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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
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: ch.gravholt{at}dadlnet.dk
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Abstract |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Subjects and Methods |
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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.
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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.
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-µm 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 avidin-biotin 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.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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). 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.
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Discussion |
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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.
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.
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Acknowledgments |
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Footnotes |
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Received March 1, 2000.
Revised May 24, 2000.
Accepted June 5, 2000.
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