Int. .I. Cancer: 61, 761-764 (1995) <$g@& Publication of the International Union Against Cancer Publication de I'Union Internationale Contre le Cancer

, -:>-*, 0 1995 Wiley-Liss, Inc. ~~

TRENDS IN INCIDENCE OF TESTICULAR CANCER IN BOYS AND ADOLESCENT MEN Henrik M0LLER1.4, Niels J0RGENSEN2 and David FORMAN3

Unit of Carcinogen Identijkation and Evaluation, International Agency for Research on Cancer, 150 cours Albert Thomas, 69372 Lyon Cedex 08, France; ?Department of Growth and Reproduction, Rigshospitalet, 9 Blegdamsvej, 21 00 Copenhagen 8, Denmark; and "orkshire Cancer Registry, Yorkshire Cancer Organisation, University of Leeds, Cookridge Hospital, Leeds LS16 QB, UK.

Several epidemiological studies have described increasing trends over time in the incidence of testicular cancer in adult men. Less attention has been given to the trends in young boys, adolescents and old men. This paper describes the incidence of testicular cancer in young boys (0-4 years) and adolescents (I 5-19 years) in Denmark, Norway and Sweden, and compares these trends with the corresponding data on adults. Although only small numbers were available, the data suggest that the incidence of testicular cancer in young boys has been constant, at a level around 0.5 per 100,000. This observation lends support to the idea that testicular cancer in young boys is aetiologically distinct from testicular cancer in adults. In all three populations we found a particularly high average annual increase in the incidence of testicular cancer in adolescents (around 6% per year). It is proposed that this increase is mainly caused by a secular trend towards earlier age at puberty. Q 1995 Wiley-Liss, Inc.

Testicular cancer occurs most commonly in men in their twenties, thirties and forties. Published reports have consis- tently shown an increase in age-adjusted incidence rates with time (Forman and Moiler, 1994; Adami et al., 1994), but few studies have considered the trends in incidence in the age groups where testicular cancer occurs less frequently, i.e., in young boys, adolescents and old men.

The aetiology of testicular cancer is not well understood. and the stages through which this malignancy progresses from the normal primordial germ cell, through the pre-invasive

stage of carcinoma in situ, to invasive cancer, are not fully characterized (Rajpert-De Meyts and Skakkebzk, 1993). It is most likely that important determinants of risk for testicular cancer operate before birth (Skakkebaek et al., 1987; M ~ l l e r , 1993). Testicular cancer is very rare before puberty, but the incidence increases rapidly thereafter, probably indicating that male sex hormones are required for invasive tumour growth. A small but distinct peak in testicular cancer incidence occurs in boys, most often before the age of 3 years. Like testis cancers in adults, these are germ-cell tumours, but with a distinct pattern of histological types dominated by yolk-sac tumours and mature teratomas (Visfeldt et al., 1994).

A recent study attempted to compare the trends over time in the incidence of testicular cancer in boys and adults in Denmark, but failed to obtain sufficient numbers of cases in boys for a conclusive comparison (Visfeldt et al., 1994). The present paper attempts to compare trends in the incidence of testicular cancer in different age groups, and describes data separately for 3 Nordic countries, Denmark, Norway and Sweden, and for the combined population of these countries.

"To whom correspondence and reprint requests should be dressed. Fax: 12 13 85 75.

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Received: November 23, 1994 and in revised form March 4, 1995.

TABLE I - ANALYSIS OF THE TRENDS IN INCIDENCE OF TESTICULAR CANCER IN DENMARK, NORWAY AND SWEDEN, 1958-1987

Age group (years) Area

0-4 Denmark Norway Sweden Total

5-14

15-19

20-34

35-54

Denmark Norway Sweden Total

Denmark Norway Sweden Total

Denmark Norway Sweden Total

Denmark Norwav Swedei Total

Average annual rate of change

% 95% CI Number of cases

-0.9 2.4

-1.3 0.5

- 1.2 1 .o

-4.9 0.1

4.8 6.9 4.5 5.6

3.1 3.5 3.3 3.2

2.2 1.9 1.9 2.1

-5.8: 4.3 -3.61 8.8 -5.7: 3.2 -2.8; 3.8

-9.7; 8.1 -2.2; 4.3 -9.7; 0.1 -3.6; 3.9

2.5; 7.2 4.5; 9.4 2.0: 7.1 4.01 7.2

2.3; 3.9 2.0; 5.0 2.4; 4.3 2.3; 4.2

1.4; 3.1 0.8; 2.9 1.4; 2.5 1.4; 2.7

32 33 39

104

13 11 17 41

165 123 131 419

2173 1208 1472 4853

1897 942

1288 4127

Estimated incidence in 1975 (per 100.000)

0.69 0.96 0.57 0.69

0.16 0.15 0.11 0.13

3.03 2.74 1.66 2.46

14.36 10.75 6.38

10.51

11.04 7.77 4.60 7.80

55-84 Denmark 0.8 -0.4; 2.0 546 3.59 Norway 1.7 -0.1; 3.5 276 2.53 Sweden -0.4 -2.3; 1.5 477 1.93 Total 0.7 -0.1; 1.5 1299 2.70

762 M0LLERETAL

MATERIAL AND METHODS

Data on testicular cancer incidence in Denmark, Norway and Sweden in the period from around 1960 to around 1985 were extracted from the IARC publications Cancer incidence in five continents (Doll et al., 1966, 1970; Waterhouse et al., 1976, 1982; Muir et al., 1987; Parkin et al., 1992).

Incidence rates were calculated for each population for the age groups 0-4, 5-14, 15-19, 20-34, 35-54, and 55-84 years. For age groups spanning more than 5 years, an adjustment was applied using equal weights to each 5-year age group within the broader age group. For the combined population of Denmark, Norway and Sweden, estimates were adjusted for population by giving equal weight to the age-adjusted esti- mates from each of the 3 populations. This adjustment was chosen because there are known differences in the incidence of testicular cancer between the 3 countries (Jensen et al., 1988; and data presented below), and the main objective of the analysis was to evaluate the incidence trends in the 3 popula- tions combined without any confounding introduced by changes in population sizes between the populations.

Analysis by calendar period was carried out in 5-year intervals: 1958-1962, 1963-1967, and so on. In some volumes of Cancer incidence in five continents, the periods covered were

0 0

0 0

4

c

L 9) a 9) 0 C 0, 0 0 C I

-

1 oc

t c

1

0. I

D e n m a r k

A

0 - 0 0 0

0

0.01 1960 1965 1970 1975 1980 1985

Year

1 O(

1 c

I

0.1

not identical. For example, data from Denmark were reported for the 4-year period 1973-76, and not for the 5-year period 1973-77. Such discrepancies were ignored in this analysis, and all data were treated as pertaining exactly to the time-point corresponding to the mid-points of the 5-year periods, i.e., 1960, 1965, etc. Four datapoints in the analysis were affected: for Denmark, the data actually used corresponded to the time-point 1974.5 instead of 1975; for Sweden the data actually used corresponded to the time-points 1963.5, 1968 and 1973 instead of 1965,1970 and 1975 respectively. The effect of these substitutions were judged to be minimal for the analysis of each population individually, and negligible for the combined analysis.

A weighted, linear least-squares regression of log incidence on period was used to estimate the slope of the incidence trend and its 95% confidence interval. The trends are presented as the average annual percentage change in the incidence of testicular cancer.

RESULTS

The results are shown in Table I and Figures 1 and 2. In all 3 populations, whether considered separately or together, statis-

N o r w a y

m

0

0 0

0.01 1960 1965 1970 1975 1980 1985

Year

1 O(

1 c

1

0.1

0.01

S w e d e n

0 0-4 0 5-14

A 15-19 8 20-34 A 35-54 0 55-84

1960 1965 1970 1975 1980 1985

Year

FIGURE 1 - Trends in incidence of testicular cancer (per 100,000) in the age groups 0-4,5-14. 15-19,20-34,35-54 and 55-84 years in Denmark, Norway and Sweden, 1958-1987.

INCIDENCE OF TESTICULAR CANCER IN BOYS AND ADOLESCENT MEN 763

0 0

0 0

9 .- L 0 a

100

10

1

0.1

0.01

Denmark, Norway and Sweden combined

wide, and the estimate was also consistent with the low rate of decrease seen in boys in Denmark and Sweden.

0 0-4 0 5-14 A 15-19 20-34 A 35-54 0 55-84

'- e .

3 0 0 0

U

0

1 I I I I I 1960 1965 1970 1975 1980 1985

Year

FIGURE 2 - Trends in incidence of testicular cancer (per 100,000) in the age groups 0-4,s-14,15-19,20-34,35-54 and 55-84 years in the combined population of Denmark, Norway and Sweden, 1958-1987.

tically significant increases in incidence over time were seen in the age groups 15-19, 20-34 and 35-54 years (Table I). The average annual increase in 15- to 19-year-old men (5.6% per year) was substantially higher than in the age groups 20-34 (3.2%) and 35-54 years (2.1%). Despite different levels of incidence in the 3 populations, the results were qualitatively very similar (Fig. 1). There was no significant increase (or decrease) in the age-groups 0-4,s-14 and 55-84years (Table I).

The level of incidence in adult men, estimated at the time-point 1975, varied among the 3 countries. The highest values occurred in Denmark and the lowest in Sweden. The same relative ranking of the countries was seen in the age group 15-19 years, but not in the age group 0-4 years. In other words, the levels of incidence in young boys and in adults were not correlated across populations.

The estimated averagc annual increases in adult men (20-34 and 35-54 years) were constant at around 2 to 3% per year, with narrow and overlapping 95% confidence intervals. In Denmark and Sweden, the average changes in the 0- to 4-year-olds were lower than this level. In Norway, the esti- mated rate of increase in 0- to 4-year-old boys was about the same as that in adult men, but the confidence interval was very

DISCUSSION

Two items will be considered below: the aetiology of testicular cancer in young boys and the trend in incidence of testicular cancer in adolescent men in the age group 15-19 years.

AetiologV of testicular cancer in young boys A previous study, based on 52 cases of testicular cancer in 0-

to 4-year old boys in Denmark, 1943-1989, could not make a conclusive comparison of the trends in boys and in adult men (Visfeldt et al., 1994). It was hoped that the combined population of Denmark, Norway and Sweden would be more informative, due to a larger number of cases (104), despite the shorter period of study (comparable data from Denmark, Norway and Sweden were available for the period 1958-1987).

The combined analysis of data from Denmark, Norway and Sweden did not readily provide a conclusive comparison between the incidence trends in young boys and in adult men. The estimate from Norway is consistent with a rate of increase in boys comparable with that in adult men and, consequently, the combined estimate is intermediate between Denmark/ Sweden and Norway.

Although these data do not allow a totally unambiguous conclusion, we judge the evidence to be most consistent with the interpretation that the trend in testicular cancer in young boys has been different from the trend in adult men. The evidence in support of this interpretation is that, in 2 of the 3 populations and in the combined population, there is no evidence for an increase in incidence among young boys. Although the Norwegian data may suggest a trend in boys comparable with that in adults, the estimate is also compatible with the hypothesis of no increase in incidence, as suggested by the data from the 2 other populations.

With this interpretation of the data, our study suggests that testicular cancer in young boys and in adult men may be aetiologically distinct disease entities. The trends over time are different, the level of incidence in adults is not predictive of the level of incidence in young boys, and the histological types of testicular cancers in young boys and adult men are different (Visfeldt el al., 1994). In addition, Jorgensen et al. (1994) did not find carcinoma in situ cells associated with 18 testicular germ-cell cancers in 0- to 4-year-old boys, whereas 93 of 99 adult testicular germ-cell cancers reported by Jacobsen et al. (1981) had carcinoma in situ cells in the testicular tissue adjacent to the cancers. The presence of carcinoma in situ cells suggests that the tumours originate from this type of cell and this difference between testicular cancers in young boys and adult men may indicate separate aetiologies (Jorgensen et al., 1994).

The trends in testicular cancer incidence in 5- to 14-year-old boys were not materially different from those in 0- to 4-year- old boys, but based on fewer cases.

Trends in testicular-cancer incidence in adolescent men The histological types of tumours which occur in adolescent

men are not of the type seen in young boys, but are similar to the types seen in adult men (Visfeldt et al., 1994). Further- more, carcinoma in situ is commonly found in the testicular tissues surrounding these cancers, probably indicating an aetiological similarly with germ-cell tumours in adults (Jor- gensen et al., 1994).

The sharp increase in incidence of testicular cancer after the age at which puberty most often occurs indicates that the adult hormonal pattern is required for the growth of most testicular cancers. An early age at puberty has been associated with an

764 MOLLER ETAL

increased incidence of testicular cancer (United Kingdom Testicular Cancer Study Group, 1994).

The occurrence of testicular cancer predominantly in young men and the rarity of the disease in old men suggest that exposure to risk factors early in life, possibly in utero, are likely to be more important than exposures in adulthood. Indeed, the age incidence pattern is compatible with the hypothesis that there is a susceptible population of men, defined at or around birth, all of whom develop testicular cancer eventually (Merller, 1993). As tumours start to grow invasively only after the onset of puberty, it follows from this idea that the cumulative probability of testicular cancer development in a man up to any particular age should be higher, the earlier he entered puberty.

In women, several studies have documented a decrease in age at menarche in women in the Nordic countries from around 17 years in 1850 to around 13 to 14 years in 1970 (Tanner, 1973; Wyshak and Frisch, 1982). No single event in the development of boys marks the transition from child to adult as clearly as menarche in girls. However, it is likely that the secular trend in growth and maturation of boys has been similar to the trend in girls (for review, see Roche, 1979). For example, the secular trend in both height and weight at a given

age has been similar in boys and girls in Sweden (Tanner, 1962; Proos, 1993).

We propose as a hypothesis that the particularly high rate of increase in incidence in adolescent men in the age group 15 to 19 years in Denmark, Norway and Sweden may be the result of a secular trend towards lower age at puberty. When the age of puberty decreases, the person-years at risk in adolescents and young men change in distribution towards more “adult” and fewer “juvenile” person-years within each age-group. In rela- tive terms, this change is more pronounced in the earlier age group, 15 to 19 years, than in later age groups, and the average annual percentage change is therefore higher in the younger than in the later age-groups. The detailed analysis by Adami et al. (1994) of incidence trends in adults supports this interpreta- tion in showing that the average annual increase in incidence in young men aged 20 to 24 is intermediate between the high increase we have seen in adolescents and the lower rates of increase in older adults.

ACKNOWLEDGEMENTS

The data analysed in this article have been made available through the publications Cancer incidence in Jive continents from the cancer registries in Denmark, Norway and Sweden.

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VISFELDT, J., J0RGENSEN, N., MULLER, J., M0LLER, H. and SKAKKE-