The incidence of testicular cancer has increased in many countries, including Sweden,
two- to four-fold over the last half a century, for unknown reasons (Bergstrom et
al, 1996; Centre for Epidemiology, 2002). Of the two main types, seminomas and nonseminomas,
the latter include teratomas with somatic differentiation and undifferentiated embryonal
tumours (Kumar et al, 1997). However, some 60% of germ cell tumours of the testis
contain multiple histological types and only 40% contain a single histological type
(Kumar et al, 1997). The aetiology of testicular cancer remains largely unknown; some
identified or suggested risk factors include undescended testis (cryptorchidism),
a prior history of cancer in one testis (the opposite testis is at increased risk),
in utero hormonal exposures, perinatal factors and family history of testicular cancer
(Forman et al, 1992,1994; Heimdal et al, 1997; Moller and Skakkebaek, 1997; Swerdlow
et al, 1997; Westergaard et al, 1998; Jacobsen et al, 2000; Hemminki and Mutanen,
2001). Compared to the relatively high incidence of testicular cancer in Sweden, first-generation
immigrants generally show a decreased risk of testicular cancer compared to the natives,
but this difference disappears in the next generation; this effect is marked among
the sons of Finnish immigrants, whose risk is doubled compared to their fathers (Hemminki
and Li, 2002b; Hemminki et al, 2002). Among the sons of the Danish immigrants, an
equally large but opposite change takes place (Hemminki and Li, 2002a).
In the present study, we have examined the genetic epidemiology of histology-specific
testicular cancer in order to distinguish the contribution of heritable and environmental
effects to etiology. Compared to the previous testicular cancer study from the Swedish
Family-Cancer Database, an extended population and hence some 50% more familial testicular
cancer cases are available (Dong et al, 2001), allowing analysis by age of onset through
parental and fraternal probands. This, the largest cohort study of familial testicular
cancer, offers new insight into the aetiology of the disease.
SUBJECTS AND METHODS
Statistics Sweden maintains a ‘Multigeneration Register’ in which offspring, born
in Sweden in 1932 and later, are registered with their parents (as declared at birth)
and they are organized as families (Hemminki et al, 2001a). Information on the Database
is available at the Nature Genetics website as ‘Supplementary information’ (Hemminki
and Granstrom, 2002). The data on families and cancers have a complete coverage, barring
some groups of deceased offspring born in the 1930s and who died before 1991. Although
this small group of offspring with missing links to parents has a negligible effect
on the estimates of familial risk (Hemminki and Li, 2003), we limited the present
study to offspring whose parents were known, to eliminate this possible source of
bias. The ‘Multigeneration Register’ was linked using the individually unique national
registration number to the Cancer Registry for the years 1958–2000. Cancer registration
is considered now to be close to 100% complete (Centre for Epidemiology, 2002).
The registered site of cancer is as a four-digit diagnostic code based on the 7th
revision of the International Classification of Diseases (ICD-7). The following ICD-7
codes were grouped: ‘upper aerodigestive tract’ cancer codes 161 (larynx) and 140–148
(lip, mouth, pharynx), except for code 142 (salivary glands), ‘lymphoma’ codes 200,
202 (non-Hodgkin lymphoma), 201 (Hodgkin's disease) and ‘leukemia’ codes 204–207 (leukemias),
208 (polycytemia vera) and 209 (myelofibrosis). Rectal cancer, ICD-7 code 154, was
subdivided into the anus (squamous cell carcinoma, 154.1) and mucosal rectum (154.0).
Basal cell carcinoma of the skin is not registered in the Cancer Registry. Up to 1992,
the histology of testicular cancers as in the Cancer Registry (WHO/HS/CANC/24.1 Histology
Code) was used, to define seminoma (pathology codes 066) and teratoma (826, also including
embryonal tumours). From 1993, ICD-O-2/ICD with histopathological data according to
the Systematized Nomenclature of Medicine (SNOMED, http://snomed.org) was used, referred
to here as ‘SNOMED’.
Standardized incidence ratios (SIRs) were used to measure cancer risks for sons (i.e.,
offspring) according to the occurrence of cancers in their families. When more than
two affected sons were found in any family, they were counted as independent events.
Standardized incidence ratios were calculated for sons whose parents or brothers had
the same, concordant cancer, that is, using parents or brothers as probands. Follow-up
started for each offspring at birth, immigration or January 1, 1961, whichever came
latest, and terminated on diagnosis of the first cancer, death, emigration, or the
closing date of the study, December 31, 2000.
Parents’ ages were not limited but sons were 0–68 years of age. All tumour incidence
rates were based on the data in the Family-Cancer Database, and they were essentially
similar to rates in the Swedish Cancer Registry. Rates were standardized to the European
population. Standardized incidence ratios were calculated as the ratio of observed
(O) to expected (E) number of cases. The expected numbers were calculated from 5-year-age-,
sex-, tumour type-, period- (5-year bands), socioeconomic status- (six groups) and
residential area- (three groups) specific standard incidence rates for all sons lacking
a family history (Esteve et al, 1994). Confidence intervals (95% CI) were calculated
assuming a Poisson distribution (Esteve et al, 1994). Risks for siblings were calculated
using the cohort method, described elsewhere (Hemminki et al, 2001b).
The kappa statistic was used as the measure of agreement between histologies: (observed
number of cases−expected number of cases)/(1−expected number of cases) (Armitage and
Berry, 1994). The kappa can assume values between −1 and 1; 0 shows a complete chance
occurrence and −1 or 1 show a completely determined occurrence. Values between 0.40
and 0.60 are considered moderately determined occurrences. A negative kappa value
would, in the present context, indicate a determined occurrence of a discordant histology,
which is biologically unlikely, so we present only positive values of kappa in this
paper.
RESULTS
The Family-Cancer Database, which covered years 1961–2000 from the Swedish Cancer
Registry, included 4082 testicular cancers in sons of ages 0–68 years and 3878 fathers
with testicular cancer (Table 1
Table 1
Numbers of cases of testicular cancer in sons and fathers
Son
Father
Histopathological type
No.
%
Mean age
Median age
No.
%
Mean age
Median age
Pathology (1961–2000)
Seminoma
2032
49.8
35.8
35
2293
59.1
41.1
39
Teratoma
1974
48.4
27.5
27
1483
38.2
33.1
33
Others
76
1.9
29.9
27
102
2.6
46.7
43
All
4082
100.0
31.7
31
3878
100
38.2
36
SNOMED (1993–2000)
Seminoma
871
56.4
37.7
36
673
66.2
42.0
39
Teratoma
385
25.0
28.8
27
193
19.0
35.6
33
Embryonal carcinoma
228
14.8
28.4
27
111
10.9
34.7
32
Others
59
3.8
28.5
28
40
3.9
42.6
37
All
1543
100.0
33.8
33
1017
100.0
40.0
37
). Seminoma accounted for 49.8% and teratoma 48.4% in sons, while in fathers the proportions
were 59.1 and 38.2%, respectively. Seminoma showed a 6–8-year later median age of
onset than teratoma (35 vs 27 in offspring and 39–33 in fathers). According to the
SNOMED histology, covering years 1993–2000, embryonal carcinoma accounted for 14.8%
in sons and 10.9% in fathers. The age-specific incidence rates of testicular cancer
among sons are shown in Figure 1
Figure 1
Age-specific incidence of testicular cancer in offspring according to the SNOMED histology
in years 1993–2000.
according to the SNOMED histology. The peak incidence for teratoma and embryonal carcinoma
occurred at ages 20–24 years, and for seminoma showed a peak incidence at 30–34 years.
Table 2
Table 2
SIR for histological type of testicular cancer in brothers by age difference
Brothers ages <5 years
Brothers ages ⩾5years
Histological types
Age at diagnosis
O
SIR
95% CI
O
SIR
95% CI
Seminoma
0–24
1
11.49
0.00
65.89
0
>24
14
10.62
5.79
17.87
11
6.81
3.38
12.22
All
15
10.67
5.96
17.65
11
6.40
3.18
11.49
Teratoma
0–24
5
11.61
3.66
27.31
5
10.74
3.39
25.26
>24
9
10.18
4.61
19.41
6
5.73
2.06
12.56
All
14
10.65
5.80
17.91
11
7.27
3.61
13.06
All types
0–24
7
13.08
5.18
27.10
5
8.54
2.69
20.08
>24
23
10.27
6.50
15.44
17
6.29
3.66
10.09
All
30
10.81
7.29
15.45
22
6.69
4.19
10.15
Bold type: 95% CI does not include 1.00. O=observed; SIR=standardised incidence ratio;
CI=confidence interval.
presents risks for the histological types among brothers according to their age difference.
Those born less than 5 years apart had higher risks, particularly at ages over 24
years, but below age 25 for the teratoma showed no age difference.
Age- and histology-specific familial risk for testicular cancer was analysed using
fathers or brothers as probands (Table 3
Table 3
SIR for histological types of testicular cancer in the offspring of paternal and fraternal
probands
Seminoma
Teratoma
All types
Histological types in proband
Age at diagnosis
O
SIR
95% CI
O
SIR
95% CI
O
SIR
95% CI
Paternal proband
Seminoma
0–24
0
3
4.62
0.87
13.69
3
3.78
0.71
11.18
>24
4
3.52
0.92
9.11
3
3.6
0.68
10.66
7
3.50
1.39
7.26
All
4
3.18
0.83
8.23
6
4.05
1.46
8.87
10
3.58
1.71
6.61
Teratoma
0–24
0
3
8.64
1.63
25.58
3
7.2
1.36
21.32
>24
2
4.01
0.38
14.76
0
2
2.28
0.22
8.39
All
2
3.61
0.34
13.27
3
4.2
0.79
12.45
5
3.87
1.22
9.1
All types
0–24
0
7
6.85
2.71
14.18
7
5.63
2.23
11.66
>24
6
3.53
1.27
7.73
3
2.42
0.46
7.15
9
3.02
1.37
5.75
All
6
3.19
1.15
6.98
10
4.42
2.1
8.15
16
3.78
2.16
6.16
Fraternal proband
Seminoma
0–24
1
11.7
0
67.04
3
7.79
1.47
23.07
5
10.29
3.25
24.22
>24
15
9.65
5.38
15.95
6
6.11
2.2
13.38
21
8.15
5.03
12.47
All
16
9.75
5.56
15.88
9
6.58
2.98
12.55
26
8.49
5.54
12.45
Teratoma
0–24
0
7
14.35
5.69
29.74
7
11.53
4.57
23.89
>24
9
6.88
3.12
13.12
9
9.95
4.51
18.98
18
8.02
4.74
12.7
All
9
6.39
2.9
12.18
16
11.50
6.55
18.71
25
8.76
5.67
12.96
All types
0–24
1
5.27
0
30.2
10
11.16
5.31
20.6
12
10.71
5.51
18.76
>24
25
8.52
5.51
12.59
15
7.77
4.33
12.84
40
8.1
5.78
11.03
All
26
8.32
5.43
12.21
25
8.84
5.72
13.07
52
8.58
6.41
11.26
Bold type: 95%CI does not include 1.00. O=observed, SIR=standardised incidence ratio;
CI=confidence interval.
). The overall SIRs were approximately two-fold higher between brothers (8.58) than
between sons and fathers (3.78). The risks were slightly higher for unmixed histologies
compared to the mixed histologies for all significant SIRs. Among brothers, the SIR
for concordant teratoma was 11.50, compared to 9.75 for seminoma. Concordant teratoma
showed the highest SIR (14.35) among brothers aged 0–24 years. The proportion of sons
with testicular cancer who had an affected father or brother was 1.67% (68 familial
cases from Table 3 to 4082 cases from Table 1). Median ages of the familial cases
did not differ from those of all cases (data not shown).
Age-specific familial SIR for seminoma is shown in Figure 2A
Figure 2
Age-specific SIR for histological type of testicular cancer in the offspring of paternal
and fraternal probands: (A) seminoma; (B) teratoma. The numbers of cases are shown
for each age group. * Shows that the 95% CI for the SIR did not include 1.00.
for sons of fathers and among brothers with testicular cancer; Figure 2B shows the
curves for teratoma. The shapes of the curves for teratoma resemble each other independent
of proband status, with two peaks at 15–24 and 30–39 years. For seminoma, the peak
SIR was observed at ages 40–44 years among brothers, and at 45–49 years among sons
of affected fathers.
We analysed using SNOMED histopathology, available only from 1993 (data not shown),
that teratoma showed an age peak at 15–29 years in sons of fathers with testicular
cancer (N=3, SIR=8.48, 95% CI 1.60–25.10). Among brothers, both SNOMED types showed
peak SIRs at 30–44 years (seminoma, N=10, SIR=11.74, 95% CI 5.59–21.68; teratoma,
N=5, SIR=26.16, 95% CI 6.26–61.55). No familial cases were found for embryonal carcinoma.
Table 4
Table 4
SIR for testicular cancer in sons of parents and among siblings with cancer
Paternal
Fraternal
Seminoma
Teratoma
Seminoma
Teratoma
Cancer sites
O
SIR
91% CI
O
SIR
95% CI
O
SIR
95% CI
O
SIR
95% CI
Upper aerodigestive tract
15
0.83
0.46
1.37
17
1.19
0.69
1.19
2
0.84
0.08
3.11
Oesophagus
12
1.94
1.00
3.40
5
1.18
0.34
2.55
2
4.19
0.39
15.41
Stomach
34
0.99
0.68
1.38
18
0.77
0.45
1.21
1
0.59
0.00
3.36
Colorectuma
123
1.37
1.14
1.64
80
1.19
0.95
1.49
5
0.73
0.23
1.72
4
0.94
0.24
2.43
Liver
21
0.93
0.57
1.42
13
0.80
0.42
1.36
1
0.73
0.00
4.20
Pancreas
35
1.52
1.06
2.12
21
1.26
0.78
1.93
1
0.74
0.00
4.22
2
2.37
0.22
8.70
Lung
77
1.32
1.04
1.65
64
1.40
1.08
1.78
3
0.56
0.11
1.66
2
0.61
0.06
2.23
Breast
120
1.28
1.06
1.53
83
1.02
0.81
1.26
25
1.00
0.65
1.48
15
0.91
0.51
1.51
Cervix
14
0.79
0.43
1.33
17
1.14
0.66
1.83
5
0.99
0.31
2.33
1
0.26
0.00
1.50
Endometrium
24
1.12
0.72
1.67
16
0.95
0.54
1.54
4
1.30
0.34
3.36
Uterus, otherb
5
1.86
0.59
4.38
6
2.69
0.97
5.89
Ovary
23
1.18
0.75
1.78
20
1.26
0.77
1.95
3
0.71
0.13
2.11
Prostate
113
1.04
0.85
1.25
81
1.01
0.80
1.25
3
0.63
0.12
1.86
2
0.78
0.07
2.87
Testis
6
3.27
1.18
7.17
10
4.50
2.15
8.32
26
8.46
5.52
12.41
25
8.95
5.79
13.23
Kidney
23
0.89
0.56
1.33
12
0.60
0.31
1.06
4
1.42
0.37
3.67
2
1.07
0.10
3.94
Urinary bladder
34
0.90
0.63
1.26
34
1.18
0.82
1.66
1
0.27
0.00
1.56
3
1.32
0.25
3.91
Melanoma
29
1.32
0.88
1.89
39
1.84
1.31
2.52
17
1.85
1.08
2.97
4
0.58
0.15
1.51
Skin, squamous cell
28
1.11
0.74
1.61
15
0.82
0.46
1.36
3
1.34
0.25
3.98
3
2.05
0.39
6.07
Nervous systemc
31
1.30
0.88
1.85
27
1.29
0.85
1.87
8
0.95
0.40
1.88
9
1.30
0.59
2.47
Thyroid gland
6
0.93
0.34
2.04
6
1.04
0.37
2.27
3
1.14
0.21
3.37
3
1.51
0.28
4.46
Endocrine glands
15
1.07
0.59
1.76
16
1.32
0.75
2.16
3
0.75
0.14
2.23
3
1.06
0.20
3.14
Connective tissue
5
0.99
0.31
2.32
4
0.94
0.24
2.43
3
2.26
0.43
6.70
2
1.86
0.18
6.84
Non-Hodgkin's lymphoma
35
1.56
1.08
2.17
22
1.19
0.75
1.81
3
0.65
0.12
1.92
6
1.85
0.66
4.04
Hodgkin's disease
9
2.40
1.09
4.58
0
2
1.03
0.10
3.79
Myeloma
12
1.04
0.54
1.83
8
0.93
0.40
1.85
Leukaemia
25
1.18
0.76
1.74
19
1.16
0.69
1.81
3
0.78
0.15
2.31
1
0.30
0.00
1.73
All
874
1.19
1.11
1.27
653
1.13
1.04
1.22
131
1.19
0.99
1.41
87
1.13
0.91
1.40
Bold type: 95% CI does not include 1.00. O=observed; SIR=standardised incidence ratio;
CI=confidence interval.
a
Three colorectal cancer-affected mothers had each two sons with testicular cancer,
giving an SIR=7.49, 95% CI=1.41–22.18; of whom two pairs of bothers had seminoma,
giving SIR=11.07 and 95% CI=1.04–40.71.
b
For all types of testicular cancer by mother's uterine cancer, SIR=2.40, 95% CI=1.23–4.20.
c
For all types of testicular cancer by father's nervous system cancer, SIR=1.50, 95%
CI=1.03–2.10.
presents associations of testicular cancer with other cancers in families, including
mothers and sisters. Both seminoma (1.19) and teratoma (1.13) were increased when
parents had any cancer (only associations at discordant sites being considered). For
seminoma, a significantly increased risk was found when parents had colorectal, pancreatic,
lung and breast cancer and non-Hodgkin's lymphoma and Hodgkin's disease. Seminoma
was also increased when a sibling (brother or sister) had melanoma. Teratoma was associated
with parental lung cancer and melanoma. For testicular cancer as a whole, an increased
risk was found when the mother was diagnosed with ‘other uterine tumours’ or the father
with nervous system cancer; these uterine tumours included three leiomyosarcomas,
two adenocarcinomas, two chorioncarcinomas, two embryonal sarcomas, one stroma cell
sarcoma and two unspecified sarcomas. It was also noteworthy that there were three
mothers with colorectal cancer, each with two sons with testicular cancer (SIR=7.49,
95% CI=1.41–22.18), of whom two pairs of brothers had seminoma (SIR=11.07, 95% CI=1.04–40.71).
The kappa test was applied to assess the histological concordance of testicular cancer
(data not shown). The overall value was 0.01 between sons and fathers, and 0.26 among
brothers; among brothers, the kappa value of seminoma was 0.23 and that of teratoma
was 0.31.
DISCUSSION
The Swedish Family-Cancer Database contains national family data linked to the Swedish
Cancer Registry. The inability to link some 10% of deceased offspring diagnosed with
cancer to their parents (see Subjects and Methods) may cause small errors in the familial
risks of fatal cancers. However, testicular cancer has had a good prognosis during
the past decades. The missing links predominantly influence those born in the 1930s
and who died before 1991, and we have not observed a difference in familial risks
in comparing different diagnostic periods (Hemminki and Li, 2003). We conclude that
this gap in parental links has no large effect on the present estimates. The markedly
improved survival in testicular cancer may also be a source of bias, but adjustment
for period should have minimized this. The many comparisons are relevant and, undoubtedly,
some associations were due to chance; consistency within this study and with other
studies, as well as biological plausibility, need assessing for causal inference.
Familial occurrence of testicular cancer is well recognized but rare. The proportion
of sons with testicular cancer who had an affected father or brother was 1.67% in
the present study, consistent with previous studies, reporting affected first-degree
relatives in 1.0–2.8% of cases (Heimdal et al, 1996; Westergaard et al, 1996; Dieckmann
and Pichlmeier, 1997; Hemminki and Czene, 2002). Even the present overall familial
risks of 3.78 (son–father) and 8.58 (brothers) were in line with the literature (Westergaard
et al, 1996; Dieckmann and Pichlmeier, 1997; Heimdal et al, 1997; Dong et al, 2001).
The SNOMED data, covering cases diagnosed between 1993 and 2000, showed an even larger
difference between the two proband groups, 3.12 (son–father) and 9.62 (brothers),
respectively. There was no large difference in familial risks between seminomas and
teratomas among father–son pairs. However, there appeared to be a large difference
in the familial risk between the pure and mixed histological types among brothers.
The risks ranged from 12 (teratoma–teratoma) and 10 (seminoma–seminoma) for pure histologies
to six for mixed histologies. Consistent with these findings, the kappa test was 0.01
between sons and fathers, whereas between brothers seminoma showed a value of 0.23
and teratoma a value of 0.31. These are still low values, but the interpretation is
difficult because of the relatively small number of cases. The lower kappa values
between sons and fathers than between brothers may be due to a more defined disease
phenotype within one generation than between two generations.
The higher familial risk for testicular cancer among brothers than father–son pairs
may suggest the involvement of a recessive mode of inheritance or an X-linked susceptibility
locus in the aetiology of testicular cancer, consistent with the segregation analysis
and the gene-mapping findings (Heimdal et al, 1997; Rapley et al, 2000). Such results
would point to the importance of the maternal lineage of inheritance and perhaps also
maternally exerted environmental factors. The difference in SIR among brothers close
in age (10.81) compared to those further apart (6.69) suggests environmental effects.
Testicular cancer has been reported as the site with the highest proportion of childhood-shared
environmental effects in a family study of all major cancers (Czene et al, 2002).
Although both histological types showed the effect of age difference, the risks for
early-onset teratoma appeared to be least influenced by the age difference. These
results suggest that environmental factors during childhood and adolescence influence
the risk of contracting a late-onset testicular cancer (Hemminki et al, 2002; Hemminki
and Li, 2002b). Identifying these factors might explain the riddle of increasing incidence
trends and also the difference between immigrants and their sons (Hemminki and Li,
2002a). On the other hand, the search for heritable effects should target brother
pairs with an early-onset teratoma.
Age-specific familial risks of Figure 2 showed the highest risks for seminoma in the
40 s, for both brothers and son–father pairs. For teratoma, two discrete peaks were
noted, particularly among brothers. The early-onset teratoma peak (20–24 years) coincided
with its peak incidence, but the late-onset peak (35–39 years) occurred 15 years later
and close to the peak fraternal risk of seminoma. Based on the risks by age difference,
the younger teratoma component may be the most heritable familial component, whereas
the later component of teratoma and seminoma may have a strong environmental origin.
In families of seminoma patients, associations were found with colorectal, pancreatic,
lung and breast cancer and non-Hodgkin's lymphoma and Hodgkin's disease among parents.
Among brothers, there was an association with seminoma and melanoma. Teratoma was
associated with parental lung cancer and melanoma. However, no association has been
found for primary melanoma or lung cancer following first testicular cancer (Dong
et al, 2001). Testicular cancer was associated with mothers’ unusual uterine tumours,
including chorionepithelioma (SIR=2.40, 95% CI 1.23–4.20). No oestrogen-related cancer
risks were observed in mothers of testicular cancer patients in a Danish study (Kroman
et al, 1996). In the 26 families in our study with two sons with testicular cancer,
three had mothers with colorectal cancer (SIR=7.49, 95% CI=1.41–22.18), of whom two
pairs of brothers had seminoma (SIR=11.07, 95% CI=1.04–40.71), but none had a father
with testicular cancer. However, there is no previous evidence of an association between
testicular and colorectal cancers, but multiple testing may have resulted in associations
due to chance.
In summary, the present study may offer some explanation to the inability in finding
susceptibility genes for testicular cancer. The high familial risk may be the product
of shared childhood environment and heritable causes and so may be difficult to untangle.
Identifying any relevant environmental factors will be challenging but may explain
some of the changes in testicular cancer incidence. For gene identification, fraternal
pairs with teratoma below age 25 may be particularly useful.