Patterns Of Occurrence

Time Trends

The lifetime risk of testicular cancer is less than 1%. Unlike the more common cancers, testicular cancer primarily affects young men (Figures 2-1 and 2-2). Among men between the ages of 20 and 35 years, testicular cancer was the most common cancer until it was surpassed by Kaposi's sarcoma, a cancer related to acquired immunodeficiency syndrome (AIDS). The occurrence of testicular cancer has been increasing for decades,1-14 and where accurate incidence data have been collected, the rates have been found to have increased by a factor of three or four in the last 50 years. Incidence rates in the United States nearly doubled from 1973 to 1999, as shown by data collected by nine registries of the Sur veillance, Epidemiology, and End Results (SEER) program (Figure 2-3). Because the increases have been so rapid and substantial, they are attributed to increasingly prevalent environmental exposures although the specific agents remain elusive.

Studies that distinguish between period and cohort effects3'9101215-18 have found that year of birth is a more important determinant of risk than year of diagnosis. These birth-cohort effects suggest that important exposures occur early in life, perhaps in utero.

SEER data show steadier rates in the 1990s among white males in the United States and even suggest a decline in the late 1990s among men aged 20 to 24 years.19 It is tempting to interpret this report as a hint that the epidemic may be abating, but past instances of stabilized rates proved to be only perturbations in the general upward trend. Rates have traditionally been more stable at the extremes of age, that is, among boys and among men over 60 years of age. One study found that the incidence of testicular cancer in boys (up to 4 years of age) and very young men (15 to 19 years of age) did not increase in Denmark, Norway, and Sweden during the period of 1960 to 1985.18 However, the authors noted that age-specific incidence continued to rise in all other age groups throughout this period, and they concluded that these younger cases may differ etiologically from the others. An additional set of analyses91516 showed stabilization of risk in several cohorts born around the time of the Second World War. However, this lull was not sustained, and risk to successive cohorts climbed thereafter.

In recent decades, remarkable advances in treatment have led to dramatically improved survival of testicular cancer patients in the industrialized world. In the United States, the improvement has been greatest among white persons, and survival is associated with socioeconomic status in many areas.314'20,21 However, it is now evident that survivors are at an elevated risk of several undesirable sequelae, including infertility,22 23 sexual dysfunction,24 other types of cancer,25 26 and second occurrences of testicular cancer.26-35 (See also Chapters 27 and 28.)

Geographic and Racial/Ethnic Distribution

There is significant variation in the geographic and racial/ethnic distribution of testicular cancer. In the United States, incidence is highest among non-Hispanic white persons (Figure 2-1). Worldwide, rates are relatively high in the United Kingdom and in northern Europe.36 There are, however, noteworthy differences even among these predominantly white groups. For example, the highest age-adjusted rates have for some time been observed in Denmark (11.1 per 100,000 in 1995) whereas in nearby Finland, rates are substantially lower (2.8 per 100,000 in 1995).36 Traditionally, rates have been far lower in Africa and Asia and among those of African and Asian descent in the United States. Schottenfeld and Warshauer concluded that underreporting does not appear to explain the lower rates in Africa, as elevated rates of other cancers were concomitantly observed.1

In humans, the vast majority of testicular tumors arise in germ cells. In Los Angeles County, rates of germ cell carcinoma for the period of 1972 to 1999 were highest among the non-Hispanic white population, followed by the Hispanic population and then several groups of Asian ancestry; rates were lowest among African Americans (Figure 2-4). These patterns were similar for subgroups of tumors defined by histologic type (nonseminoma, mixed germ cell tumor, and seminoma).

Age Distribution

Testicular germ cell tumors have a distinctive pattern of age at onset, with a small spike in the first few years of life and with a second broad peak beginning just after puberty. This characteristic shape of the age-incidence curve is observed for all racial and ethnic groups (as shown by the "total"

Testicular Cancer Age Related Incidence
Figure 2-1. Incidence rates of testicular cancer reported to eleven Surveillance, Epidemiology, and End Results (SEER) registries, 1995 to 1999, for five racial/ethnic groups (group-specific spikes at 54, 64, and 84 years interpreted as statistical variation in small populations).
Testicular Cancer Rate Statistics
Figure 2-2. Incidence of testicular germ cell carcinoma among the non-Hispanic white population in Los Angeles County, 1972 to 1999, showing age distribution of all tumors and of three categories of histologic types. (GCT = germ cell tumor.)

curve in Figure 2-4) and could be seen in past decades even as age-specific rates were rising.

There are some measurable differences in the age distribution of histologic subtypes. Germ cell tumors of early childhood are limited to nonsemi-noma (predominantly yolk sac tumors). Nonsemi-noma and mixed germ cell tumors are more com mon among adolescents and the youngest adults whereas seminoma predominates among men who are in their early twenties and older (see Figure 2-2). The age-incidence pattern for all germ cell tumors (total curve in Figure 2-2) results from the age-dependent distributions of these histologic subgroups.

Germ Cell Testicular Cancer
Figure 2-3. Age-adjusted (United States standard population, 2000) racial group-specific incidence rates of testicular cancer reported to nine Surveillance, Epidemiology, and End Results (SEER) registries, 1973 to 1999.
Nonseminoma Mixed GCT Seminoma Total

□ African American ■Chinee BJjl|Mne*£ ■Filipino HKrireiän -J Hispanic 11 \fiiv-l-lü|>anic White OOtherGroups ■ All Groups

Figure 2-4. Racial/ethnic group-specific incidences of testicular germ cell carcinoma in Los Angeles County, 1972 to 1999. (GCT = germ cell tumor.)

Several etiologic models have been proposed to account for the unusual age distribution of testicular germ cell tumors, which shows a preponderance of occurrence in early adulthood.

In 1983, Henderson and colleagues37 proposed a biologic model with two critical periods. The initial event occurs in utero if elevated levels of free estrogen (and perhaps other steroids) are present when testicular germ cells begin to differentiate. This event is postulated to alter germ cells permanently, and they then remain dormant throughout childhood. The second critical period is puberty, when the altered germ cells are stimulated to multiply by rising levels of hormones, presumably gonadotropins. At the time it was proposed, this model could account for all germ cell tumors except the small fraction occurring during early childhood, prior to the events of puberty. It is now apparent, however, that even this early group accords with the model because more recent research38,39 has demonstrated that male infants experience a transient elevation in both testosterone and gonadotropins, with levels approaching those of puberty. However, this model does not account for the lower incidence of testicu-lar cancer that is observed in later decades of life.

Paradoxically, this is a time when age-related biologic processes are presumed to enhance carcinogenic processes, leading to the dramatic rise in the incidence of most adult tumors.

In 1999, Aalen and Tretli40 described a mathematical model that addresses both the lower incidence of testicular cancer seen in later decades of life and the increasing temporal trends. Underlying their model is the idea that a subgroup of men is susceptible to testicular cancer and that the susceptibility results from a combination of genetic and environmental factors during fetal life. It is presumed that susceptible individuals develop testicu-lar cancer after the hormonal processes of puberty begin. By fitting their model to testicular cancer incidence data collected in Norway from 1953 through 1993, they estimated the proportion of susceptible men among cohorts born between 1885 and 1975. They inferred that (1) a very small proportion of men in each cohort were born with susceptibility to either seminoma or nonseminoma (0.6% and 0.5%, respectively, for the most recent cohort) and that (2) the proportion of susceptible men increased in successive birth cohorts, rising by a factor of 10 during the 90-year period. The dra matic increase in the proportion of susceptible individuals explains the temporal trend in population rates, which would rise as birth cohorts with successively higher proportions of susceptible individuals completed puberty.

The two models taken together offer an explanation of why testicular cancer occurs primarily in young men. The model of Henderson and colleagues explains that incidence rises early in adulthood because the onset of disease follows puberty. The results of Aalen and Tretli explain why age-specific incidence rates fall again in later decades.40 They found that the proportion of susceptible individuals in any birth cohort is extremely small. Most susceptible individuals develop testicular cancer during the first few decades after puberty, resulting in a relatively high incidence in early adulthood. By the time a birth cohort reaches older ages, however, very few susceptible individuals remain disease free, so rates fall.

In 1995, Buetow41 reviewed components of an unrelated hypothesis suggesting that the age distribution of testicular cancer results from a viral etiology. This explanation has its roots in an earlier observation that testicular cancer shares epidemiologic features with Hodgkin's disease, for which a similar mechanism had been suggested. According to this model, infection at an early age has low patho-genicity and imparts immunity but delayed infection results in neoplasm.

Impressions from Descriptive Data

The patterns of occurrence described above were observed in data collected and compiled by cancer registries. The long histories of some registries and the high quality of the incidence and demographic data that have been collected allow one to confidently conclude that (1) testicular cancer is primarily a disease of young men and has different geographic and racial/ethnic distributions; (2) its incidence increased dramatically during the twentieth century, at least partly due to birth cohort effects; and (3) its mortality has decreased more recently in industrialized countries. The first two sets of observations provide some hints about the etiology of testicular cancer. However, to find specific causes and develop preventive measures, analytic studies that measure causal factors at the individual level are needed. The analytic studies described in the next section have identified a series of conditions that seem to occur more frequently among individuals with testicular cancer. These conditions include the major known risk factor, cryptorchidism. Family history of testicular cancer is the only other well-established risk factor (although analytic studies have begun to explore the possible etiologic role of additional factors).

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