Germ Cell Tumours III: Proceedings of the Third Germ Cell Tumour Conference Held in Leeds, UK, on 8th—10th September 1993

Health

Embryological Mechanisms of Maldescent and Tumourigenesis

John M. Hutson, Marilyn L. Baker, Masaru Terada, Baiyun Zhou and Georgia Paxton,     Surgical Research Unit, Royal Children’s Hospital, Research Foundation, Melbourne, Victoria, Australia, 3052

ABSTRACT

Testicular descent occurs in two stages with separate morphology and hormonal control. The key structure in mediating descent is the gubernaculum, which enlarges in the first phase to anchor the testes near the inguinal regions as the embryo enlarges. In the second phase, the gubernaculum migrates from the inguinal region to the scrotum. Non-androgenic hormones control the first phase, with conflicting evidence about whether Müllerian inhibiting substance (MIS) is the active agent. Testosterone controls the second phase, apparently indirectly via the nervous system. Calcitonin gene-related peptide (CGRP) has been identified recently within the gentofemoral nerve and has been postulated to act as a final common pathway for androgenic control of descent. Animal models of undescended testes, including the androgen resistant mouse, the TS rat, and the flutamide-treated rat all have an absence or deficiency of gubernacular migration and abnormality of CGRP.

These studies suggest that undescended testes may be caused by physiological or anatomical abnormalities of the gentofemoral nerve. The commonest cause of maldescent would appear to be failure of gubernacular migration, leaving the testes in the groin or so- called superficial inguinal pouch.

The abnormally high temperature of the undescended testes leads to deficiencies in postnatal secretion of testosterone and MIS. In addition, germ cell maturation from fetal gonocyte to type A spermatogonium is significantly inhibited. Gonocytes which fail to undergo this transformation either die off leading to infertility, or develop signs of dysplasia, eg. carcinoma-in-situ.

At present, it is not proven in humans that early surgery can prevent these hormonal and anatomical changes. However, animal experiments strongly support the view that early surgery, prior to these changes occurring, can prevent their development.

Introduction

The gubernaculum, or genitoinguinal ligament, enlarges in the male fetus between 10 and 15 weeks. The enlarged gubernaculum holds the testis near the future inguinal canal as the embryo enlarges. By contrast, failure of the homologous structure in the female to enlarge allows the ovary to ascend with the kidney, as seen in rodents, or to remain near the enlarging uterus, as seen in humans. The difference between the ovarian position in rodents and humans is probably related to the greater fusion of the Müllerian ducts in humans to form a solid uterus, thereby preventing further ovarian ascent. In either mammalian species, the long attenuated female gubernaculum is unable to anchor the ovary near the inguinal region and is preserved postnatally as two separate parts known as the ligament of the ovary and the round ligament.

The second phase, or inguinoscrotal descent, begins at 26–28 weeks of gestation, when the gubernaculum begins to migrate from the future inguinal canal towards the scrotum. A peritoneal diverticulum known as the processus vaginalis develops within the gubernaculum, allowing the testes to descend intra-peritoneally. By 35 weeks of gestation the gubernaculum has reached the scrotum and the testis arrives shortly after. Standard anatomical textbooks describe a gubernaculum attached to the bottom of the scrotum, but this is not the case until after descent is complete. Migration from the groin to the scrotum is a precarious journey of 3-5 cms for a gubernaculum which is only 1 cm in diameter. The gubernaculum after enlargement becomes gelatinous and mucoid at its distal end, and its proximal end is hollowed out by the processus vaginalis. The mucoid caudal end of the gubernaculum remains palpable until descent is complete, and then reabsorption of the extracellular matrix molecules causes it to regress. The postnatal gubernaculum is usually made up of fibrous attachments of the caudal epididyMIS and testis to the bottom of the processus vaginalis and adjacent scrotal subcutaneous tissue.

Hormonal Control

At one time it was believed that testicular descent was controlled by androgens from the fetal testis under maternal or chorionic gonadotrophin stimulation. In 1932, Engle (1) showed that the testis of immature Macaque monkeys were stimulated to descend with extracts from the anterior pituitary gland and with pregnancy urine. Since that time, cryptorchidism has been treated in many parts of the world with hCG and/or LHRH (2, 3). Although there are numerous clinical descriptions of abnormalities of the hypothalamic-pituitary-testicular axis which cause cryptorchidism, the role of androgens in controlling testicular descent has been controversial. This is because many natural mutants and experimental studies showed that the effect of androgen was absent or only partial. In particular, the second or inguinoscrotal phase of descent is absent in androgen resistant mice and humans (4). Furthermore, inguinoscrotal descent is absent in the hypogonadal mouse (5). Prenatal treatment with flutamide, which is an antiandrogen, also blocks the inguinoscrotal phase of descent (6, 7). Although the postnatal or inguinoscrotal phase of descent is blocked in the rat by flutamide, the flutamide only works when given prenatally. By contrast, no androgenic effects on descent of the testis could be observed in the fetus (8, 9). Also, androgens failed to produce the swelling reaction in the gubernaculum (8), and pituitary disconnection also failed to stop gubernacular swelling (10).

The apparent contradictions in the results of studies of androgens have been reconciled by the hypothesis that testicular descent occurs in two separate steps under independent hormonal control (11).

The first phase of testicular descent in mice can be inhibited by administering exogenous oestrogens to the pregnant dams, and this treatment also causes retention of the Müllerian ducts (5, 12). In addition, in the persistent Müllerian duct syndrome where there is a genetic defect in the synthesis of MIS or its receptor, the swelling reaction of the gubernaculum is absent in association with high intraabdominal testis and retained Müllerian ducts (13, 14). Both the oestrogen-injected mouse and the human with a mutation in the MIS gene provide evidence for an important role for this testicular hormone. However, there is some experimental evidence against a role for MIS, including the fact that immunisation of pregnant rabbits against purified MIS failed to stop testicular descent (15). Also, purified MIS did not stimulate fetal pig gubernacular fibroblasts in vitro (16).

The mechanism by which androgens control the second or inguinoscrotal phase of descent has remained obscure (17). The mechanism whereby the gubernaculum migrates from the inguinal region to the scrotum is also not understood. Although the gubernaculum was thought to be the primary target for androgens, measurement of significant numbers of androgen receptors has been controversial (18–20). A clue to an alternative site for androgen action was revealed by a study done by Lewis (21), where the gentofemoral nerve was transected in neonatal rats. This caused undescended testes which Lewis interpreted as evidence for a role by the cremaster muscle. Recently, we repeated this study and found a similar result (22). We went on to investigate the possibility that the primary action of androgen may be indirect on the gubernaculum via the central nervous system and the gentofemoral nerve. Careful study of gubernacular migration in the rodent postnatally showed that nerve transection inhibited migration (23). Looking at children with spina bifida in the high lumbar region where the gentofemoral nerve arises, we found 36% cryptorchidism (24). More importantly, when we did retrograde labelling of the gentofemoral nerve motor neurons, we found that the motor nucleus in the anterior horn is sexually dimorphic. Also, we found that the neonatal male gentofemoral nerve contains a much higher content of calcitonin gene-related peptide (CGRP) than the female equivalent (25).

In recent years we have investigated the possible role of CGRP in mediating gubernacular migration and testicular descent. CGRP receptors were identified within the cremaster muscle within the gubernaculum, (26). Also, in organ culture CGRP was found to induce rapid rhythmic contraction of the gubernacular cremaster muscle in both the rat (27) and the mouse (28) (Table 1).

Table 1

Evidence for CGRP having a role in gubernacular migration

Undescended Testis

We have looked at three rodent models of undescended testis to see if there is an abnormality of the gentofemoral nerve and/or CGRP. (Table 2). These studies show that the androgen resistant or deficient rodent has decreased CGRP in the nerve and decreased gubernacular contractions, accompanied by increased sensitivity to exogenous CGRP. By contrast, the mutant (TS) rat has excess CGRP in the gentofemoral nerve accompanied by decreased sensitivity of the gubernaculum in culture. There results suggest a very strong link between a normal gentofemoral nerve and CGRP mechanism and normal testicular descent.

Table 2

CGRP in animal models of cryptorchidism (31)

Aetiology of cryptorchidism in the human

Undescended testis are caused by a number of developmental defects with rare mutations in the gene for Müllerian inhibiting substance preventing normal transabdominal migration. In the inguinoscrotal phase of descent where the gubernaculum must migrate across the pubis to the scrotum, the commonest cause of undescended testis appears to be deficient or abnormal migration. This may be caused by prenatal hormone deficiency of the hypothalamic pituitary axis. In addition, we would predict that it would also be caused by anatomical and physiological abnormalities of the gentofemoral nerve or its neurotransmitter CGRP.

Effect of Undescended Testis

Cryptorchidism leads to a cosmetic anomaly, decreased fertility and an increased risk of testicular cancer (32). There has been argument about whether the subsequent infertility and risk of malignancy is a primary or secondary anomaly of the testis. Recent evidence suggests that they are probably secondary effects of cryptorchidism, as biopsies of testes from children of different ages show that the histology of the testis is normal in infancy but becomes progressively more abnormal with age (2). The high temperature of the non-scrotal testis is believed to be the cause of the secondary degeneration.

Early postnatal germ cell differentiation, from gonocyte to Type A spermatogonium and through to Type B and primary spermatocytes is deranged in undescended testis. (2). Although the early postnatal development of the gonocyte was thought to be controlled by androgens, and hence may be treated by gonadotropins (33), work in our laboratory suggests that gonocyte maturation is controlled by MIS. (34). In normal human males the serum level of MIS is elevated in the first year of life (35). By contrast, in infants with undescended testis this postnatal increase of MIS secretion appears to be absent (36).

In undescended testis the germ cells fail to transform from gonocytes into Type A spermatogonia and tend to die off by 2–3 years of age. This would lead to oligo- or azoospermia later in life. However, residual gonocytes within the tubules are likely to become dysplastic with increasing time, and are likely to be the origin of carcinoma-in-situ leading to malignancy subsequently. As the gonocyte is normally replaced in the tubule by a more differentiated form of germ cell its persistence beyond infancy could lead to malignancy by many potential physiological derangements. For instance, the abnormal gonoctye may develop polyploidy or begin expressing abnormal proteins, such as alkaline phosphatase as seen in carcimona-in-situ in older males.

We have proposed that MIS may be used in the future to treat infants with undescended testis to stimulate gonocyte transformation to Type A spermatogonia. Our intention was to reverse the otherwise significant infertility that these children have in adult life. In addition, it may be possible to prevent the development of carcinoma-in-situ germ cells by treatment with MIS. The carcinoma-in-situ cell itself may even be still responsive to MIS which might stimulate it to differentiate into a more advanced and hence benign germ cell. This recent insight into the control of early postnatal germ cell development now gives us an opportunity to investigate the possible role of germ cell maturation in tumourigenesis.

References

1. Engle, E.T. Experimentally induced descent of testis in the Macacus monkey by hormones from anterior pituitary and pregnancy urine. Endocrinology. 1932; 16:513–520.

2. Hadziselimovic, F.Cryptorchidism. Management and Implications. Berlin: Springer-Verlag, 1983.

3. Hutson, J.M., Beasley, S.W.Descent of the Testis. London: Edward Arnold, 1992.

4. Hutson, J.M. Testicular feminization: a model for testicular descent in mice and men. J. Pediatr Surg. 1986; 21:195–198.

5. Grocock, C.A., Charlton, H.M., Pike, M.C. Role of the fetal pituitary in cryptorchidism induced by exogenous maternal oestrogen during pregnancy in mice. J. Reprod. Fert. 1988; 83:295–300.

6. Spencer, J.R., Torrado, T., Sanchez, R.S., et al. Effects of flutamide and finasteride on rat testicular descent. Endocrinology. 1991; 129:741–748.

7. Husmann, D.A., McPhaul, M.J. Time-specific androgen blockade with flutamide inhibits testicular descent in the rat. Endocrinology. 1991; 129:1409–1416.

8. Wensing, C.J.G. Testicular descent in some domestic mammals. III Search for the factors that regulate the gubernacular reaction. Proc. Kon. Nederland. Akad. Wetensch. Series C. 1973; 76:196–202.

9. Habenicht, U.F., Neumann, F. Hormonal regulation of testicular descent. Adv. Anat. Embryol. Cell Biol. 1983; 81:1–54.

10. Colenbrander, B., van Rossum-Kok, C.M., van Straaten, H.W.M., Wensing, C.J.G. The effect of fetal decapitation on the testis and other endocrine organs in the pig. Biol. Reprod. 1979; 20:198–204.

11. Hutson, J.M., Donahoe, P.K. The hormonal control of testicular descent. Endocr Rev. 1986; 7:270–283.

12. Hutson, J.M. Exogenous oestrogens prevent transabdominal testicular descent in mice with complete androgen resistance (testicular feminization). Pediatr. Surg. Int. 1987; 2:242–246.

13. Hutson, J.M., Chow, C.W., Ng, W.D. Persistent Müllerian duct syndrome with transverse testicular ectopia. An experiment of nature with clues of understanding testicular descent. Pediatr. Surg. Int. 1987; 2:191–194.

14. Josso, N., Cate, R.L., Picard, J.Y., et al. Anti-Müllerian hormone: the Jost factor. Recent Prog. Horm. Res. 1993; 48:1–59.

15. Tran, D., Picard, J.Y., Vigier, B., et al. Persistence of Müllerian ducts in male rabbits passively immunized against bovine anti-Müllerian hormone during fetal life. Dev. Biol. 1986; 116:160–167.

16. Fentener van Vlissingen, J.M., van Zoelen, E.J.J., Ursem, P.J.F., Wensing, C.J.G. In vitro model of the first phase of testicular descent: identification of a low-molecular weight factor from fetal testis involved in proliferation of gubernaculum testis cells and distinct from specified polypeptide growth factors and fetal gonadal hormones. Endocrinology. 1988; 123:2868–2877.

17. van der Schoot, P. Androgens in relation to prenatal development and postnatal inversion of the gubernacula in rats. J. Repord. Fert. 1992; 95:145–158.

18. Heyns, C.F., Pape, V.C. Presence of a low capacity androgen receptor in the gubernaculum of the pig fetus. J. Urol. 1991; 145:161–167.

19. Rajfer, J. Hormonal regulation of testicular descent. Eur. J. Pediatr. 1987; 146(Suppl 2):56–57.

20. Husmann, D.A., McPhaul, M.J. Localization of the androgen receptors in the developing rat gubernaculum. Endocrinology. 1991; 128:383–387.

21. Lewis, L.G. Cryptorchidism. J Urol. 1948; 60:345–356.

22. Beasley, S.W., Hutson, J.M. Effect of division of the genitofemoral nerve on testicular descent in the rat. Aust. N.Z. J. Surg. 1987; 57:49–51.

23. Fallat, M.E., Williams, M.P.L., Farmer, P.J., Hutson, J.M. Histologic evaluation of inguino-scrotal migration of the gubernaculum in rodents during testicular descent and its relationship to the genitofemoral nerve. Pediatr Surg Int. 1992; 7:265–270.

24. Hutson, J.M., Beasley, S.W., Bryan, A.D. Cryptorchidism in spina bifida and spinal cord transection: a clue to the mechanism of transinguinal descent of the testis. J. Pediatr Surg. 1988; 23:275–277.

25. Larkins, S.L., Hutson, J.M., Williams, M.P.L. Localization of calcitonin gene-related peptide immunoreactivity within the spinal nucleus of the genitofemoral nerve Pediatr. Surg. Int. 1991; 6:176–179.

26. Yamanaka, J., Metcalfe, S.A., Hutson, J.M. Demonstration of calcitonin gene-related peptide receptors in the gubernaculum by computerized densitometry. J. Pediatr Surg. 1992; 27:876–878.

27. Park, W.H., Hutson, J.M. The gubernaculum shows rhythmic contractility and active movement during testicular descent. J. Pediatr. Surg. 1991; 26:615–617.

28. Momose, Y., Griffiths, A.L., Hutson, J.M. Testicular descent III The neonatal mouse gubernaculum shows rhythmic contraction in organ culture in response to calcitonin gene-related peptide. Endocrinology. 1992; 131:2881–2884.

29. Griffiths, A.L., Middlesworth, W., Hutson, J.M. (in press) Exogenous calcitonin gene-related peptide (CGRP) causes gubernacular development in neonatal mice with complete androgen resistance (TFM). J Pediatr Surg.

30. Samarakkody, U.K.S., Hutson, J.M. Intrascrotal CGRP (8–37) causes a delay in testicular descent in mice. J. Pediatr. Surg. 1992; 27:874–875.

31. Momose, Y., Goh, D.W., Middlesworth, W., Hutson, J.M. The relationship between CGRP, androgens and guernacular development in three animal models of cryptorchidism. J Urol. 1993. [(in press)].

32. Giwercman, A., Muller, J., Skakkebaek, N.E. Cryptorchidism and testicular neoplasia. Hormone Res. 1988; 30:157–163.

33. Huff, D.S., Hadziselimovic, F., Snyder, H.M., et al. Postnatal testicular maldevelopment in unilateral cryptorchidism. J. Urol. 1989; 142:546–548.

34. Zhou, B., Watts, L.M., Hutson, J.M. The effect of Müllerian inhibiting substance (MIS) on germ cell development of the neonatal mouse testis in vitro. J Urol. 1993. [(in press)].

35. Baker, M.L., Metcalfe, S.A., Hutson, J.M. Serum levels of Müllerian inhibiting substance in boys from birth to 18 years, as determined by enzyme immunoassay. J. Clin. Endocr. Metab. 1990; 70:11–15.

36. Yamanaka, J., Baker, M.L., Metcalfe, S.A., Hutson, J.M. Serum levels of Müllerian inhibiting substance in boys with cryptorchidsm. J Pediatr Surg. 1991; 26:621–623.

The Epidemiological Association between Undescended Testis, Inguinal Hernia and Testicular Cancer: Results from the U.K. National Case-Control Study of Testicular Cancer

D. Forman*, C. Chilvers†, G. Davey* and C. Coupland†

(on behalf of U.K. Testicular Cancer Study Group),     *ICRF Cancer Epidemiology Unit, Gibson Building, Radcliffe Infirmary, Oxford OX2 6HE, UK; †Department of Public Health Medicine and Epidemiology, University of Nottingham Medical School, Nottingham NG7 2UH, UK

Publisher Summary

This chapter discusses the results from the U.K. National Case-Control Study of Testicular Cancer. This study is a large population-based epidemiological investigation into the etiology of germ cell tumors of the testis. In the study, all men diagnosed with a testicular germ cell tumor between January 1984 and September 1986 who were aged between 15 and 49 years at diagnosis and resident in selected areas were included. Controls, matched on date of birth to within one year, were chosen from the list of the general practitioner (GP) with whom the case was registered. Each case-control pair was interviewed by the same interviewer with a questionnaire that included questions on a wide range of potential risk factors. After interview, ancillary data on medical history were abstracted from the GP notes for cases and controls while details of the cases’ cancers were abstracted from hospital notes. The results showed that there was a significantly increased risk of cancer in men with inguinal hernia but this risk was confined to men who had a hernia diagnosed before the age of 15 years. As with undescended testis, men with unilateral hernia cancers were more frequently diagnosed on the same side as the hernia.

The U.K. National Case-Control Study of Testicular Cancer is a large population-based epidemiological investigation into the aetiology of germ-cell tumours of the testis. The study was carried out in defined geographic areas within 9 of the U.K Regional Health Authorities and all men, diagnosed with a testicular germ-cell tumour between January 1984 and September 1986 who were aged between 15 and 49 years at diagnosis and resident in these areas, were included in the study. Controls, matched on date of birth to within one year, were chosen from the list of the General Practitioner (GP) with whom the case was registered. Each case-control pair was interviewed by the same interviewer with a questionnaire which included questions on a wide range of potential risk factors. After interview, ancillary data on medical history were abstracted from the GP notes for cases and controls while details of the cases’ cancers were abstracted from hospital notes. Pathology reports were centrally reviewed and all tumours were divided into those with pure seminoma and those with any other germ-cell histology. Tumours with combined histologies were placed in the latter category.

A diagnosis of undescended testis (UDT) was regarded as definite only if there was evidence of successful orchidopexy or of surgical investigation at which a testis was found to be missing or impossible to correct; otherwise the testis had to remain undescended at diagnosis. Testes that were retractile or that descended either spontaneously or with hormonal therapy were not regarded as undescended.

Interviews were completed with 794 case-control pairs. This represents 92% of all eligible cases within the study areas. The comparable control response rate was 83%. There were 400 cases with a pure seminoma histology and 394 cases with other germ-cell histology. Table 1 shows the risk of testicular cancer associated with UDT and inguinal hernia. Sixty-five cases and 17 controls had a definite history of UDT giving an overall odds ratio (OR) of 3.8 (95% CI=2.2–6.5). Nineteen cases and no controls had bilateral UDT (OR=∞, 95% CI=5.9-∞) whereas 46 cases and 17 controls had unilateral UDT (OR=2.7, 95% CI=1.6–4.7).

Table 1

Number (%) of cases and controls and odds ratios (95% confidence intervals) for diagnosis of undescended testis and inguinal hernia.

aAll men with undescended testis (65 cases and 17 controls) were excluded from analysis.

A split of our study group at the median age (31 years) shows that the prevalence of UDT in controls was 3.3% (13/395) in the younger men and 1.0% (4/399) in the older men. Comparable figures for the cases were 8.1% (32/395) and 8.3% (33/399) respectively, resulting in ORs of 2.5 (95% CI= 1.3-4.7) and 8.3 (95% CI=2.9-23.3) for younger and older men respectively. The risk was, therefore, reduced considerably in younger men, although the proportion of cases with UDT remained similar.

Table 2a shows the relationship, in the cases, between the side of UDT and the side of the cancer. Twelve of the 46 cases (26.1%) with unilateral UDT had cancer in the contralateral testis to that which was undescended ie an OR of 1.4 in comparison with the 34 cases (73.9%) with cancer in the ipsilateral testis, an OR of 4.0.

Table 2

Number of cases with a) undescended testis and b) inguinal hernia and c) inguinal hernia < 15 yrs by side of cancer and by side of defect

Table 3 shows that the risk of pure seminoma after a diagnosis of UDT was significantly greater than the risk for other histologies (OR = 12.7 compared with 1.9, p = 0.002). This difference was also seen in those with unilateral UDT (OR=7.7 compared with 1.6, p=0.016). These differences in risk were largely due to differences in the distribution of UDT in the control groups. The risk of pure seminoma after a diagnosis of UDT was similar for those younger than, and those at or older than, the median age (OR= 12.0, 95% CI= 1.6–92.3 and 13.0, 95% CI=3.1–54.8 respectively). For both age groups these risks were greater than the comparable risks for other histologies (OR=1.7, 95% CI=0.8–3.4 and OR=3.5, 95% CI=0.7–16.8 respectively).

Table 3

Number (%) of cases and controls and odds ratios (95% confidence intervals) for diagnosis of undescended testis and hernia by histological group (pure seminoma/all other histologies) of tumour.

Twelve of the 16 cases with uncorrected UDT (unilateral or bilateral) had a pure seminoma (75.0%) compared with 26 of the 49 cases with a corrected UDT (53.1%) and 362 of the 729 cases with a normally descended testis (49.7%).

The results for the risk of testicular cancer subsequent to inguinal hernia in Tables 1, 2 and 3 are shown after exclusion of all subjects with UDT. This was because of the close association between the two conditions and the need to look at hernia independently from UDT. Table 1 shows that there was a significantly increased risk of cancer in men with inguinal hernia (OR= 1.9, 95% CI= 1.1-3.2) but this risk was confined to men who had a hernia diagnosed before the age of 15 years (OR=2.6, 95% CI= 1.3–5.3). As with UDT, in men with a unilateral hernia cancers were more frequently diagnosed on the same side as the hernia; 21 out of 35 men (60.0%) with unilateral hernias and 15 out of 25 men (60%) with hernias diagnosed before the age of 15 years having cancer in the ipsilateral testis (Table 2 b and c). This results in ORs of 2.3 and 1.5 to the ipsilateral and contralateral testes respectively after an inguinal hernia and ORs of 3.2 and 2.1 respectively after a hernia diagnosed at less than 15 years.

There were no significant differences between the risks for the different histological types of cancer after an inguinal hernia (Table 3). However for all hernias and for hernias diagnosed at less than 15 years, the risks for pure seminoma were less than those for other tumours. This is the opposite of the effect seen for UDT.

The risks associated with UDT and inguinal hernia were much as expected from previous studies (1, 2) i.e. bilateral UDT carries a substantial risk of cancer, whereas unilateral UDT or an inguinal hernia early in life carry more moderate risks (both about three-fold in this study). Our overall risk estimate of 3.8 associated with UDT is somewhat lower than that reported previously. Chilvers and Pike (2) reported a summary estimate of 5.8 from an overview of nine studies published since 1979.

There are two explanations for this reduction. Previous estimates have been based largely on recall of the diagnosis by cases and controls. Men may recall retractile or late descending testes as UDT and cases, who may know of the association between UDT and cancer, may be more likely to misclassify their condition in this way. This could result in an over-estimate of the relative risk. Misclassification of UDT has been reduced in our study by seeking verification of the diagnosis in the GP notes.

A second reason for a reduced risk estimate may arise from the increasing incidence of UDT over time (3, 4). If the population prevalence of UDT has increased since earlier studies took place while the proportion of cases with UDT has remained constant, this will produce a reduced relative risk (4) as we have demonstrated by splitting our study group at the median age.

Our results also suggest that men who had a unilateral UDT which was successfully corrected before the age of 10 years, were no longer at increased risk of developing a cancer (OR=0.6, 95% CI=0.2–1.7). This is consistent with some (5, 6) but not all (7, 8) studies which have addressed this issue although there are few data on men with an age at correction below 10 years. If these findings on unilateral UDT are confirmed, the recent trend to reduce the age at which correction is carried out should be encouraged and the effect on testicular cancer rates closely monitored.

Although previous studies have shown a stronger association between UDT and seminoma than between UDT and other histologies (9, 10) the magnitude of the difference in risk by histological type which we observed was substantial (OR= 12.7 vs 1.9). The difference in risk was maintained after splitting the group at the median age and thus, the greater relative risk did not occur just because seminoma develops at a later age than other histologies and the prevalence of UDT is lower in older men. The fact that the difference between the histological groups is largely a result of the distribution of UDT in the controls indicates that chance may explain some or all of the observed effect. We also observed an increased proportion of seminomas in men with an uncorrected UDT than in men with normally descended testes or successfully corrected UDTs. This effect is consistent with several other studies (2, 11), and it has been suggested that orchidopexy, and resulting trauma, might cause progression of the disease to a more malignant form.

In keeping with most other studies (1), we found a small increased risk associated with having had a hernia and, consist ant with several (10, 12, 13) but not all (5) studies, the risk increased for hernias diagnosed in childhood. Comparison between studies is complicated by the fact that not all analyses clearly distinguish between UDT and hernia and because there are misclassification problems for both conditions when relying on self-report.

Acknowledgement: This study was funded by the Imperial Cancer Research Fund, the Cancer Research Campaign and the Medical Research Council.

REFERENCES

1. Forman, D. Epidemiology of testis cancer. In: Oliver RTD, Blandy JP, Hope-Stone HF, eds. Urological and Genital Cancer. Oxford: Blackwell Scientific Publications; 1989:289–305.

2. Chilvers, C, Pike, MC. Cancer risk in the undescended testicle. European Urology Update Series. 1992; 1:74–79.

3. John Radcliffe Hospital Cryptorchidism Study Group. (1986) Cryptorchidism: an apparent substantial increase since 1960. Br Med J; 293:1401–1404.

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The Epidemiology of Cryptorchidism: Results from the John Radcliffe Hospital Cryptorchidism Study

(*on behalf of the John Radcliffe Hospital Cryptorchidism Study Group)

Clair Chilvers, Pat Ansell, Diana Bull, Carol Coupland and Malcolm Pike

*Members of the study group:

P.E. Ansell, V. Bennett, D. Bull, M.B. Jackson, L.A. Pike and M.C. Pike,     (Imperial Cancer Research Fund’s Epidemiology Unit, Oxford)

C.E.D. Chilvers,     (Institute of Cancer Research, Sutton, Surrey)

N.E. Dudley, M.H. Gough, D.M. Griffiths, C. Redman and A.R. Wilkinson,     (John Radcliffe Hospital, Oxford)

A. Macfarlane,     (Oxfordshire District Health Authority, Oxford)

C.A.C. Coupland,     (Nottingham University Medical School, Nottingham)

Publisher Summary

This chapter presents the results from the John Radcliffe Hospital cryptorchidism study analyzing the epidemiology of cryptorchidism. All babies born between November 1, 1984, and October 31, 1988, to mothers resident in a defined area within the boundaries of the Oxfordshire Health Authority were included in the study. Most of these (98.2%) were born in John Radcliffe Hospital, Oxford. Each boy born in John Radcliffe Hospital was examined for cryptorchidism during the first 24 hours of life by one of four specially trained research nurses. Particular attention was paid to the examination technique. The testis was manipulated into the lowest position along the pathway of normal anatomical descent without tension being applied. The study confirmed the substantial increase in undescended testis suggested by the initial investigation of orchidopexy rates. It was also concluded that birth weight is an important determinant of cryptorchidism not only at birth where it may simply reflect immaturity but also three months after the expected delivery date.

Introduction

A history of undescended testis is the only well-established risk factor for testicular cancer, with approximately 10% of testicular cancer patients having a history of cryptorchidism. Recent studies show a five-fold increased risk of testicular cancer associated with a history of undescended testis (1). In the UK the overall cumulative lifetime risk of testicular cancer is 1 in 480 (2), but a man with a history of undescended testis will have a cumulative risk of developing testicular cancer of about 1 in 100. A history of bilateral undescended testis confers a greater risk of developing a testicular tumour (cumulative risk 1 in 44) than does a history of unilateral cryptorchidism (cumulative risk 1 in 120) (1).

Fertility may also be impaired in men with a history of undescended testis. A review of papers reporting adult fertility in terms of sperm density in men with a history of treated or untreated undescended testis, excluding those presenting to infertility clinics, suggested that approximately 40% of men with treated unilateral cryptorchidism and 75% of men with treated bilateral cryptorchidism had a sperm density of less than 20 × 10⁶ per ml (3). Treatment did not appear to affect the results for men with unilateral cryptorchidism, but all men with untreated bilateral cryptorchidism had azospermia or