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Keywords:

  • cryptorchism;
  • hypospadias;
  • infertility;
  • inguinal hernia;
  • familial;
  • testicular germ cell tumor

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Abstract  Background:  A retrospective study was conducted to examine the host factors of 240 testicular germ cell tumor patients. This study was performed to address a new theory proposed by Skakkebaek called testicular dysgenesis syndrome which claims that cryptorchism, hypospadias, poor semen quality and testicular germ cell tumors are symptoms of an underlying testicular dysgenesis in uterus.

Methods:  The past health histories and familial episodes of 240 testicular germ cell tumor patients were examined. The past health histories included cryptorchism, hypospadias, infertility, atrophic testis and inguinal hernia.

Results:  Of the 240 patients, 13 (5.4%) had a history of cryptorchism or orchidopexy. Two (0.8%) showed existence of hypospadias or had experienced urethroplasty. Among 129 married couples, 104 (80.6%) couples were fertile. Three (1.3%) patients developed testicular tumors after they were diagnosed as infertile or came to the hospital with the complaints of infertility. Four (1.7%) had contralateral atrophic testis. 19 (7.9%) had experienced inguinal herniorrhaphy before age 15. Three (1.3%) had testicular germ cell tumor patients among their family or relatives.

Conclusions:  The testicular germ cell tumor patients showed a considerable incidence of complications such as cryptorchism, hypospadias and incomplete closure of processus vaginalis. Cryptorchism, perinatal factors and familial factors could be risks for developing testicular germ cell tumors.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Testicular germ cell tumors (TGCT) are the most common cancers among young men and unlike most other cancers, the incidence does not increase with aging.1 Over the past several decades, the incidence of TGCT has been steadily increasing in the Western world.2 While non-seminoma rates among the white population are reaching plateaus, the overall incidence is still increasing in the USA3 while the incidence of most other major cancers has been generally declining or reaching a plateau.4 Both environmental and genetic factors could contribute to causing TGCT.5 But the most hotly debated topic in TGCT is the effect of endocrine disruptors6 and the exposure of the embryo in uterus, very likely in the first few weeks of gestation.7 Skakkebaek proposed a new theory called testicular dysgenesis syndrome which suggests that cryptorchism, hypospadias, poor semen quality and TGCT are symptoms of an underlying testicular dysgenesis in the uterus.8 To address this issue, a retrospective study was conducted to examine the host factors of 240 TGCT patients.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Between March 1975 and March 2002, 240 TGCT patients were treated in Tohoku University School of Medicine Hospital. The age of diagnosis ranged from 9 months to 75 years (median, 30 years; mean, 30.8 years) (Fig. 1). Among 240 patients, 96 patients were diagnosed with seminomas, 138 patients with non-seminomas, 1 patient with a burned out tumor, 3 patients with epidermoid cysts and 2 patients were not known pathologically because of chemotherapy before orchiectomy.

image

Figure 1.  Age distribution of TGCT patients. There are two peaks of patients age, 0–4-years and 30–34 years. (median 30 years and mean 30.8 years)

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The past health histories and family episodes were examined from the medical records. The past health histories included cryptorchism, hypospadias, infertility, atrophic testis and inguinal hernia. The family episodes focused on TGCT of the patients’ families and relatives.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Cryptorchism

Of the 240 patients (Table 1), 13 (5.4%) had a history of cryptorchism or orchidopexy (Table 2). Among the seven cases of one-sided cryptorchism, five cases developed testicular tumors on the cryptorchism side and two cases developed tumors in the normally positioned testis. Among the six cases of bilateral cryptorchism, one case developed bilateral testicular tumors and another case developed a testicular tumor on the migratory testis, although the contralateral testis was located in the inguinal region.

Table 1.   Summary of rates of complications in 240 TGCT patients/normal populations
ComplicationNo. patients (%)% (population)
Cryptorchism13 (5.4)1 (general)11
Hypospadias 2 (0.8)0.023 (Japan)16
Infertility (prior to tumor development) 3 (1.3)not available
Contralateral atrophic or small testis 4 (1.7)not available
Inguinal hernia (Herniorrhaphy before puberty)19 (7.9)1–5 (general)18
Table 2.   Characteristics of patients who had a history of cryptorchism or orchidopexy
Age (years)Tumor sideTesticular positionPathologyOrchidopexyOther past history
  1. Bil., bilateral; EC, embryonal carcinoma; I, inguinal testis; Lt, left; M, migratory testis; Rt, right; S, seminoma; T, teratoma; VSD, ventricular septal defect; YST, yolk sac tumor.

Tumor on the same side of cryptorchism
 3LtMYST
67LtMSRt inguinal hernia
55RtIS12 y.o.
29RtIS 0 y.o.Bil. herniorrhaphy (0 y.o)
18LtIEC, YST 2 y.o.
Tumor on the contralateral side of cryptorchism
32LtIS10 y.o.
 6RtMT 6 y.o.VSD ope (6 y.o)
Tumor on either side of bilateral cryptorchism
32LtI/IS15 y.o.
28Bil.I/IRt.S, Lt.SchildhoodInfertility
29RtI/IS14 y.o.Rt herniorrhaphy (14 y.o)
34RtM/IS34 y.o.Hypoxia on birth
 1LtM/MYST 1 y.o.
34RtM/MS

Hypospadias

Two (0.8%) patients had hypospadias (Table 3). One patient was found to have hypospadias when he developed a testicular tumor and the other patient had undergone urethroplasty in childhood. The latter patient also had contralateral atrophic testis.

Table 3.   Characteristics of patients who had a history of hypospadias or urethroplasty
AgeTumor sidePathologyMeatal positionUrethroplasty (age)Other complications
  1. CC, choriocarcinoma; Lt, left; Rt, right; S, seminoma.

30RtS, CCcoronal
28RtSpenile3 & 6 yearsLt atrophic testis

Infertility

Among 129 married couples, 104 (80.6%) couples were fertile at diagnosis. Three of the 240 (1.3%) patients had a previous complaint of infertility or had visited hospital with a complaint of infertility (Table 4). Among the three infertile patients, one had undergone testicular biopsy four years before developing a tumor of the contralateral testis. Semen analysis revealed azoospermia and biopsy of the testis revealed of Johnson score of five. Another patient developed a small nodule of tumor four years after the diagnosis of infertility. Partial orchiectomy was performed according to the wishes of the patient. The remaining infertile patient came to our hospital due to two years sterility after marriage without contraception and a small nodule of tumor was found by the urologist. Partial orchiectomy was performed against the tumor.

Table 4.   Characteristics of patients who had visited the hospital with a complaint of infertility
AgeTumor sidePathologyPeriod of infertilitySemenOther complications
  1. E, epidermoid cyst; Lt, left; MT, malignant teratoma; Rt, right; S, seminoma.

35LtS4 yearsazoospermia
31LtMT4 yearssevere oligospermia
33RtE2 yearsoligospermia

Atrophic testis

Contralateral testis turned out to be atrophic (less than 12 mL) or small (15 mL) in four (1.7%) patients when they came to the hospital (Table 5). One patient with contralateral atrophic testis had hypospadias and had undergone urethroplasty as already described.

Table 5.   Characteristics of patients who had an atrophic (small) testis contralateral to the tumor
AgeTumor sidePathologySizeOther complications
  1. Rt, right; S, seminoma.

42RtS<12 mL
38RtS<12 mL
36RtS 10 mL
28RtS 15 mLHypospadias

Inguinal hernia

Nineteen (7.9%) patients experienced inguinal herniorrhaphy before the age of 15 (Table 6). Among them, six patients (31.6%) developed TGCT on the same side, nine (47.4%) on the opposite side and two (10.5%) on either side of the bilateral inguinal hernia. There was no description of the side of hernia in two (10.5%) patients. Among the 19 cases, seven were diagnosed as seminoma, 11 as non-seminoma and one case as a burned out tumor. Two cases had concomitant cryptorchism.

Table 6.   Characteristics of patients who experienced inguinal herniorrhaphy before age 15
AgeTumor SidePathologyHerniorrhaphy (age, years)Other complications
  1. Bil., bilateral; EC, embryonal carcinoma; IT, immature teratoma; Lt, left; Rt, right; S, seminoma; T, teratoma; TC, teratocarcinoma; YST, yolk sac tumor.

Tumor on the same side of the inguinal hernia.
28RtS15(–)
26LtEC 1Rt hydrocele testis
24RtEC, YST, T 3(–)
29RtS14Bil. cryptorchism
55RtScar tissue 2–3(–)
36LtIT, EC, S 3(–)
Tumor on the opposite side of the inguinal hernia
23RtEC 5(–)
 2LtYST 2(–)
38RtS12(–)
23LtEC, CC 4(–)
16LtCC, YST, TC 2–3Kawasaki's disease
25LtS 1(–)
18LtIT, EC, CC 3(–)
41RtS 2–3(–)
37LtS 6(–)
Tumor on either side of bilateral inguinal hernia
29RtS 0Rt cryptorchism
36LtS, CC 5(–)
Others (No description of site of inguinal hernia)
31LtEC 2(–)
23RtIT, EC, CC 6(–)

Family histories

Three (1.3%) patients had episodes of TGCT in their families or relatives (Table 7). Among them, two patients had a cousin with TGCT and did not exhibit a male to male transmission pattern. The other patient had a brother with TGCT. The mean age at diagnosis was 26.7 while that of the other sporadic cases (except those younger than 15) was 32.8.

Table 7.   Characteristics of patients who had testicular germ cell tumor patients among their families or relatives
AgeTumor SidePathologyOther complicationsRelationship
  • , this case is a patient from another hospital and not included in the 240 testicular germ cell tumor patients. EC, embryonal carcinoma; Lt, left; Rt, right; S, seminoma; T, teratoma; TC, teratocarcinoma.

21LtTCCousin (via father)
25LtS, ECCousin (via mother)
34RtSAsthmaElder brother
†27LtTYounger brother

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Testicular germ cell tumors (TGCT) have been of particularly concern to urologists because they mostly affect young men. TGCT is now becoming a social concern because the incidence of TGCT has continued to increase during much of the 20th century.5 Although the incidence of many cancers is decreasing or reaching a plateau in the USA, the incidence of TGCT has not been a part of this general trend.5 Recent health statistics from Denmark show that almost 1% of men are treated for TGCT, 5–6% of school boys have cryptorchism, almost 1% have penile abnormalities and 40% have subnormal sperm counts.8 In accordance with the seriousness of these problems, Skakkebaek proposed a new theory called testicular dysgenesis syndrome which suggests that cryptorchism, hypospadias, poor semen quality and TGCT are symptoms of an underlying testicular dysgenesis in the uterus.8 According to the theory, dysgenesis could come from environmental or genetic factors and the growing incidence of these problems could be explained by endocrine disruptors.9

Some  risk  factors  of  TGCT  have  been  discussed but very little is established. One of the most well discussed risk factors is cryptorchism. The relative risk of TGCT in men with a history of cryptorchism is reported to be 2.5–40.1,10,11 In the present study, two cases developed tumors on the descended testis, but not on the undescended testis and one case of bilateral cryptorchism developed a tumor on the migratory testis, but not on the inguinal testis. Six patients developed tumors in spite of previous orchidopexy, even though two patients underwent orchidopexy before age 2. The present report, in combination with previous reports,12 supports the idea that TGCT and cryptorchism share a common etiology rather than cryptorchism itself predisposes the patients to TGCT. This idea is also supported by the fact that Kallmann syndrome, a condition of congenital hypogonadotropic hypogonadism, is characterized by cryptorchism but the patients rarely develop TGCT.13 Skakkebaek hypothesized that abnormal gonocytes which deviated from normal differentiation in the fetus should grow by stimulation of testosterone at birth and puberty to develop testicular carcinoma in situ.14,15 In the present study, the incidence of cryptorchism among TGCT patients was 5.4%, which seems apparently higher than that of normal population (Table 1). The incidence of cryptorchism declines about 1% by 1 year of age and remains constant throughout adulthood.11

In regard to other risk factors, hypospadias, inguinal hernia, tersticular atrophy, hydrocele testis have also been reported.10 The current data shows that 0.8% of TGCT patients had been born with hypospadias, and this rate seems higher than that of the normal population in Japan (Table 1). In Japan, the average rate of hypospadias by year of birth from 1980 to 1988 was reported as 0.023%16 and the rates by year of birth from 1972 to 1996 show a net increase between 0 and 5 per 10 000 total births.17 To our surprise, 7.9% of TGCT patients experienced inguinal herniorrhaphy before the age of 15 (Table 1) and 1.2% had an episode or history of contralateral hydrocele testis before puberty (data not shown). In infants, the incidence of inguinal hernia is 1–5% with 60% on the right side, 25% on the left side and 15% bilateral.18 The data of the present report shows similar incidence rates: 59% (10/17) on the right side, 29% (5/17) on the left side and 12% (2/17) bilateral, while the tumor incidence was eight cases on the right side and nine cases on the left side, explaining why tumors developed on the opposite side of the hernia more often than the same side. A patent processus vaginalis is found in more than 90% of patients with an undescended testis and a higher incidence of epididymal anomalies is associated with a patent processus vaginalis, supporting the theory that androgenic stimulation may be required for a closure of the processus.11 We speculate that the incomplete closure of processus vaginalis in TCGT patients could be explained by testicular dysgenesis syndrome, although premature birth could be the common etiology which can not be revealed from our clinical records.5,18 In the present study, four (1.7%) patients turned out to have atrophic contralateral testis and one patient had concomitant hypospadias. The two or three different concomitant conditions could be explained by testicular dysgenesis. Skakkebaek reported that men with atrophic testes are considered to be at the highest risk of having testicular carcinoma in situ.8 Nonspecific or mumps-associated atrophy of the testis has been suggested as a potential causative factor in TGCT.12

Among 129 married couples, 80.6% were fertile but we could not determine whether the other couples were infertile as there was no mention of contraception. However, the three patients listed as infertile had at least 2–4 years of infertility before they developed tumors. Since the tumors were detected when they were still nodules in the testes and serum βhCG levels were quite normal in all cases,19 we speculate that infertility preexisted tumor formation. Men with TGCT had significantly fewer children than controls prior to development of their tumors.20 The recent cohort study demonstrated that abnormal semen characteristics are a risk in developing TGCT.21

Family history is another well established risk factor.5 However, hereditary factors have been poorly established because testicular tumor patients have less opportunity of paternity.5,22,23 The relative risk of developing TGCT in first-degree male relatives of TGCT patients is between 2 and 12.24,25 The risk is greater if the first degree relative is a brother rather than a father.22 This fact causes us to speculate that environmental factors could contribute to developing TGCT rather than inherited genetic factors.25 In the present study, the mean age at diagnosis of familial cases was lower than that of the other sporadic cases. In a similar study, TGCT cases with family history had a significantly earlier age onset (29 years of age) when compared with cases that reported no family episode (32.5 years of age).24 Among the patients listed, two patients were cousins and did not exhibit a male to male transmission pattern. Most recently, the localization among families of a TGCT susceptibility gene to Xq27 has been reported.26

In the present study, we found considerable incidence of complications such as cryptorchism, hypospadias, atrophic testis and incomplete closure of processus vaginalis in TGCT patients which coincide with a previous report.10 These results are compatible with the concept of testicular dysgenesis syndrome proposed by Skakkebaek.8 In several studies, the incidence of TGCT has been found to be more consistent with a birth-cohort effect than with a calendar time effect27,28 and a cohort of men born in Denmark, Norway and Sweden during the years surrounding World War II (1939–1945) did not experience an increase in risk,27 leading us to speculate that economic activity and environment has something to do with these problems. There have been no published English-language reports of Japanese trends in the prevalence of TGCT, cryptorchism, infertility or atrophic testis yet and only the International Clearinghouse for Birth Defects Monitoring Systems reported the increase of hypospadias in Japan.17 It seems an imminent necessity to examine whether the incidence of these reproductive problems are also increasing in Japan and the true reasons if this is the case because TGCT is no longer only a problem for individuals, but may be a problem for the species.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

We thank Dr Kenji Obara from the Department of Urology, Niigata University, for the quotation of one case of familial testicular tumor in Table 7.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References