0021-972X/00/$03.00/0
The Journal of Clinical Endocrinology & Metabolism
Copyright © 2000 by The Endocrine Society
Vol. 85, No. 9
Printed in U.S.A.
Occurrence of Gonadoblastoma in Females with Turner
Syndrome and Y Chromosome Material:
A Population Study*
CLAUS HØJBJERG GRAVHOLT, JENS FEDDER, RUNE WEIS NAERAA,
JØRN MÜLLER
AND
Medical Department M (Endocrinology and Diabetes) and Medical Research Laboratories, Århus
Kommunehospital, Århus University Hospital (C.H.G.); Department of Gynecology and Obstetrics,
Skejby Sygehus, Århus University Hospital (J.F.); Pediatric Department A, Skejby Sygehus, Århus
University Hospital (R.W.N.); Cytogenetic Laboratory, Department of Biological Psychiatry, Institute
for Basic Research, Psychiatric Hospital (C.H.G.), DK-8000 Århus; and Department of Growth and
Reproduction, Rigshospitalet (J.M.), 2100 Copenhagen, Denmark
ABSTRACT
The presence of Y chromosome material in patients with Turner
syndrome is a risk factor for the development of gonadoblastoma.
However, no cases with gonadoblastoma or other ovarian malignancies have been found in epidemiological studies of cancer, morbidity,
or mortality in Turner syndrome. We examined 114 females with
Turner syndrome for the presence of Y chromosome material by PCR.
Initially, five different primer sets were used. Y Chromosome-positive
individuals were further examined with an additional four primer
sets. We found 14 (12.2%; 95% confidence interval, 6.9 –19.7%) patients who had Y chromosome material. The karyotype in 7 of these
patients did not suggest the presence of Y chromosome material.
Seven of the patients had been ovariectomized before entering the
study due to verified Y chromosome material, whereas three patients
T
HE PRESENCE OF Y chromosome material in females
with Turner syndrome is associated with the development of the benign tumor gonadoblastoma, which has considerable malignant potential. It has been estimated that the
risk of developing gonadoblastoma is more than 30% (1–3).
In Denmark approximately 5% of all diagnosed women with
Turner syndrome are known to have karyotypes containing
Y chromosome material after cytogenetic examination (Danish Cytogenetic Central Registry). The introduction of the
PCR technique has revealed the existence of hidden mosaics
not detected at the cytogenetic examination (4 – 6). Currently
it is recommended to perform an ovariectomy in women with
Y chromosome material. However, recent epidemiological
studies have questioned the postulated high incidence of gonadoblastoma (7, 8). The critical region for developing gonadoblastoma has recently been tentatively localized to a small region near the centromere of the Y chromosome (9). The present
Received March 1, 2000. Revision received May 24, 2000. Accepted
June 5, 2000.
Address all correspondence and requests for reprints to: Dr. Claus
Højbjerg Gravholt, Medical Department M (Endocrinology and Diabetes), Århus Kommunehospital, DK-8000 Århus C, Denmark. E-mail:
[email protected].
* This work was supported by Danish Health Research Council Grant
9600822 (to Århus University-Novo Nordisk Center for Research in
Growth and Regeneration) and a research fellowship from the University of Århus (to C.H.G.).
were operated upon after the DNA analysis. The histopathological
evaluations showed that 1 of the 10 ovariectomized patients actually
had a gonadoblastoma. The rest of the patients did not have gonadoblastoma or carcinoma in situ on histopathological evaluation. Three
patients (age, ⬎50 yr) positive for Y chromosome material chose not
to have ovariectomy performed, and detailed ultrasonographies did
not suggest the presence of gonadoblastoma. The frequency of Y chromosome material is high in Turner syndrome (12.2%), but the occurrence of gonadoblastoma among Y-positive patients seems to be low
(7–10%), and the risk may have been overestimated in previous studies, perhaps due to problems with selection bias. This study emphasizes the need for prospective unbiased studies. (J Clin Endocrinol
Metab 85: 3199 –3202, 2000)
study was performed to establish the frequency of Y chromosome material in individuals with Turner syndrome and to
examine the association between presence of Y chromosome
material and the development of gonadoblastoma.
Subjects and Methods
Study population
The study group consisted of 114 females with phenotypic Turner
syndrome. None showed any signs of virilization. We recruited all
known women and girls with Turner syndrome at random, through the
Danish Turner Association, and through pediatric departments in Denmark. None of the patients approached declined to participate. All
women and girls with Turner syndrome were studied regardless of
previous cytogenetic diagnosis, which was not known to us before
inclusion in the study. In Table 1 the karyotype distribution is presented.
The mean (⫾sd) age of the study population was 27 ⫾ 13 (range 1– 66)
yr. As gonadoblastoma presumably is present at birth, the inclusion of
young girls should not confound the results.
The study was approved by the local ethical scientific committee, and
all subjects received oral and written information concerning the study
before giving written informed consent.
Design
In all participants DNA was extracted and screened for the existence
of Y chromosome material using PCR with five different primer sets
spanning the Y chromosome. In all Y chromosome-positive patients PCR
was performed with an additional five sets of primers. All handling of
the blood samples, the DNA extraction, and the PCR reaction were
performed by two female laboratory technicians.
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GRAVHOLT ET AL.
TABLE 1. Distribution of Turner syndrome karyotypes among
the 114 patients
Karyotype
n (%)
45,X; 45,X,15⫹
63 (55)
45,X/46,XX; 45,X/46,XX/47,XXX; 45,X/47,XXX;
45,X/46,XX/47,XXX/48,XXXX, etc.
12 (11)
45,X/46,X,i(Xq); 46,X,i(Xq);
45,X/46,X,i(Xq)/47,X,i(Xq),i(Xq) etc.
17 (15)
45,X/46,X,del(X); 46,X,del(X)
8 (7)
⫹Ring or marker
7 (6)
45,X/46,XY
Others with Y material
4 (4)
3 (3)
Total
114
PCR
DNA was isolated from blood according to standard procedures. PCR
was performed in accordance with the original papers describing the
primers used. For the initial screening of Y chromosome material, we
used the following primers spanning the Y chromosome: SRY (10, 11),
ZFY (12, 13), DYZ3 (14), DYS132 (15), and DYZ1 (16, 17). Individuals
positive for Y chromosome material were further examined with an
additional set of primers, YRRM (18), SY67 (14), SY69 (14), SY70 (14), and
spanning the suspected gonadoblastoma region (9).
Immunohistochemical staining
The procedure was performed as described previously (19). In short,
4-␮m sections were cut, and the following antibodies were used: 1)
polyclonal antibody against placenta-like alkaline phosphatase (PLAP)
(DAKO Corp., Copenhagen, Denmark), using a peroxidase-antiperoxidase technique; and 2) monoclonal antibody TRA-1– 60, using an avidinbiotin complex technique. Evaluation of immunostaining was performed by light microscopy as previously described (19).
Vaginal sonography
The gonads were identified and, by Grey scale sonography, examined
according to size, echogenecity, and occurrence of protruding solid
parts, cysts, or separation.
Statistical analysis
All statistical calculations were performed with SPSS for Windows,
version 8.0 (SPSS, Inc., Chicago, IL) on a Pentium personal computer.
Data were examined by Student’s two-tailed unpaired t test. Results are
expressed as the mean ⫾ sd. The binomial distribution was used to
calculate confidence limits. Fisher’s exact test was used to test for differences between the frequency of gonadoblastoma in the present series
and in the series described by Manuel et al. (2). Significance levels less
than 5% were considered significant.
Results
We found 14 [12.2%; 95% confidence interval (CI), 6.9 –
19.7%] patients who had Y chromosome material by one or
more primers applied. Seven of these patients had a karyotype that did not suggest the presence of Y chromosome
material, whereas the remaining 7 patients had a karyotypically verified presence of Y chromosome material (Table 2).
In the group of Y-positive patients a more detailed analysis
was performed with primers spanning the area of the Y
chromosome recently implicated in the development of gonadoblastoma (9). PCR analysis in 10 of these patients also
showed the presence of material detected by the primers
YRRM, SY67, SY69, and SY70 (Table 2). Two patients, Y12
and Y79, were not positive for SY67, but were positive for the
remaining primers (YRRM, SY69, and SY70). All Y chromosome-positive patients (n ⫽ 14) were offered ovariectomy.
Three patients positive for Y chromosome material chose not
to have ovariectomy performed, and detailed ultrasound
scans did not suggest the presence of gonadoblastoma. These
3 patients were all more than 50 yr old (66, 53, and 51 yr). One
additional patient was only positive for DYZ1; the cytogenetic diagnosis was 45,X,15p⫹, compatible with a translocation of pseudoautosomal material from the Yq, and ovariectomy was not deemed necessary. In all patients in whom
ovariectomy was performed (n ⫽ 10), a histopathological
evaluation and, if possible, an immunohistochemical examination were carried out (n ⫽ 2). In 1 case DNA was isolated
from a homogenate of the tissue obtained by the surgical
procedure, and PCR was performed. The result was not
different from the result of the PCR performed on DNA
extracted from blood. Seven of these subjects had been operated
on before entering the study due to verified Y chromosome
material, whereas 3 patients were operated on after the DNA
analysis. The light microscopic pathological evaluations
showed that 1 of the 10 patients who had ovariectomy performed actually had gonadoblastoma (10%; 95% CI, 1– 44%). In
the case of gonadoblastoma, the diagnosis was confirmed by
the presence of PLAP-positive germ cells within the gonadoblastoma nests. These germ cells had the resemblance of carcinoma in situ germ cells. In 1 case (Y77) stained with PLAP and
TRA-60, no positive cells were found in the streaks confirming
the absence of premalignant germ cells. The rest of the patients
did not have gonadoblastoma on light microscopic evaluation.
Neither were carcinoma in situ changes detected.
The mean age of the Y chromosome-positive women was
higher than the mean age of the Y chromosome-negative
women (37 ⫾ 16 vs. 26 ⫾ 13 yr; P ⫽ 0.003).
Discussion
The presence of Y chromosome material can cause the
development of gonadoblastoma; the risk has previously
been estimated to be larger than 30% (2, 3). Gonadectomy is
generally recommended; however, this consensus is questioned by the present study. In the present material of 114
randomly selected females with phenotypically verified
Turner syndrome, 14 patients were Y chromosome positive.
Of these 14, 7 had previously been detected by routine cytogenetic karyotyping, whereas Y chromosome material was
only detected by the use of PCR in the other 7. None of the
patients with only PCR-detected Y chromosome material
developed gonadoblastoma, pointing toward a low risk of
development of gonadoblastoma in this situation. Only 1 of
the study participants of the 14 patients positive for Y chromosome material could be positively identified to have suffered from gonadoblastoma based on histopathological microscopic and immunohistochemical findings. This patient
had the 45,X/46,XY karyotype. Four patients did not have
their ovaries removed. One patient was not considered at risk
for the development of gonadoblastoma due to the fact that
she had the tip of Yq (the pseudoautosomal region) translocated to chromosome 15. In the study protocol and in the
information material given to the patients before entering the
GONADOBLASTOMA IN FEMALES WITH TURNER SYNDROME
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TABLE 2. Complete results of PCR analysis for the 14 patients that showed presence of Y-chromosome material after the initial
screening with primer sets ZFY, SRY, DYZ3, DY132, and DYZ1
Patients
Y3
Y6
Y7
Y12
Y25
Y29
Y33
Y40
Y55
Y68
Y77
Y79
Y101
Y119
Karyotype
Age (yr)
ZFY
SRY
DYZ3
YRRM
SY67
SY69
SY70
DYS132
DYZ1
Ov.
45,X
45,X/46,XY
45,X/46,X,i(Yq)
45,X
45,X,15p⫹
45,X/46,XY
45,X/46,X,⫹mar
45,X/46,X,r(Y)
45,X/46,XY
45,X/46,X,del(X)(p22p11q11)
45,X/46,del(X)(q11)
46,X,i(Yq)
45,X/46,XY
45,X
53
39
66
46
27
51
51
16
28
32
29
48
15
17
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A positive result is indicated by ⫹, and a negative result is indicated by ⫺. Whether any individual patient had an ovariectomy (Ov.) performed
is indicated by ⫹ or ⫺.
study, it was recommended and stressed that all patients
positive for Y chromosome material should undergo ovariectomy due to the greatly increased risk of gonadoblastoma
hitherto found in the literature. However, this increased risk
of gonadoblastoma seems to be present in younger age
groups and not in women above the age of 50 yr (3). After
extensive consultations the 3 women testing positive and
above the age of 50 yr chose not to undergo prophylactic
ovariectomy. Despite the fact that a detailed vaginal ultrasound scan did not raise suspicion of malignancy in the
ovaries, we cannot exclude the existence of a “burnt-out”
gonadoblastoma in any of these patients, and only inspection
of the gonads would enable the exclusion of this condition.
The sensitivity of a vaginal ultrasound scan in detecting
ovarian malignancy is not firmly established, but is generally
considered to be very high (20, 21), suggesting that if gonadoblastoma was present in any of these women, it would
have been detected at the ultrasound examination. The
present findings confirm most earlier reports that some
Turner females with a karyotype that does not contain Y
chromosome material indeed have low level mosaicism (4 – 6,
22–27), whereas others have not found any evidence of hidden Y chromosome material (28). At the same time the data
may suggest that knowledge of the existence of cryptic Y
mosaicism should not lead to ovariectomy, although the
material is not sufficiently large to allow for any definite
statistical comparison between the group with cytogenetically verifiable Y chromosome material and the group with
only cryptic Y chromosome material. Surely the findings
need to be verified in a larger setting.
The pathogenesis of gonadoblastomas and their malignant
potential is still rather obscure. They are composed of germ
cells, sex cord derivatives resembling immature granulosa
and Sertoli cells, and sometimes stromal elements (29). In
normal males, if malignancy is not present at the time of
operation, it is generally accepted that carcinoma in situ
findings must be present if one is to expect the later development of a tumor (seminoma or nonseminoma) (19). This
association of carcinoma in situ and later development of
malignancy has not been systematically examined in patients
with gonadal dysgenesis. In none of the cases examined by
light microscopy was a burnt-out gonadoblastoma found
(29). The present findings are supported by three recent
register studies from Denmark using three different registers
of cancer, morbidity, and mortality that are not cross-linked.
In one study morbidity was assessed using the Danish National Registry of Patients (7), and no case of gonadoblastoma
was encountered in any known patient with Turner syndrome in Denmark, including patients with Y chromosome
material. In another study cancer incidence was studied (8)
using the Danish Cancer Register, and no case of gonadoblastoma or related cancers was found in females with
Turner syndrome. In the last study mortality was assessed in
subjects with Turner syndrome using the Danish National
Register of Death (30), and no case of death after gonadoblastoma was encountered. A bias in all of these studies may
be that a gonadoblastoma previously could have been classified as hamartoma or dysgerminoma or not reported at all.
However, these diagnoses were not encountered in the study
of the Danish Cancer Register (8). Furthermore, gonadoblastoma and Turner syndrome, especially Turner syndrome
with Y chromosome material, are rare occurrences, and this,
of course, may introduce additional bias. In summary, however, these epidemiological data suggest that the incidence of
gonadoblastoma in Turner syndrome is low.
The gonadoblastoma locus on the Y chromosome (GBY)
may have a physiological function in normal testes (31). GBY
seems different from the testis-determining gene (SRY) (32),
but might be identical to the structural gene for H-Y transplantation antigen, which has been suggested to be functional in spermatogenesis in mice (33) and man (34). In the
dysgenetic gonad GBY might be oncogenic (31). The presence
of H-Y antigen seems closely associated with the development of gonadoblastoma and other gonadal tumors in 46,XY
women with gonadal dysgenesis (35). Thus, H-Y antigen might
be an oncogene, and the low occurrence of gonadoblastoma in
Turner females with Y chromosome material might be related
to the lower level of H-Y antigen found in Turner patients (36,
37). The lack of a regulatory Y chromosome gene or genes on
the X chromosome, which may influence the level of H-Y antigen or other potential carcinogenic oncogenes, might be the
reason why Y chromosome material in Turner syndrome seems
to cause the development of gonadoblastoma to a much lesser
degree than in XY females.
3202
GRAVHOLT ET AL.
This study is, to our knowledge, the first cross-sectional
study in Turner syndrome evaluating the risk of malignancy
when Y chromosome material is present and where the inclusion criterion solely is the presence of phenotypical
Turner syndrome. The study includes all women and girls
with Turner syndrome known to us and willing to participate. All previous studies evaluating the risk of gonadoblastoma are marred by selection bias, i.e. most are case reports
or compilations of cases from the literature or from different
laboratories. However, due to the rather small number of Y
chromosome-positive patients, the CI concerning the risk of
development of gonadoblastoma remains rather large, and in
comparison with the “unbiased” part of the study by Manuel
et al., there is no significant difference in the number of Y
positives developing gonadoblastoma [this series, 1 positive
vs. 13 negative (7.1%); Manuel et al., 12 positive vs. 61 negative (19.7%; 95% CI, 10.6 –31.8%; by Fisher’s exact test, P ⫽
0.7) (2). Of the Turner women for whom ovarian material was
available for microscopy, 1 in 10 developed gonadoblastoma
(10%; 95% CI, 1– 44%). A risk of 7–10% for the development
of gonadoblastoma is lower than the previously reported
figures, but it may still be unacceptably high in many situations, and parents may still prefer ovariectomy. Likewise,
physicians may advise their patients to have an operation
performed on these premises. Detailed vaginal sonography,
supplemented with color Doppler sonography of the gonads
at regular intervals, may be sufficient to monitor some
Turner patients with Y chromosome material, especially in
cases where patients or parents prefer not to have an operation performed. Ultrasonography, however, is probably
only sufficiently sensitive to discover a tumor, whereas more
discrete changes may go unnoticed. Therefore, gonadectomy
is still the procedure of choice if one wants to exclude malignancy with absolute certainty.
In summary, the present study and available data from
register studies in Denmark suggest that the occurrence of
gonadoblastoma is low in the Turner syndrome population.
We propose that future studies be undertaken to focus on the
incidence of gonadoblastoma in the presence of Y chromosome material in all diagnosed females with Turner syndrome. This study emphasizes the need for prospective unbiased studies.
Acknowledgments
Anette Tillebeck and Mie Fastrup are thanked for expert technical
assistance. The Danish Turner Association and all participants are
thanked for their enthusiasm. Ole Andersen, M.D., and Carsten Pedersen, M.D., are thanked for their kind referral of patients.
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