57 00:02:47.910 --> 00:02:50.850 Non-seminomas often represent tumors of mixed histology, 58 00:02:50.850 --> 00:02:54.030 and may include a wide variety of histologic subtypes. 59 00:02:54.030 --> 00:02:55.800 A recent study evaluating the histology 60 00:02:55.800 --> 00:02:58.650 of mixed germ cell tumors reported a strong association 61 00:02:58.650 --> 00:03:01.083 between teratomas, and yolk sac tumors. 62 00:03:04.590 --> 00:03:06.600 So to turn to incidence in prevalence. 63 00:03:06.600 --> 00:03:11.340 During 2012, 55,266 new cases of testicular cancer 64 00:03:11.340 --> 00:03:13.110 were diagnosed globally, 65 00:03:13.110 --> 00:03:15.903 and a little over 10,000 men died of the disease. 66 00:03:16.830 --> 00:03:19.050 The annual incidence of testicular cancer worldwide 67 00:03:19.050 --> 00:03:21.360 has remained stable during the last decade, 68 00:03:21.360 --> 00:03:24.540 at about 1.5 cases per 100,000 men. 69 00:03:24.540 --> 00:03:26.687 However, the incidence rates vary more than 20-fold, 70 00:03:26.687 --> 00:03:30.440 among nations ranging from less than 0.5 per 100,000, 71 00:03:30.440 --> 00:03:33.229 in some Asian and African, or African American populations, 72 00:03:33.229 --> 00:03:37.713 to over 12 per 100,000 in Norway, Denmark, and Switzerland. 73 00:03:38.730 --> 00:03:41.340 The annual mortality of testicular cancer worldwide 74 00:03:41.340 --> 00:03:43.470 has also remained stable during the last decade, 75 00:03:43.470 --> 00:03:46.800 at about 0.3 deaths per 100,000 men. 76 00:03:46.800 --> 00:03:48.450 Mortality rates are highest in nations 77 00:03:48.450 --> 00:03:49.590 of high incidence rates, 78 00:03:49.590 --> 00:03:51.333 and access to therapy is limited. 79 00:03:52.320 --> 00:03:56.040 In 2020, the age-standardized incidence of testicular cancer 80 00:03:56.040 --> 00:03:57.930 was 1.8 per 100,000 men, 81 00:03:57.930 --> 00:04:01.143 and the mortality was 0.22 per 100,000 men. 82 00:04:02.460 --> 00:04:04.740 The annual incidence has steadily increased over time 83 00:04:04.740 --> 00:04:07.683 in some populations, particularly in developed nations. 84 00:04:08.610 --> 00:04:10.320 For example, the incidence more than doubled 85 00:04:10.320 --> 00:04:13.290 in Great Britain during 1975 to 2010. 86 00:04:14.229 --> 00:04:15.570 In the face of rising incidence rates 87 00:04:15.570 --> 00:04:18.540 of testicular cancer, mortality rates are steadily declining 88 00:04:18.540 --> 00:04:19.953 in many populations. 89 00:04:21.570 --> 00:04:23.850 The incidence of testicular cancer among American men 90 00:04:23.850 --> 00:04:26.640 has almost doubled over the last 40 years. 91 00:04:26.640 --> 00:04:29.250 Increases are most pronounced in white males, 92 00:04:29.250 --> 00:04:33.180 though definitive evidence of causation remains elusive. 93 00:04:33.180 --> 00:04:35.921 The age-specific incidence of testicular cancer is distinct 94 00:04:35.921 --> 00:04:38.190 from that of other cancers. 95 00:04:38.190 --> 00:04:40.200 The majority of incidence cases are diagnosed 96 00:04:40.200 --> 00:04:42.390 between the ages of 20 and 40 years, 97 00:04:42.390 --> 00:04:44.640 though a second much smaller peak occurs 98 00:04:44.640 --> 00:04:46.620 after 80 years of age. 99 00:04:46.620 --> 00:04:49.530 An even smaller peak occurs in infants. 100 00:04:49.530 --> 00:04:52.260 Non-seminomas tend to occur prior to age 30, 101 00:04:52.260 --> 00:04:54.390 whereas seminomas show a slightly larger age 102 00:04:54.390 --> 00:04:55.473 of onset pattern. 103 00:04:56.719 --> 00:04:58.380 Within nations, the incidence 104 00:04:58.380 --> 00:05:00.630 of testicular cancer varies markedly by race 105 00:05:00.630 --> 00:05:02.430 with African Americans, and other people of color 106 00:05:02.430 --> 00:05:04.530 exhibiting extremely low rates in comparison 107 00:05:04.530 --> 00:05:06.390 to white populations. 108 00:05:06.390 --> 00:05:09.030 In the US, the incidence of testicular cancer in 2012 109 00:05:09.030 --> 00:05:11.460 was about five times higher among white people, 110 00:05:11.460 --> 00:05:14.853 than African Americans during 1975 to 2010. 111 00:05:16.913 --> 00:05:21.360 Testicular germ cell tumor carrier types are characterized 112 00:05:21.360 --> 00:05:24.030 by neotriploid with chromosome numbers ranging 113 00:05:24.030 --> 00:05:29.030 from 50 to 70, as opposed to the typical diploid, 46. 114 00:05:29.580 --> 00:05:34.580 That is in these germ cell tumors, 115 00:05:34.800 --> 00:05:36.290 there are extra chromosomes. 116 00:05:36.290 --> 00:05:40.710 There's also frequent appearance more than 50% of the time. 117 00:05:40.710 --> 00:05:43.711 There's an isochromosomes of the short arm of chromosome 12, 118 00:05:43.711 --> 00:05:44.847 called i(12p). 119 00:05:46.140 --> 00:05:47.580 That's exhibited here on the slide. 120 00:05:47.580 --> 00:05:52.350 Whereas for chromosome 12, rather than having one short arm, 121 00:05:52.350 --> 00:05:54.783 and one long arm, it has two short arms. 122 00:05:56.220 --> 00:05:57.960 The high chromosome number has been attributed 123 00:05:57.960 --> 00:06:00.720 to the formation of tetraploid carcinoma in situ cells 124 00:06:00.720 --> 00:06:02.910 followed by chromosomal losses that ultimately lead 125 00:06:02.910 --> 00:06:05.073 to tumor forms that are more advanced. 126 00:06:07.230 --> 00:06:09.900 There's a number of risk factors for testicular cancer. 127 00:06:09.900 --> 00:06:14.900 One is cryptorchidism, or MDT, or maldescended testes. 128 00:06:16.380 --> 00:06:18.510 In this case, the testicle lies 129 00:06:18.510 --> 00:06:21.300 above the external inguinal ring, either 130 00:06:21.300 --> 00:06:23.624 within the inguinal canal, or within the abdomen. 131 00:06:23.624 --> 00:06:28.419 This is non-palpable in the anesthetized patient, 132 00:06:28.419 --> 00:06:32.940 and the abnormality can be unilateral, or bilateral. 133 00:06:32.940 --> 00:06:35.250 MDT is associated with a 2 to 4-fold increase 134 00:06:35.250 --> 00:06:36.840 in the risk of testicular cancer, 135 00:06:36.840 --> 00:06:40.470 with a population attributable risk of 10%. 136 00:06:40.470 --> 00:06:42.390 Some studies have reported a relative risk 137 00:06:42.390 --> 00:06:44.820 for testicular cancer associated with MDT in the range 138 00:06:44.820 --> 00:06:46.320 of 5 to 10-fold. 139 00:06:46.320 --> 00:06:48.056 And MDT prevalence has increased 140 00:06:48.056 --> 00:06:52.650 in Denmark over the last 40 years. 141 00:06:52.650 --> 00:06:53.880 There are striking differences 142 00:06:53.880 --> 00:06:56.760 in testicular cancer incidents between Denmark and Finland, 143 00:06:56.760 --> 00:07:01.260 despite their geographic proximity. 144 00:07:01.260 --> 00:07:02.520 Recently, two large studies 145 00:07:02.520 --> 00:07:04.731 have demonstrated large differences 146 00:07:04.731 --> 00:07:06.643 between the two countries in the prevalence 147 00:07:06.643 --> 00:07:08.850 of MDT at birth, and at three months of age. 148 00:07:08.850 --> 00:07:11.341 Genetic lifestyle and environmental factors may be involved 149 00:07:11.341 --> 00:07:14.403 in the etiology of MDT, and testicular cancer. 150 00:07:17.190 --> 00:07:22.190 MDT can be treated by orchiopexy before the age of 10 years, 151 00:07:24.761 --> 00:07:27.510 and rapid detection of MDT, 152 00:07:27.510 --> 00:07:29.940 and timely surgical correction is essential 153 00:07:29.940 --> 00:07:32.793 in lowering the risk of developing testicular cancer. 154 00:07:33.732 --> 00:07:38.370 There also is a possible role of high endogenous estrogens 155 00:07:38.370 --> 00:07:42.270 during gestation in the risk of testicular cancer. 156 00:07:42.270 --> 00:07:43.920 Firstborn males may be at higher risk, 157 00:07:43.920 --> 00:07:45.180 and fraternal twins may be 158 00:07:45.180 --> 00:07:47.610 at higher risk than identical twins. 159 00:07:47.610 --> 00:07:49.470 Males with a female co-twin may also be 160 00:07:49.470 --> 00:07:51.510 at higher risk of testicular cancer, 161 00:07:51.510 --> 00:07:54.543 though evidence is inconsistent for all of these cases. 162 00:07:56.910 --> 00:08:01.910 Mumps can also lead to a higher rate of testicular cancer. 163 00:08:02.820 --> 00:08:04.740 Mumps is a contagious disease of childhood, 164 00:08:04.740 --> 00:08:07.920 and young adulthood, and it is spread by contact 165 00:08:07.920 --> 00:08:10.020 with respiratory secretions. 166 00:08:10.020 --> 00:08:13.350 Vaccinations do exist, and common symptoms are swelling 167 00:08:13.350 --> 00:08:17.103 of salivary glands, orchitis, and epididymitis in males. 168 00:08:18.090 --> 00:08:20.573 In a 1987 case control study, it was found 169 00:08:20.573 --> 00:08:25.460 that mumps infection raises... 170 00:08:26.617 --> 00:08:27.450 There are those with mumps infection 171 00:08:27.450 --> 00:08:30.870 have a 5.8 times greater chance 172 00:08:30.870 --> 00:08:33.753 of developing testicular cancer than those without mumps. 173 00:08:36.772 --> 00:08:39.000 Other risk factors include in utero exposure 174 00:08:39.000 --> 00:08:42.053 to diethylstilbestrol which we discussed 175 00:08:42.053 --> 00:08:44.460 in a previous lecture. 176 00:08:44.460 --> 00:08:47.344 While there's insufficient evidence to show that exposure 177 00:08:47.344 --> 00:08:52.061 to DES in utero is a risk factor for testicular cancer, 178 00:08:52.061 --> 00:08:53.520 it has been found 179 00:08:53.520 --> 00:08:56.130 that there was a nonsignificant 3-fold increase in risk 180 00:08:56.130 --> 00:08:58.980 in men exposed to DES in utero in one study. 181 00:08:58.980 --> 00:09:01.200 However, this study only involves seven cases 182 00:09:01.200 --> 00:09:04.263 of testicular cancer in the DES-exposed group. 183 00:09:05.160 --> 00:09:08.670 There also potentially are maternal risk factors, 184 00:09:08.670 --> 00:09:11.640 including late, or early age of pregnancy, prematurity, 185 00:09:11.640 --> 00:09:14.177 low birth weight, congenital malformations, 186 00:09:14.177 --> 00:09:16.950 and exposure to tobacco and alcohol 187 00:09:16.950 --> 00:09:18.843 though evidence is inconsistent. 188 00:09:20.820 --> 00:09:22.830 Occupational lifestyle, socioeconomic, 189 00:09:22.830 --> 00:09:25.500 and other risk factors have demonstrated mixed associations 190 00:09:25.500 --> 00:09:27.480 with testicular cancer. 191 00:09:27.480 --> 00:09:31.050 Hormonal imbalance, that is high estrogens and low androgens 192 00:09:31.050 --> 00:09:34.620 in various life stages may initiate testicular cancer. 193 00:09:34.620 --> 00:09:36.870 Lifestyle and occupational exposures occurring later 194 00:09:36.870 --> 00:09:38.910 in life may play a role in promoting the disease, 195 00:09:38.910 --> 00:09:41.810 although they're not likely involved in cancer initiation. 196 00:09:43.169 --> 00:09:47.580 In a case controlled study of non-seminoma testicular cancer 197 00:09:47.580 --> 00:09:52.580 involving 163 cases, and 292 healthy controls, it was found 198 00:09:53.010 --> 00:09:55.680 that marijuana use doubled the risk of testicular cancer, 199 00:09:55.680 --> 00:09:58.276 but cocaine use reduced the risk, 200 00:09:58.276 --> 00:10:03.213 suggesting that more studies are important. 201 00:10:05.190 --> 00:10:07.830 We also see that testicular teratomas and yolk sac tumors 202 00:10:07.830 --> 00:10:11.730 of prepubertal boys are rare. 203 00:10:11.730 --> 00:10:14.444 The annual rate is 1.2 per million. 204 00:10:14.444 --> 00:10:18.210 Though testicular teratomas are usually benign, 205 00:10:18.210 --> 00:10:20.880 and curable by orchidectomy. 206 00:10:20.880 --> 00:10:23.340 Yolk sac tumors typically show aneuploidy, 207 00:10:23.340 --> 00:10:27.060 often tetraploidy, and have invasive malignant potential, 208 00:10:27.060 --> 00:10:29.490 thus requiring combination therapy. 209 00:10:29.490 --> 00:10:33.180 Again, mentioning that these tumors are related 210 00:10:33.180 --> 00:10:34.980 to abnormal numbers of chromosomes. 211 00:10:34.980 --> 00:10:38.340 That tetraploidy means having four copies 212 00:10:38.340 --> 00:10:42.213 of the chromosome set as opposed to the typical two. 213 00:10:44.190 --> 00:10:46.350 The identification and monitoring of individuals 214 00:10:46.350 --> 00:10:48.660 with carcinoma in situ can lead to early detection 215 00:10:48.660 --> 00:10:52.080 of testicular cancer, which is key to successful treatment. 216 00:10:52.080 --> 00:10:54.150 It is possible that detection of testicular cancer 217 00:10:54.150 --> 00:10:57.228 could eventually be aided by the identification of CIS 218 00:10:57.228 --> 00:11:00.080 in younger adolescent males, since all cases of CIS 219 00:11:00.080 --> 00:11:02.463 of the testis eventually progressed to cancer. 220 00:11:03.300 --> 00:11:06.600 Thus mitigating the factors that cause carcinoma in situ 221 00:11:06.600 --> 00:11:09.197 in preventing the progression of the CIS to invasive cancer, 222 00:11:09.197 --> 00:11:12.180 may help in reducing testicular cancer incidents, 223 00:11:12.180 --> 00:11:14.043 and increasing survival rates. 224 00:11:15.510 --> 00:11:17.610 At present, surgical testicular biopsy 225 00:11:17.610 --> 00:11:18.600 is the most common method 226 00:11:18.600 --> 00:11:21.690 of diagnosing testicular carcinoma in situ. 227 00:11:21.690 --> 00:11:24.090 Because of its invasive nature, biopsy is not suitable 228 00:11:24.090 --> 00:11:25.590 as a screening tool, 229 00:11:25.590 --> 00:11:27.690 and there are several new noninvasive technologies, 230 00:11:27.690 --> 00:11:29.400 including scrotal ultrasonography, 231 00:11:29.400 --> 00:11:33.720 and the analysis of semen for carcinoma in situ cells. 232 00:11:33.720 --> 00:11:36.150 Due to the difficulty of diagnosing carcinoma in situ, 233 00:11:36.150 --> 00:11:38.520 in apparently healthy men, it is not possible 234 00:11:38.520 --> 00:11:41.000 to obtain a valid estimate of the prevalence of CIS 235 00:11:41.000 --> 00:11:43.113 in the general population at this time. 236 00:11:44.370 --> 00:11:46.500 Finally, treatment of testicular cancer usually 237 00:11:46.500 --> 00:11:49.770 involves surgery, usually orchiectomy, 238 00:11:49.770 --> 00:11:52.500 and retroperitoneal lymph node dissection, 239 00:11:52.500 --> 00:11:54.600 depending on the stage of the cancer. 240 00:11:54.600 --> 00:11:57.030 After surgery, the patient usually undergoes radiation 241 00:11:57.030 --> 00:11:58.589 and, or chemotherapy. 242 00:11:58.589 --> 00:12:00.750 And advances in treatment have led to an increase 243 00:12:00.750 --> 00:12:02.820 in the five-year survival for testicular cancer, 244 00:12:02.820 --> 00:12:06.983 during the last 30 years, from 63% to 90%. 245 00:12:07.980 --> 00:12:11.700 Current research on testicular cancer treatment, focuses 246 00:12:11.700 --> 00:12:14.893 on individualizing therapy for specific patients, 247 00:12:14.893 --> 00:12:18.033 so that survival is not compromised.