CRYPTORCHISM, ORCHIOPEXY, AND THE RISK OF TESTICULAR CANCER

Transcription

1 AMERICAN JOURNAL OF EPIDEMIOLOGY Copyright 1988 by The Johns Hopkins University School of Hygiene and Public Health All rights reserved Vol. 127, No. 5 Printed in U.S.A. CRYPTORCHISM, ORCHIOPEXY, AND THE RISK OF TESTICULAR CANCER CLIFTON H. STRADER, 1 NOEL S. WEISS, " JANET R. DALING, 11-3 MARGARET R. KARAGAS, 2-3 AND BARBARA MCKNIGHT 2-4 Strader, C. H., N. S. Weiss, J. R. Daling (The Fred Hutchinson Cancer Research Center, Seattle, WA 98104), M. R. Karagas, and B. McKnight. Cryptorchism, orchiopexy, and the risk of testicular cancer. Am J Epidemiol 1988;127: Adult white male residents of 13 counties of western Washington State in whom germ cell testicular cancer was diagnosed between 1977 and 1983 (n = 333) were interviewed by telephone regarding their history of cryptorchism and its treatment. The same interview was given to a sample of 675 men selected from the population of these counties by dialing telephone numbers at random. Men who reported a history of cryptorchism were 5.9 times (95 per cent confidence interval ) more likely than men without such a history to develop testicular cancer. Compared with noncryptorchid men, those with unilateral cryptorchism were at greater risk of developing a tumor on the side of nondescent (relative risk = 8.0) than on the opposite side (relative risk = 1.6). The size of the increased risk tended to be smaller among cryptorchid men who had undergone orchiopexy by age 10 than for other cryptorchid men, but the influence of orchiopexy in early childhood could not be evaluated in this population. These observations offer support for the hypothesis that one or more local factors (e.g., temperature elevation) account for the major part of the increased risk of germ cell testicular tumors in cryptorchid men. cryptorchism; testicular neoplasms A history of cryptorchism is associated with a three- to 10-fold increase in risk of testicular cancer (1-4). There is some debate as to whether the increased risk results from the effects of the testis not being located in the scrotum or from some underlying abnormality responsible for both the failure of the testis to descend and the increased risk of malignancy (5). The former hypothesis, which attributes the increased risk to the abnormal location per se, would be supported if 1) among men with unilateral cryptorchism, the excess risk were confined to the undescended testis, and 2) correction of the cryptorchid testis diminished or eliminated the increased cancer risk. Unfortunately, the studies that have examined these issues have produced conflicting results (2, 4, 6, 7). Received for publication March 23, 1987, and in final form July 20, Hanford Environmental Health Foundation, Richland, WA. 2 Division of Public Health Sciences, The Fred Hutchinson Cancer Research Center, 1124 Columbia Street (W-108), Seattle, WA (Reprint requests to Dr. Janet R. Daling.) 3 Department of Epidemiology, School of Public Health and Community Medicine, University of Washington, Seattle, WA * Department of Biostatistics, School of Public Health and Community Medicine, University of Washington, Seattle, WA. This work was supported in part by Grants 1-RO1- CA-30279,5-R35-CA39779, and 5-RO1-CA40664 from the National Cancer Institute, and by Institutional Cancer Grant IN-26U from the American Cancer Society. The authors thank Dr. Norman Breslow for his suggestions regarding the analysis of laterality of tumor in relation to laterality of nondescent.

2 1014 STRADER ET AL. As part of a case-control study of testicular cancer in western Washington State, we explored the question of laterality of tumor occurrence in relation to laterality of cryptorchism as well as the impact of orchiopexy in cryptorchid men. In doing so, we sought not only to address the above issue concerning the pathogenesis of testicular cancer but also to provide data that would bear on the efficacy of orchiopexy at various ages in the prevention of testicular cancer. MATERIALS AND METHODS Men with germ cell testicular cancer were identified through the Cancer Surveillance System, a population-based tumor registry serving the 13 counties of western Washington State since Potential study subjects were white males aged 20 to 69 years who had been diagnosed from January 1977 through December 1983, who lived in a residence that had a telephone, and who spoke English. With the permission of each patient's physician, we attempted to conduct a telephone interview with those patients not known to be deceased. Interviews were completed with 333 (72.5 per cent) of 459 eligible cases. Forty-seven (10.2 per cent) of the patients were deceased, 39 (8.5 per cent) refused to be interviewed, and 40 (8.7 per cent) were lost to followup. Controls were selected for telephone interview during by random digit dialing (8). Using a list of all three-digit telephone prefixes having any residential phone numbers assigned in the 13-county area of western Washington, we randomly selected a subset of these prefixes and added randomly chosen two-digit sequences to each prefix, thereby creating five-digit primary sampling units. A computer program added a randomly selected two-digit sequence to each primary sampling unit to create a "stage 1" telephone number. Stage 1 numbers were called to determine whether they were residential. For those primary sampling units of stage 1 numbers found to be residential, additional terminal digits were randomly assigned to provide additional "stage 2" telephone numbers. A total of three residential phone numbers (one stage 1 and two stage 2 numbers) were identified for each primary sampling unit that had generated a residential stage 1 number. A household census was obtained for 1,193 (87.7 per cent) of 1,361 residences contacted. We recontacted 1,103 of the 1, to 69-year-old men identified in these households and completed telephone interviews with 717 (65.0 per cent) of them. An additional 209 (18.9 per cent) men refused to be interviewed, and 177 (16.0 per cent) were lost to follow-up. Of the 717 men who completed an interview, 42 nonwhite males were later excluded, leaving 675 controls available for analysis. All interviews were conducted by four male interviewers who were specifically trained for this purpose. Cases and controls were assigned to specific interviewers as they were identified, without regard to casecontrol status. Because cases and controls were not approached in the same manner, interviewers were aware of the case-control status of the participants. However, they were not made aware of the specific hypothesis being tested. The interview included questions concerned with a number of urogenital conditions including cryptorchism and inguinal hernia, and demographic characteristics such as marital status, educational attainment, and years of residence in Washington State. We failed to obtain an answer to questions on undescended testes from seven cases and two controls; these subjects were excluded from further analysis. The prevalence of cryptorchism may have changed over time (9, 10), as have physicians' recommendations regarding the age at which orchiopexy should be performed. Because cases and controls differed somewhat with regard to their distribution of year of birth, we examined case-control differences within each of four year-of-birth strata ( , , , and ). The results were pooled according to

3 CRYPTORCHISM AND TESTICULAR CANCER 1015 the method of Mantel and Haenszel (11). The results of a comparison analysis using four age strata (20-29, 30-39, 40-49, and years) closely paralleled those of the year-of-birth analysis. To examine the effects of laterality of cryptorchism on the laterality of tumor, we fitted polytomous logistic regression models by maximum likelihood (12). Hypothesis tests about these models were made by comparing likelihood ratio statistics to their large-sample distributions, and confidence intervals for relative risks were based on the large-sample distribution of parameter estimates. Details about these models are given in the Appendix. RESULTS A history of cryptorchism was reported by 40 (12.0 per cent) cases and 15 (2.2 per cent) controls. The relative risk (RR), adjusted for year of birth, was 5.9 (95 per cent confidence interval (CI) ). The magnitude of the association was similar for seminomatous tumors (RR = 6.2) and nonseminomatous germ cell tumors (RR = 5.6), in each of the four year-of-birth groups, and similar for whether one or both testes had been undescended. Among the 31 cases who reported a history of unilateral cryptorchism, four could not recall the side of nondescent. Of the remainder, 22 reported the cryptorchid testis to have been the one in which the tumor arose: 14 of 18 men with a right-side tumor and eight of nine men with a left-side tumor (table 1). Among the 10 controls who reported a history of cryptorchism, there were seven in whom the right testis had been involved. On the basis of results obtained from fitting a polytomous logistic regression model (described in the Appendix) to the data presented in table 1, we estimated that the risk of an ipsilateral testicular tumor in a man with a history of cryptorchism, relative to the risk in a man with no such history, was 8.0 (95 per cent CI ). The relative risk for contralateral tumors was 1.6 (95 per cent CI ). Only six cases and three controls recalled having received hormonal treatments for cryptorchism, and four of the six cases and two of the three controls also underwent orchiopexy. We were therefore unable to assess the possible role of hormonal therapy on the excess risk of testicular cancer associated with cryptorchism. Twenty of the 40 cases and eight of the 15 controls with a history of cryptorchism reported having undergone orchiopexy for the condition. One control could not recall whether he had had corrective surgery and was excluded from this portion of the analysis. Compared with men who reported no history of cryptorchism, those men with uncorrected cryptorchism had a relative risk of 7.3 (table 2). The risk of testicular cancer was somewhat lower for men who had undergone orchiopexy and declined steadily with increasingly early age at orchiopexy. For men in whom the surgery had been performed prior to 11 years of age, the risk of testicular cancer was 2.6 times that of noncryptorchid men. Because of the small number of subjects who had had surgery prior to age 11 (five cases and four TABLE 1 Laterality of undescended testis in testicular cancer cases and controls, by side of tumor, western Washington state* Laterality of tumor Controls Cases, left side Cases, right side None Laterality of undescended testis Left Right Bilateral * Excludes a) three cases and three controls with a history of undescended testis who were unable to state whether this was unilateral or bilateral; b) four cases with unilateral nondescent of unknown laterality; and c) one case with bilateral undescended testes in whom the laterality of the tumor was unknown

4 1016 STRADER ET AL. TABLE 2 History of and age at orchiopexy in cryptorchid testicular cancer cases and controls, western Washington state Cases Controls Relative risk* 95% confidence interval Not cryptorchid Cryptorchid No orchiopexy Ochiopexy (all ages) 14 years years 10 years t 8t * Relative risk adjusted for year of birth by the method of Mantel and Haenszel (11). t The same control with unknown orchiopexy status was removed from each analysis. controls), we were unable to examine the influence of earlier ages at orchiopexy. DISCUSSION At least two limitations of this study suggest the need for caution in the interpretation of the results. First, a substantial portion of the potentially eligible subjects did not participate. We completed interviews with 72.5 per cent of the testicular cancer cases. Of the 1,361 control households screened for eligibility, 12.3 per cent refused to complete the screening. Among the eligible controls recontacted for an interview, 18.9 per cent refused to participate, and 16.0 per cent could not be reached despite repeated attempts. Second, the history of cryptorchism and its laterality and treatment was determined only by self-report during a telephone interview, and no confirmation from medical reports was attempted. While we have no reason to suspect any lack of comparability between cases and controls reporting conditions and events such as these, we are obviously unable to conclude that equally valid information was obtained from men in the two groups. Perhaps of some reassurance is the fact that the relative risk associated with a history of cryptorchism that we observed (RR = 5.9) fits comfortably within the range of values reported in prior studies (1-5), as does the proportion of controls who reported a history of cryptorchism (2-4, 7) Gilbert and Hamilton (13) reported that 3.2 per cent of the testicular tumors occurring among men with a history of unilateral cryptorchism were found in the contralateral (descended) testis. More recent studies have suggested that contralateral tumor occurrence may range from 10 to 24 per cent (2, 3, 6,14,15). Our observation that 19 per cent of the tumors occurred in the descended testis is consistent with the results of these more recent investigations. We found that in cryptorchid men, the risk of testicular cancer was far greater in the organ that had been or still was undescended than in the normally descended testis. In dispute, however, is the presence of any increase in risk to the descended testis in unilaterally cryptorchid men. A number of investigators have noted that the scrotal testis of unilaterally cryptorchid men may also sustain some loss of germinal epithelium (16) and incomplete maturation (17, 18). If testicular hypoplasia is associated with an increased risk of testicular cancer, the descended testis would also be at increased risk for this disease (7). Henderson et al. (2) pooled the results of several studies to estimate a twofold elevation in risk of cancer in the descended testis of unilaterally cryptorchid men relative to men without cryptorchism, whereas the relative risk obtained by Pottern et al. (4) was 1.1. In our study, the risk was 1.6 times that of the corresponding testis of noncryptorchid men, and the confidence limits around this

5 CRYPTORCHISM AND TESTICULAR CANCER 1017 estimate were wide (0.6, 4.1). It is apparent that this issue is unresolved at the present time. We observed a steady reduction in the excess risk of testicular cancer in cryptorchid men associated with increasingly early age at orchiopexy, a reduction similar to that found in the case-control study by Pottern et al. (4). This observation is consistent with two earlier reports (14,15) that examined the ratio of ipsilateral to contralateral tumor occurrence as a function of age at orchiopexy. In unilaterally cryptorchid men who had not undergone orchiopexy until after 10 years of age or who had not undergone orchiopexy at all, the ratio of ipsilateral to contralateral tumors was about 6.5:1 (two studies combined). If orchiopexy had been performed at or prior to age 10, the corresponding ratio was only 4:1. Our results are also consistent with the observation that orchiopexy performed prior to puberty prevents, to some extent, the degenerative changes that typically occur in uncorrected cryptorchid testes (19, 20). In contrast, Pike et al. (6) found the distribution of age at orchiopexy of cryptorchid British men with and without testicular cancer to have been almost identical. In none of these studies (including ours), however, were there more than a few men whose orchiopexy occurred in early childhood, so that the effect of early treatment of cryptorchism cannot be measured well. While the benefits of orchiopexy at various ages remain uncertain, there is substantial evidence that the major portion of the excess risk of testicular cancer in cryptorchid men is associated with a local effect on the abnormally positioned testis. The following observations support this view: 1) In unilaterally cryptorchid men, the excess risk is largely confined to the undescended testis, and 2) nonmalignant morphologic changes in the testes of experimental animals, similar to those noted in cryptorchid men, can be produced by placement of the testis in the inguinal canal or abdominal cavity (21-25) or simply by raising the temperature of the scrotal testis (25, 26). Whether there is an additional basis for the increased cancer risk in cryptorchid men remains uncertain at present. REFERENCES 1. Morrison AS. Cryptorchidism, hernia, and cancer of the testis. JNCI 1976;56: Henderson BE, Benton B, Jing J, et al. Risk factors for cancer of the testis in young men. Int J Cancer 1979;23: Schottenfeld D, Warshauer ME, Sherlock S, et al. The epidemiology of testicular cancer in young adults. Am J Epidemiol 1980;112: Pottern LM, Brown LM, Hoover RN, et al. Testicular cancer risk among young men: role of cryptorchidism and inguinal hernia. JNCI 1985;74: Henderson BE, Ross RK, Pike MC, et al. Endogenous hormones as a major factor in human cancer. Cancer Res 1982;42: Pike MC, Chilvers C, Peckham MJ. Effect of age at orchidopexy on risk of testicular cancer. Lancet 1986;l: DePue RH, Pike MC, Henderson BE. Cryptorchidism and testicular cancer. (Letter). JNCI 1986;77: Waksberg J. Sampling methods for random digit dialing. J Am Stat Assoc 1978;73: Schottenfeld D, Warshauer ME. Testis. In: Schottenfeld D, Fraumeni J, eds. Cancer epidemiology and prevention. Philadelphia, PA: WB Saunders, 1982: Davies TW, Williams DDR, Whitaker RH. Risk factors for undescended testis. Int J Epidemiol 1986;15: Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. JNCI 1959:22: Fienberg SE. The analysis of cross-classified categorical data. 2nd ed. Cambridge, MA: The MIT Press, Gilbert JB, Hamilton JB. Studies in malignant testis tumors. III. Incidence and nature of tumors in ectopic testes. Surg Gynecol Obstet 1940;71: Batata MA, Chu FCH, Hilaris BS, et al. Testicular cancer in cryptorchids. Cancer 1982;49: Gehring GG, Rodriguez FR, Woodhead DM. Malignant degeneration of cryptorchid testes following orchiopexy. J Urol 1974;112: Mengel W, Heinz HA, Sippe WG, et al. Studies on cryptorchidism: a comparison of histological findings in the germinative epithelium before and after the second year of life. J Pediatr Surg 1974:9: Hecker WC, Heinz HA. Cryptorchidism and fertility. J Pediatr Surg 1967;2: Werder EA, Illig R, Torresani T, et al. Gonadal function in young adults after surgical treatment of cryptorchidism. Br Med J 1976;2: Kieswetter WB, Shull WR, Fetterman GH. His-

6 1018 STRADER ET AL. tologic changes in the testis following anatomically successful orchiopexy. J Pediatr Surg 1969;4: Charny CW, Wolgin W. The management of cryptorchidism. Surg Gynecol Obstet 1956;102: Moore CR. Experimental studies on the male reproductive system. J Urol 1951;65: Moore CR, Quick WJ. The scrotum as a temperature regulator for the testes. Am J Physiol 1924;68: Sadi A. Experimental cryptorchidism in rats and its influence on the spermatogenic function. Urol Int 1957;5: Nelson WO. Mammalian spermatogenesis: effect of experimental cryptorchidism in the rat and non-descent of the testis in man. Rec Prog Horm Res 1951;6: Moore CR, Oslund R. Experiments on the sheep testis cryptorchidism, vasectomy and scrotal insulation. Am J Physiol 1924;67: Moore CR. Properties of the gonads as controllers of somatic and psychical characteristics. VIII. Heat application and testicular degeneration; the function of the scrotum. Am J Anat 1924;34: APPENDIX For fit of the polytomous logistic model, each subject was treated as having the following three possible outcomes: no tumor, tumor left side, tumor right side, according to a trinomial distribution with probabilities PN,PL, and p R, that sum to one. For the covariates cryptorchid left side otherwise and cryptorchid right side X R fotherwise the polytomous logistic model in its most general form would be given by and where and p N = 1/(1 + e" 1 + e >), PL = e'7(l + e 1 "- + e"), P«= e'"/(l + e" + e"), y L X R X L, y"x R X L. When the tumor is rare, ratios of the denominators of these probabilities for different covariate values are approximately one, so that in a model where the interaction terms y L and y" are zero, the /3 coefficients can be interpreted as log relative risks; thus, exp (/9?) approximates the relative risk of developing a rightside tumor due to left-side cryptorchism, and exp(/3fl) approximates the relative risk of developing a left-side tumor due to right-side cryptorchism, for example. To examine the influence of cryptorchism on the occurrence of both ipsilateral and contralateral tumors, we set./ = y» = o, PL = P R (= log RR due to cryptorchism for a contralateral tumor), PR = PL (= log RR due to cryptorchism for an ipsilateral tumor), and fit the resulting model by maximum likelihood using the equivalent log-linear model (12). Likelihood ratio tests of each of the above constraints did not reject the null hypothesis at the 5 per cent level; estimates of the relative risk parameters in this model and confidence intervals based on the estimates of their asymptotic standard errors are given in the body of the paper.