Cryptorchidism, Hernia, and Cancer of the Testis 1,2,3 Alan S. Morrison 4, 5
A case-control study of cancer of the testis was con· ducted in the U.S. Army to relate a number of social and medical characteristics to risk of this disease. Here data are reported on two genital tract defects: unde· scended testis, which has been implicated as a risk factor in previous studies, and inguinal hernia, which has received little attention in this context. METHODS
All patients in this study had been hospitalized for the first time with primary testicular cancer while in the Army between 1950 and 1970. An initial roster of 1,034 names was assembled from lists provided by the Armed Forces Institute of Pathology and the tumor registries of the seven Army teaching hospitals. The military rec· ords of each patient were requested through an office of the Army Surgeon General. Records were obtained from facilities at Fort Benjamin Harrison, Indiana, Alexan· dria, Virginia, and St. Louis, Missouri. Information not available in the records of patients discharged from ac· tive service was requested from the Veterans Adminis· tration when it was possible to identify the specific facility in which the necessary records were located. During the abstracting of records, 98 subjects were excluded either because there was no diagnosis of a primary testicular malignancy or because this diagnosis was not first made during active Army service between 1950 and 1970. Records were obtained for 702 eligible patients; 4 were excluded because year of discharge or age at diagnosis was unknown. Indication of histologic confirmation of a primary testicular malignancy was found in the records of 95.8% of the remaining eligible patients. The sampling frame for controls was a list of 0.1% of persons on active service at any time during the study period. This list was assembled by selection on the ter· minal digits of the Army service number or Social Se· curity account number, and was furnished by the Follow· up Agency, Division of Medical Sciences, National Academy of Sciences-National Research Council. A roster of 1,325 names was constructed from all the listed names of men on active duty between 1960 and 1970 at an age of 30 or greater and, by further terminal digit selection, one-tenth of the remaining names in the
sampling frame. Four individuals whose names had been included incorrectly in the initial roster were excluded from the control series; the service records of 624 eligible controls were retrieved. An additional 102 patients and 22 controls were excluded from the present analysis because information on genital tract defects was not available. If subjects found ineligible for the study were excluded from the denominator, the rate of record retrieval was 75.0% for patients but only 47.2% for controls. The discrepancy was due principally to the fact that a major fire at the St. Louis record facility destroyed a large number of records of servicemen discharged before 1960. Requests for the records of most patients had been acted upon before this fire, but retrieval of control records was in progress. However, it seems unlikely that loss of records in this fire could have led to serious bias. This study was designed to use information on "ex· posure" characteristics recorded before malignant disease developed. Status with respect to a specific characteristic was considered to be that which existed at or before entry on active duty, as indicated in the earliest avail· able military personnel, medical history, or physical examination form which contained the necessary infor· mation. Data from physical examination were accepted only if examination occurred before diagnosis of testicu· lar cancer. Subjects were considered to have an undescended testis if this was noted at physical examination or if the con· dition had been treated surgically. A hernia was con· sidered to have been present only if it had been surgi. cally treated before age 15. No subject began active service with an existing hernia. Risk ratios were estimated by the odds ratio. Estimates were similar with and without adjustment for age, year of discharge, and ethnic group. Therefore, crude risk ratio estimates are presented here. Ninety-five percent confidence intervals (CI) and two·tailed P values were computed by a modified exact procedure (1). RESULTS
Undescended testis was noted in 17 patients and 2 controls (table 1). The risk ratio estimate was 8.8 (2.356.3, 95% CI). In 12 patients, this condition was present Received November 7, 1975; accepted November 13, 1975. Supported in part by Public Health Service grant 5 POI CA06373 from the National Cancer Institute. 3 This material has been reviewed by the Walter Reed Army Institute of Research, and there is no objection to its presentation and/or publication. The opinions or assertions containcd herein are the private views of the author and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense. 4 Division of Preventive Medicine, Walter Reed Army Institute of Research, Washington, D.C., and the Department of Epidemiology, Harvard School of Public Health, 677 Huntington Ave., Boston, Mass. 02115. Address reprint requests to Dr. Morrison at the Department of Epidemiology, Harvard School of Public Health. 5 I thank Dr. F.K. Mostofi, the tumor registrars of the Army tcaching hospitals, and Mr. Seymour Jablon for help in assembling lists of patients and control subjects. I am grateful to Dr. Thomas Mack, who suggested that hernias be studied. Ms. Charlene Evans and Mrs. Hazel Coven assisted with record abstracting and coding. 1
2
JOURNAL OF THE NATIONAL CANCER INSTITUTE, VOL. 56, NO.4, APRIL 1976
731
Downloaded from http://jnci.oxfordjournals.org/ at The Chinese University of Hong Kong on February 19, 2015
SUMMARY-Risk of cancer of the testis was related to non· descent and hernia in a comparison of 596 testicular cancer patients and 602 unaffected men who had been in active service in the U.S. Army between 1950 and 1970. Medical histories were obtained from routine service records. Undescended testis was associated with a testicular cancer risk S.S times that of normal. Among cancer patients with a history of undescended testis, seminomas were nearly twice as frequent as in the remaining patients. Of 14 patients with unilateral undescended testis, 12 had the tumor on the side of the defect. Testicular cancer risk was estimated to be 2.9 times higher in men who had reported having had an inguinal hernia than in those who had not. Side of hernia and side of tumor were not associated; histologic type was not related to history of hernia.-J Natl Cancer Inst 56: 731-733, 1976.
732
MORRISON TABLE
I.-Numbers of patients and controls and risk ratio according to history of undescended testis '
Undescended testis
Patients
Controls
Risk ratio
yes ___________ No ____________
17 579
2 600
8.8 a
TotaL ____
596
602
1.0
• 2.3-56.3, 95 % CI.
2.-Numbers of patients and controls and risk ratio according to history of hernia operation before age 15 '
TABLE
Patients
Controls
yes ___________ No ____________
22 557
592
TotaL ____
579
600
8
Risk ratio 2.9 a
1.0
·1.3-7.0, 95% CI.
at physical examination. In the remammg 5 patients and the 2 control subjects, the condition had been treated surgically. The side of occurrence of undescended testis and testicular tumor were closely related. Informa· tion on both the side of tumor and the side of undescended testis was available for 14 patients with the unilateral defect. In 12, the tumor occurred in the testis that had been undescended. In 7 patients this occurred on the left and in 5, on the right (P=0.02). Undescended testis also was associated with histologic type. Of tumors in patients with a history of undescended testis, 65% (11/17) were seminomas. Of the remaining tumors for which information was available, 38% (212/552) were seminomas (P=0.04). Four patients who had had a hernia also had an undescended testis. After all subjects with undescended testis were excluded, testicular malignancy was estimated as 2.9 (1.3-7.0) times more likely to occur in a person who had reported an operation for hernia (table 2). Unlike undescended testis, the side of the hernia was unrelated to the side of the tumor which followed, and a hernia was not associated with tumors of a specific histologic type. For 10 patients information was available on both the side of a unilateral hernia and the side of the tumor. Of 6 left-sided tumors, 3 followed a leftsided hernia and 3 followed a right-sided hernia. Of 4 right-.sided tumors, 2 followed each type of hernia. HistolOgIC type was not known for the tumor of I patient who ha~ had ~ hernia. Of the patients for whom the tumor hIstologIC type was known, 33% (7/21) had seminomas.
DISCUSSION There are three peaks in testicular cancer morbidity and mortality-2 years of age, early adulthood, and old age (2-4). Since the present study was restricted to men serving in the Army, the results may pertain only to the disease characteristic of young adults. The particular strength of these Army data is that information on undescended testis and other exposures was obtained similarly for cases and controls, and the quality of the information was not likely to have been affected by the occurrence of testicular cancer. As computed from data in three previous reports, estimates of the risk ratio for testicular cancer associated with unde-
REFERENCES (1) MIETIINEN OS: Comment. J Am Stat Assoc 69:380-382, 1974 (2) LI FP, FRAUMENI JF: Testicular cancers in children: Epidemio. logic characteristics. J Natl Cancer lnst 48:1575-1582, 1972 (3) GRUMET RF, MACMAHON B: Trends in mortality from neo· plasms of the testis. Cancer 11:790-797, 1958 (4) EISENBERG H: Cancer in Connecticut. Incidence and Rates, 1935-1962. Connecticut State Department of Health, 1966
Downloaded from http://jnci.oxfordjournals.org/ at The Chinese University of Hong Kong on February 19, 2015
Hernia operation
sce~ded testis were. 11.4, 14.8, and 53.6 (5-7). The present estImate of 8.8, with an upper confidence limit of 56.3, is compatible with each of the former estimates. Taken together, however, these studies suggest a risk ratio closer to 10 than to a much larger figure. Tumors in men who had an undescended testis tended to occur in the ectopic organ and to be seminomas. Both ?f .these associations, also reported previously (5, 7), mdicate anatomic specificity of the relationship between nondescent and cancer. However, whether undescended testis is a cause of malignancy or whether another factor causes both conditions is unclear. A reduction in rate of testicular cancer related to surgical correction of undescended testis would tend to support the idea that the defect i~self is ~ausal. Although there have been reports on orchIOpexy m men who had undescended testis and who later developed testicular cancer (5, 8), comparable orchiopexy data are not available for men who had undescended testis but were unaffected by the malignancy. In the present study, the subjects with orchiopexy were too few to be informative. Li and Fraumeni (2) suggested that the relative frequency of inguinal hernia in children with testicular cancer was high. The present data on young adults show a moderate elevation of risk among subjects with repaired hernias. Hernia tends to coexist with undescended testis (7). The .Army medical history forms ask specifically about herma but not about undescended testis. If some of the persons who reported "hernia" operations also had undescended testis, this mechanism might explain the obse~ved association. The lack of a relationship between hernIa and tumor histology and between side of hernia and side of tumor does not support this interpretation, but the data on these characteristics were sparse. Because hernias are relatively frequent, it would be worthwhile to study further the question of whether men with hernia but not undescended testis are in fact at elevated risk of testicular cancer. Although incomplete patient ascertainment and record retrieval might have introduced bias in the risk ratio estimates reported here, large errors seem unlikely. Since service records of all patients in the initial roster were not. obta!ned, the. total number of identified eligible patIe.nts IS. un.certam. On the basis of comparisons with publIshed mCld~nce ~ates, however, it appears that most new cases were Identified, so the effect of any ascertainm~nt bias probably ~as small. Incomplete record retneval was a more senous problem. Records lost in the 1973 fire were primarily those of controls, but destructiOl~ probably was unrelated to history of undescended testis or herma. Other reasons for nonretrieval of records, such as loan to governmental agencies, could have produced substantial bias only if availability of records were related to history of previous genital tract defects to a markedly different degree for patients than for controls.
CRYPTORCHIDISM, HERNIA, AND CANCER OF TIlE TESTIS
7SS
(5) MILLER A, SELJELID R: Histologic classification and natural history of malignant testis tumors in Norway, 1959-1963. Can
A case-control study of cancer of the testis was con· ducted in the U.S. Army to relate a number of social and medical characteristics to risk of this disease. Here data are reported on two genital tract defects: unde· scended testis, which has been implicated as a risk factor in previous studies, and inguinal hernia, which has received little attention in this context. METHODS
All patients in this study had been hospitalized for the first time with primary testicular cancer while in the Army between 1950 and 1970. An initial roster of 1,034 names was assembled from lists provided by the Armed Forces Institute of Pathology and the tumor registries of the seven Army teaching hospitals. The military rec· ords of each patient were requested through an office of the Army Surgeon General. Records were obtained from facilities at Fort Benjamin Harrison, Indiana, Alexan· dria, Virginia, and St. Louis, Missouri. Information not available in the records of patients discharged from ac· tive service was requested from the Veterans Adminis· tration when it was possible to identify the specific facility in which the necessary records were located. During the abstracting of records, 98 subjects were excluded either because there was no diagnosis of a primary testicular malignancy or because this diagnosis was not first made during active Army service between 1950 and 1970. Records were obtained for 702 eligible patients; 4 were excluded because year of discharge or age at diagnosis was unknown. Indication of histologic confirmation of a primary testicular malignancy was found in the records of 95.8% of the remaining eligible patients. The sampling frame for controls was a list of 0.1% of persons on active service at any time during the study period. This list was assembled by selection on the ter· minal digits of the Army service number or Social Se· curity account number, and was furnished by the Follow· up Agency, Division of Medical Sciences, National Academy of Sciences-National Research Council. A roster of 1,325 names was constructed from all the listed names of men on active duty between 1960 and 1970 at an age of 30 or greater and, by further terminal digit selection, one-tenth of the remaining names in the
sampling frame. Four individuals whose names had been included incorrectly in the initial roster were excluded from the control series; the service records of 624 eligible controls were retrieved. An additional 102 patients and 22 controls were excluded from the present analysis because information on genital tract defects was not available. If subjects found ineligible for the study were excluded from the denominator, the rate of record retrieval was 75.0% for patients but only 47.2% for controls. The discrepancy was due principally to the fact that a major fire at the St. Louis record facility destroyed a large number of records of servicemen discharged before 1960. Requests for the records of most patients had been acted upon before this fire, but retrieval of control records was in progress. However, it seems unlikely that loss of records in this fire could have led to serious bias. This study was designed to use information on "ex· posure" characteristics recorded before malignant disease developed. Status with respect to a specific characteristic was considered to be that which existed at or before entry on active duty, as indicated in the earliest avail· able military personnel, medical history, or physical examination form which contained the necessary infor· mation. Data from physical examination were accepted only if examination occurred before diagnosis of testicu· lar cancer. Subjects were considered to have an undescended testis if this was noted at physical examination or if the con· dition had been treated surgically. A hernia was con· sidered to have been present only if it had been surgi. cally treated before age 15. No subject began active service with an existing hernia. Risk ratios were estimated by the odds ratio. Estimates were similar with and without adjustment for age, year of discharge, and ethnic group. Therefore, crude risk ratio estimates are presented here. Ninety-five percent confidence intervals (CI) and two·tailed P values were computed by a modified exact procedure (1). RESULTS
Undescended testis was noted in 17 patients and 2 controls (table 1). The risk ratio estimate was 8.8 (2.356.3, 95% CI). In 12 patients, this condition was present Received November 7, 1975; accepted November 13, 1975. Supported in part by Public Health Service grant 5 POI CA06373 from the National Cancer Institute. 3 This material has been reviewed by the Walter Reed Army Institute of Research, and there is no objection to its presentation and/or publication. The opinions or assertions containcd herein are the private views of the author and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense. 4 Division of Preventive Medicine, Walter Reed Army Institute of Research, Washington, D.C., and the Department of Epidemiology, Harvard School of Public Health, 677 Huntington Ave., Boston, Mass. 02115. Address reprint requests to Dr. Morrison at the Department of Epidemiology, Harvard School of Public Health. 5 I thank Dr. F.K. Mostofi, the tumor registrars of the Army tcaching hospitals, and Mr. Seymour Jablon for help in assembling lists of patients and control subjects. I am grateful to Dr. Thomas Mack, who suggested that hernias be studied. Ms. Charlene Evans and Mrs. Hazel Coven assisted with record abstracting and coding. 1
2
JOURNAL OF THE NATIONAL CANCER INSTITUTE, VOL. 56, NO.4, APRIL 1976
731
Downloaded from http://jnci.oxfordjournals.org/ at The Chinese University of Hong Kong on February 19, 2015
SUMMARY-Risk of cancer of the testis was related to non· descent and hernia in a comparison of 596 testicular cancer patients and 602 unaffected men who had been in active service in the U.S. Army between 1950 and 1970. Medical histories were obtained from routine service records. Undescended testis was associated with a testicular cancer risk S.S times that of normal. Among cancer patients with a history of undescended testis, seminomas were nearly twice as frequent as in the remaining patients. Of 14 patients with unilateral undescended testis, 12 had the tumor on the side of the defect. Testicular cancer risk was estimated to be 2.9 times higher in men who had reported having had an inguinal hernia than in those who had not. Side of hernia and side of tumor were not associated; histologic type was not related to history of hernia.-J Natl Cancer Inst 56: 731-733, 1976.
732
MORRISON TABLE
I.-Numbers of patients and controls and risk ratio according to history of undescended testis '
Undescended testis
Patients
Controls
Risk ratio
yes ___________ No ____________
17 579
2 600
8.8 a
TotaL ____
596
602
1.0
• 2.3-56.3, 95 % CI.
2.-Numbers of patients and controls and risk ratio according to history of hernia operation before age 15 '
TABLE
Patients
Controls
yes ___________ No ____________
22 557
592
TotaL ____
579
600
8
Risk ratio 2.9 a
1.0
·1.3-7.0, 95% CI.
at physical examination. In the remammg 5 patients and the 2 control subjects, the condition had been treated surgically. The side of occurrence of undescended testis and testicular tumor were closely related. Informa· tion on both the side of tumor and the side of undescended testis was available for 14 patients with the unilateral defect. In 12, the tumor occurred in the testis that had been undescended. In 7 patients this occurred on the left and in 5, on the right (P=0.02). Undescended testis also was associated with histologic type. Of tumors in patients with a history of undescended testis, 65% (11/17) were seminomas. Of the remaining tumors for which information was available, 38% (212/552) were seminomas (P=0.04). Four patients who had had a hernia also had an undescended testis. After all subjects with undescended testis were excluded, testicular malignancy was estimated as 2.9 (1.3-7.0) times more likely to occur in a person who had reported an operation for hernia (table 2). Unlike undescended testis, the side of the hernia was unrelated to the side of the tumor which followed, and a hernia was not associated with tumors of a specific histologic type. For 10 patients information was available on both the side of a unilateral hernia and the side of the tumor. Of 6 left-sided tumors, 3 followed a leftsided hernia and 3 followed a right-sided hernia. Of 4 right-.sided tumors, 2 followed each type of hernia. HistolOgIC type was not known for the tumor of I patient who ha~ had ~ hernia. Of the patients for whom the tumor hIstologIC type was known, 33% (7/21) had seminomas.
DISCUSSION There are three peaks in testicular cancer morbidity and mortality-2 years of age, early adulthood, and old age (2-4). Since the present study was restricted to men serving in the Army, the results may pertain only to the disease characteristic of young adults. The particular strength of these Army data is that information on undescended testis and other exposures was obtained similarly for cases and controls, and the quality of the information was not likely to have been affected by the occurrence of testicular cancer. As computed from data in three previous reports, estimates of the risk ratio for testicular cancer associated with unde-
REFERENCES (1) MIETIINEN OS: Comment. J Am Stat Assoc 69:380-382, 1974 (2) LI FP, FRAUMENI JF: Testicular cancers in children: Epidemio. logic characteristics. J Natl Cancer lnst 48:1575-1582, 1972 (3) GRUMET RF, MACMAHON B: Trends in mortality from neo· plasms of the testis. Cancer 11:790-797, 1958 (4) EISENBERG H: Cancer in Connecticut. Incidence and Rates, 1935-1962. Connecticut State Department of Health, 1966
Downloaded from http://jnci.oxfordjournals.org/ at The Chinese University of Hong Kong on February 19, 2015
Hernia operation
sce~ded testis were. 11.4, 14.8, and 53.6 (5-7). The present estImate of 8.8, with an upper confidence limit of 56.3, is compatible with each of the former estimates. Taken together, however, these studies suggest a risk ratio closer to 10 than to a much larger figure. Tumors in men who had an undescended testis tended to occur in the ectopic organ and to be seminomas. Both ?f .these associations, also reported previously (5, 7), mdicate anatomic specificity of the relationship between nondescent and cancer. However, whether undescended testis is a cause of malignancy or whether another factor causes both conditions is unclear. A reduction in rate of testicular cancer related to surgical correction of undescended testis would tend to support the idea that the defect i~self is ~ausal. Although there have been reports on orchIOpexy m men who had undescended testis and who later developed testicular cancer (5, 8), comparable orchiopexy data are not available for men who had undescended testis but were unaffected by the malignancy. In the present study, the subjects with orchiopexy were too few to be informative. Li and Fraumeni (2) suggested that the relative frequency of inguinal hernia in children with testicular cancer was high. The present data on young adults show a moderate elevation of risk among subjects with repaired hernias. Hernia tends to coexist with undescended testis (7). The .Army medical history forms ask specifically about herma but not about undescended testis. If some of the persons who reported "hernia" operations also had undescended testis, this mechanism might explain the obse~ved association. The lack of a relationship between hernIa and tumor histology and between side of hernia and side of tumor does not support this interpretation, but the data on these characteristics were sparse. Because hernias are relatively frequent, it would be worthwhile to study further the question of whether men with hernia but not undescended testis are in fact at elevated risk of testicular cancer. Although incomplete patient ascertainment and record retrieval might have introduced bias in the risk ratio estimates reported here, large errors seem unlikely. Since service records of all patients in the initial roster were not. obta!ned, the. total number of identified eligible patIe.nts IS. un.certam. On the basis of comparisons with publIshed mCld~nce ~ates, however, it appears that most new cases were Identified, so the effect of any ascertainm~nt bias probably ~as small. Incomplete record retneval was a more senous problem. Records lost in the 1973 fire were primarily those of controls, but destructiOl~ probably was unrelated to history of undescended testis or herma. Other reasons for nonretrieval of records, such as loan to governmental agencies, could have produced substantial bias only if availability of records were related to history of previous genital tract defects to a markedly different degree for patients than for controls.
CRYPTORCHIDISM, HERNIA, AND CANCER OF TIlE TESTIS
7SS
(5) MILLER A, SELJELID R: Histologic classification and natural history of malignant testis tumors in Norway, 1959-1963. Can
