Urogenital Conditions Associated With Testicular Cancer

Cryptorchidism

Cryptorchidism is a common congenital disorder in which one or both testicles fail to descend into the scrotum before birth. Over half of the boys who are born with cryptorchidism experience spontaneous testicular descent during the first year of life. A history of persistent cryptorchidism, in which spontaneous descent does not occur, is the major established risk factor for testicular cancer. Epidemiologic studies consistently find associations between a personal history of cryptorchidism and risk of testicular cancer, and reported estimates of relative risk range from 2.5 to 18.1 5 11 42-60 Some studies found cryp-torchidism to be more strongly associated with seminoma than with other histologic types.

The specific mechanisms whereby a history of cryptorchidism predisposes an individual to testicu-lar cancer are not known although two general scenarios have been postulated. The "abdominal-location hypothesis" asserts that pathogenic effects of the suprascrotal position are responsible for malignant transformation of germ cells. Often taken as support for this hypothesis is the observation that among men with a history of cryptorchidism, the risk of testicular cancer is lower for those who were treated for cryptorchidism at an early age. However, an alternate explanation is that groups treated at earlier ages include higher proportions of boys who would have otherwise experienced spontaneous tes-ticular descent—and who are presumably at lower risk for testicular cancer.

A second set of observations interpreted as supporting this hypothesis comes from surgical models of cryptorchidism in rodents. In these experiments, histologic and molecular changes were observed in testes that were presumed to be normal until they were surgically retained or elevated into the abdomen. Changes included an increased apoptosis of primary spermatocytes61 and spermatids62; a significant and permanent decrease in testosterone levels; and the induction of messenger ribonucleic acids (mRNAs) encoding transforming growth factor (TGF)-p2, TGF-ps, tumor necrosis factor (TNF)-a receptor, Fas,62 and an ovarian-specific transcript of the luteinizing hormone (LH) receptor.63 While it is clear that prolonged periods in a suprascrotal position can induce numerous changes, mechanistic studies are needed to determine which changes (if any) contribute to the malignant potential of rodent or human testes.

The alternative "common-cause hypothesis" suggests that one or more factors cause both testicular cancer and cryptorchidism. Several sets of findings are consistent with this possibility. First, among men with a history of unilateral cryp-torchidism, elevated rates of neoplasm occur even in contralateral normally descended testi-cles.5'46'51,53 Second, several specific factors have been implicated in the etiologies of both conditions. These include low birth weight and several indicators of in utero exposure to high levels of free estrogen.46,64-66 Finally, a few observations suggest that while a prolonged suprascrotal position may induce a variety of germ cell changes, very early germ cell changes in undescended testes of cryptorchid boys do not necessarily result from the suprascrotal position. For example, in a series of boys with cryp-torchidism who were under a year old, germ cell hypoplasia was found in the suprascrotal testes of boys who were without a symptomatic inguinal hernia but not in the suprascrotal testes of those who had this accompanying condition.67 The authors of the study suggest that the latter group may be interpreted as being made up of boys with normal testes in whom the descent of the testes was inhibited mechanically by the hernia.

It would be instructive to compare temporal trends in the incidence of testicular cancer with temporal trends in the prevalence of cryptorchidism. Unfortunately, the occurrence of cryptorchidism is not well documented. Data from birth defect reg istries are inadequate, for two reasons. First, some registries classify cryptorchidism as a minor malformation and record it only when it occurs in conjunction with an additional major malformation. Second, the frequent occurrence of spontaneous testicular descent complicates the determination of persistently undescended testes. As a result, limited inferences about the occurrence of cryptorchidism are usually based on follow-up studies of boys born with cryp-torchidism in selected hospitals. One study of this type suggests that 3 to 4% of boys born in the United States have undescended testicles and that about two-thirds of these boys experience spontaneous descent in infancy, leaving about 1% with persistent cryp-torchidism at 1 year of age.68 More comprehensive data from the United Kingdom show that more than 1% of males have persistent cryptorchidism and that the condition has become more common since 1960. Some part of the increased prevalence may be attributable to the increased survival of premature infants. However, in two large studies, the elevated prevalence of persistent cryptorchidism among boys who were born prematurely appeared to be attributable to low birth weight rather than to early gestational age when these variables were adjusted for each other.65,69 Two recently published extensive reviews of occurrence data suggest that where reliable data have been collected over time, cryptorchidism has become more prevalent in recent decades.70,71 Of relevance to the etiology of testicular cancer is the recent report that the prevalence of cryptorchidism in Denmark is about twice that in Finland.72*

Hypospadias

Hypospadias is a congenital condition in which the urethral opening is abnormally located. Several epidemiologic studies report an association between history of hypospadias and the occurrence of testicular cancer.11 Registry data for

*Editor's note: In a case-control study in Australia, cryptorchidism occurred statistically significantly more often in patients with germ cell tumors (GCT) than in healthy males without cancer, but it was also noted that the occurrence of multiple atypical cutaneous nevi was a more frequent association, an observation that was confirmed in the Netherlands (see Chapter 1).

hypospadias are not reliable, largely because variation in the severity of this condition leads to inconsistent reporting of cases. Limited data suggest that hypospadias has become more common in parts of Europe and the United States in recent decades and that prevalence varies geographi-cally.70,71 Hypospadias and cryptorchidism occur together more often than would be expected by chance66 and so may share etiologic features.

Other Congenital Conditions

Results of studies of inguinal hernia and testicular cancer have been inconsistent although the weight of the evidence suggests an association.11,51,59,73

There are numerous reports of testicular cancer in individuals with testicular atrophy, various forms of gonadal dysgenesis, and conditions such as renal abnormalities that are often undiagnosed. Although these reports are intriguing because of the postulated fetal origins of testicular cancer, systematic studies of associations between testicular cancer and the conditions mentioned above are not available.

Poor Semen Quality and Subfertility

Testicular cancer is associated with poor semen quality and may be associated with infertility and reduced fertility. Studies of spermatogenesis in men with testicular cancer prior to orchiectomy were reviewed by Petersen and colleagues,74 who concluded that the majority of patients with testicular germ cell carcinoma have very poor semen quality. Two case-control studies found significant associations with infertility50,59; two others did not.20,75 A single case-control study found nearly twice the risk of testicular cancer among men with low relative fertility, a measure based on the number of children each man fathered. However, it is not clear that any of these conditions existed before the onset of sub-clinical disease. Significantly impaired testicular function is observed even in men with carcinoma in situ, the presumptive precursor to germ cell carci-noma.76 Therefore, one cannot rule out the possibility that the observed associations between these reproductive variables and testicular cancer result from the effects of undetected neoplasia.

Explanations for the Occurrence of Testicular Cancer with Other Urogential Conditions

Two related hypotheses that address associations between testicular cancer and the conditions discussed above have recently been proposed.

The "endocrine disruptor" hypothesis suggests that some chemicals in the environment disrupt endocrine function, resulting in numerous adverse effects that may include testicular cancer, cryptorchidism, hypospadias, and poor semen quality.77 Compounds postulated to have this property are termed endocrine disruptors, and developing organisms are thought to be particularly susceptible to their effects.

Boisen and colleagues78 suggest that male genital abnormalities—testicular cancer, reduced semen quality, and subfertility—are elements of a common entity they term the testicular dysgenesis syndrome, which results from a disruption of embryonal programming and gonadal development during fetal life. They suggest that the prevalence of this syndrome is rising and that the increases are causally linked to endocrine disrupters that are affecting genetically susceptible individuals.

While these hypotheses are unproven, they provide intriguing explanations for numerous observed patterns and also provide a theoretical framework that may be useful in future etiologic and mechanistic studies of testicular cancer.

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