Beitr. Path. Bd. 157,251-259 (1976)
Abteilung fur Pathologie (Leiter: Prof. Dr. med. A. Gropp) and Abteilung fUr Gynakologie und Geburtshilfe (Leiter: Prof. Dr. med. F. Oberheuser) der Medizinischen Hochschule Lubeck
Dysgerminoma in Turner's Syndrome Dysgerminom bei Turner-Syndrom HELGA REHDER and TH. MELCHER With 4 Figures' Received June 19, 1975 . Accepted in revised form January 7, 1976
Key words: Turner's syndrome - Gonadal dysgenesis - Dysgerminoma - Gonadoblastoma - Gonadal tumour
Summary The importance of the Y-chromosome for the germ cell tumour development in gonadal dysgenesis has been emphasized many times. In contrast, only two cases of dysgerminoma or gonadoblastoma had been published so far in the XO-Turner's syndrome. With this report, another case of Turner's syndrome developing a dysgerminoma in a gonadal streak is presented. No Y-chromosome containing stem line could be detected in the patient nor in the tumour. A primary genetic etiology or a mechanism related to early secondary regression or dysgenesis of the gonad are discussed as causative factors in germ cell tumour development within gonadal streaks.
The high incidence of gonadal germ cell tumours in inters exes and in gonadal dysgenesis has been emphasized in numerous publications (Teter and Boczkowski, 1967; Teter, 1970; Scully, 1970; Hughesdon and Kumarasamy, 1970; Talerman et aI., 1973). In almost all of these cases karyotypes with a Y-chromosome were found. The tumour rate quoted for gonadal dysgenesis ranges from 37.5% in cases with an 46,XY karyotype (Barr et aI., 1967) to 17.6% in cases with a mosaic karyotype 45,XO/46,XY (van Campenhout et aI., 1968). Other forms of male pseudohermaphroditism including testicular feminization syndrome obviously bear a lower tumour risk of 10% and less (Morris, 1953; Dewhurst
25 2 .
H. Rehder and Th. Melcher
et aI., 1971) depending on the grade of differentiation and on the position of the gonad. So far few cases of gonadoblastoma or dysgerminoma have been observed in females with abnormal gonadal development, whose karyotype, however, does not include a Y-chromosome. Thus, only two cases of such tumours have been reported in association with Xo-Turner's syndrome (Dominguez and Greenblatt, 1962; Jirasek, 1972) and one case of gonadoblastoma in XX-gonadal dysgenesis (Salet et aI., 1970). Two further observations of gonadoblastoma, one occurring in a patient with 46,XX/ 45,XO mosaicism (Patel and Prentice, 1972), the other in a pregnant woman with 46,XX karyotype, reported to have been suffering from severe oligmenorrhea prior to pregnancy (Bergher de Bacalao and Dominguez, 1969), have to be considered as doubtful with regard to the published karyotypes.
Fig.
1.
Patient with clinical features of Turner's syndrome.
Dysgerminoma in Turner's Syndrome . 253
This communication presents another patient with clinical and cytogenetical evidence of XO-Turner's syndrome, who developed a germ cell tumour in the gonadal streak.
Case report The observation concerns a 38 year old woman, who displayed typical features of Turner's syndrome (Fig. I): a broad neck, resembling a webbed neck, an extremely low posterior hairline, a shieldlike chest and far apart nipples as well as scarce axillary and pubic hair. Only her height of 156 cms exceeded slightly the average height of Turner women. However, she mentioned that her family members were all extremely tall, her brother being more than 190 cms and her sister 180 cms tall. She consulted the gynaecologist first at the age of 28 years because of primary amenorrhea. Slight menstrual bleedings could be provoked during a six years period of therapeutic hormonal substitution with Primosiston, a compound of estrogenes and gestagenes. With the cessation of hormonal treatment the menstrual bleedings stopped. But after four more years of amenorrhea, genital bleedings recurred. The histological examination of
Fig.
2.
Dysgerminoma in the gonadal streak. HE; X
200.
254 . H. Rehder and Th. Melcher
uterine curettage material displayed abortive proliferative changes, suggesting hormonal stimulation of an atrophic mucosa. Subsequently a leftsided adnexal tumour was diagnosed and removed together with the uterus and the contralateral adnexa. Gonadotrophin- and estrogene levels had not been examined before removal of the gonadal tumour.
Morphological findings Grossly the tumour seemed to be well encapsulated, measuring 16 X 10 X 6 cms in diameter. Its cut surface was grey, soft and friable with areas of hemorrhage and extensive focal necrosis resulting in cyst formation. Histologically the tumour showed in some parts solid and alveolar arrangements of large clear germ cells and a delicate fibrous stroma with scattered lymphocytes (Fig. 2). In other parts of the tumour, tubular and papillary structures prevailed, which were difficult to interpret but in view of the fact that the tumour was rather necrotic, the tubular pattern
x
Fig. 3.
The patient's karyotype-45, XO. Giemsa banding technique.
Dysgerminoma in Turner's Syndrome. 255
Fig. 4 a
Fig. 4 b
Fig. 4. Y-body fluorescence (Quinacrine-dihydrochloride), X 2,250. a) negative fluorescence in the nuclei of the dysgerminoma, b) positive fluorescence (control) in male testicular tissue (see text).
was interpreted to be an artefact and to result from shrinking of tumour cells pulling away from the stroma. Thus, the diagnosis was dysgerminoma. No ovarian tissue was found near the tumour. On the contralateral side the adnexa consisted of the Fallopian tube only. A tiny white spot at the back of the ligamentum latum could be identified histologically as fibrotic dysgenetic gonadal tissue.
Cytogenetical findings The pathomorphological finding of a germ cell tumour in gonadal dysgenesis prompted a chromosome analysis of the patient. From two subsequent lymphocyte cultures, the evaluation of 60 metaphases confirmed the previously made tentative assumption of a 45,XO karyotype (Fig. 3). No Barr-body was seen in the nuclei of hair root cells. All attempts to demonstrate an F-body in nuclei of hair root cells, of buccal epithelium, in lymphocytes and in granulocytes of blood smear by Quinacrine fluor-
256 . H. Rehder and Th. Melcher
escence staining failed. Neither could an F-body (= Y-body) be identified in the nuclei of the gonadal tumour cells by the fluorescence method on paraffin sections following the procedure of Khudr and Benirschke (1973) (Fig. 4 a). A control section of paraffin embedded male testicular tissue was F-body positive with this technique (Fig. 4 b). The diagnosis of XO-Turner's syndrome without evidence of mosaicism involving a Y-chromosome was supported by the clinical findings.
Discussion The dysgerminoma in the gonadal dysgenesis and intersex state designates an undifferentiated gonadal germ cell tumour that can not be distinguished from the dysgerminoma of the ovary in the chromosomally normal female nor from the seminoma of the testis in the chromosomally normal male. Granulomatous and giant cell reactions, however, are quite rare (Scully, 1970)' Very often structural elements resembling gonadoblastoma are found within the tumour or on the contralateral side as well as calcifications that are frequent in the gonadoblastoma and normally do not occur in pure dysgerminoma. In fact, the "dysgenetic dysgerminoma" (Jid.sek, 1972) might be considered to have arisen from a gonadoblastoma. The gonadoblastoma, however, as it was first described by Scully (1953), is the most frequent tumour of the dysgenetic gonad. In addition to the germ cell elements it also contains constituents related to the cell types of the sexually differentiated gonadal parenchyma, Sertoli- or granulosa cells, and interstitial Leydig- or lutein cells, thus imitating testicular as well as ovarian structures and being capable of producing androgenes as well as estrogenes (Scully, 1953 and 1970; Borghi et aI., 1962; Griffiths et aI., 1966). This ambiguous morphological and endocrine behaviour has led to the definition "tumour of the undifferentiated gonad" for the gonadoblastoma, whereas the dysgenetic dysgerminoma is considered to be its malignant variant. Teter (1960) in his classification of the gonadal germ cell tumours preferred the designation "gonocytoma I-IV", referring to the number of different gonadal cell elements that participate in the tumour. The gonocytoma I, a pure germ cell tumour, thus stands for the dysgerminoma. The gonocytome II and III, showing in addition Sertolior granulosa cells in the first and Sertoli- or granulosa cells plus Leydig- or lutein cells in the latter case correspond to the "gonoblastoma of Scully". The gonocytoma IV again shows pure germ cell elements with an interstitial cell proliferation outside the tumour. Scully (1970) does not accept this classification, since he considers the appearance of interstitial cells within a germ cell tumour to depend on the stimulation by the pituitary gland after puberty.
Dysgerminoma in Turner's Syndrome . 257
In our patient, a germ cell tumour, resembling a dysgerminoma could be identified in the left gonadal streak. Yet, no gonadoblastoma structures were present in the numerous sections made. One may, however, presume that the dysgerminoma had overgrown a preexisting gonadoblastoma that had been hormonally active. This would explain the endometrial proliferation and episodes of bleeding in our patient. Dysgerminoma developing in the gonadal streak of a patient with Turner's syndrome is certainly a rare condition. Compared with the high risk of gonadal tumour development in patients with XY-gonadal dysgenesis and related mosaics, it seems rather surprising that a different situation should exist in XO-gonadal dysgenesis, i.e. in Turner's syndrome. In histological sections the gonadal streaks look completely alike in both conditions. Both, the XY- and the XO-gonadal dysgenesis patients display an increased gonadotrophin (FSH) blood level, which has been discussed as a possible promoting factor of tumour development or tumour growth (Frasier et aI., 1964), considering the fact that germ cell tumours are most often described as occuring after puberty. It looks, however, from the majority of the cases, as if a Y-chromosome in at least one stemline is responsible for the origin of a gonadal tumour. This could imply that the directly or indirectly Y-linked mutant gene responsible for preventing gonadal differentiation in XY-gonadal dysgenesis may at the same time enhance gonadal tumour development. However, it has to be emphasized that an XY-containing stemline could not be ascertained in our patient, neither in lymphocytes and in nuclei of hair root cells and buccal epithelial cells, nor in the gonadal tumour, in the latter case by the use of the technique of Khudr and Benirschke (1973). It should be mentioned here that a Y-body can very well be demonstrated in dysgerminoma cells of a patient with XY-gonadal dysgenesis (own observation).
On the other hand, the pathogenetic process of gonadal dysgenesis itself may represent a causative factor of gonadal tumour development preferentially in XY-gonadal dysgenesis. It is known that in Turner's syndrome ovarian differentiation is primarily induced and then continued until secondary regression occurs, mostly in later embryonic life. In contrast, gonadal differentiation does not take place primarily in XY-gonadal dysgenesis. Thus, if gonadoblastoma or "dysgenetic dysgerminoma" is to be considered a tumour of the undifferentiated gonad, XY-gonadal dysgenesis may bear a greater tumour risk, while the Xo-Turner's syndrome falls into this category only if gonadal regression starts early. Some authors consider dysgerminoma of the intersex state as well as gonadoblastoma to be tumours of the testes (Philip and Teter, 1964;
258 . H. Rehder and Th . Melcher
Fathalla et al., I966). They believe, that an inCIpIent and almost abortive testicular differentiation occurring in very early embryonic development might explain the findings of these tumours in XY-gonadal dysgenesis. We must, however, presume, that the male determining gene product of the Y-chromosome, probably a histocompatibility Y-antigen (HY-antigen), bound to the cell surface and functioning as a marker for testicular differentiation is missing in XY-gonadal dysgenesis (Wachtel et al., 1975; Ohno, in print). The existence of this HY -antigen, for example, has already been ascertained in the XX-male syndrome. On the other hand, a hypothesis for gonadal tumour development in gonadal dysgenesis, basing on an abortive testicular differentiation can not be applied to Turner's syndrome, while the conditions brought about by an early onset of ovarian degeneration could well represent a causative factor of the development of a germ cell tumour as in the patient described in this report. There is no indication, whatsoever, that the hormonal treatment, which the patient received for six years, induced the gonadal tumour. Certainly, many cases of Turner's syndrome get hormonal treatment, and a coincidence of steroid hormone treatment and development of ovarian germ cell tumour is not known.
Zusammenfassung Die Bedeutung des Y-Chromosoms bei der Entstehung von Keimzelltumoren in dysgenetischen Gonaden erscheint unumstritten. Dagegen sind Dysgerminome oder Gonadobias tome beim XO-Turner-Syndrom nur in zwei Eillen beschrieben. Ober einen weiteren Fall eines Turner-Syndroms mit Dysgerminom im Bereich der linken Gonadenleiste wird hier berichtet. Primar chromosomal-genetische oder sekundar pathogenetische Ursachen in Zusammenhang mit der genetisch determinierten Regression der Gonadenanlage konnten bei der Entstehung derartiger Gonadenleistentumoren eine Rolle spielen.
References Barr, M. L., Carr, D. H., Plunkett, E. R., Soltan, H. c., and Wiens, R. G.: Male pseudohermaphroditism and pure gonadal dysgenesis in sisters. Amer. J. Obstet. Gynec. 99, 1047- 10 55 (19 6 7) Bergher de Bacalao, E., and Dominguez, J.: Unilateral gonadoblastoma in a pregnant woman. Amer. J. Obstet. Gynec. 105,. 1279-1281 (1969) van Campenhout, J., Lord, J., Vauclair, R., Lanthie, A., and Berard, M.: The phenotype and gonadal histology in XO/XY mosaic individuals: report of two personal cases. ]. Obstet. Gynaec. Brit. Cwlth. 76, 631-639 (1969) Dewhurst, C. J., Ferreira, H. P., and Gillett, P. G.: Gonadal Malignancy in XY females. J. Obstet. Gynaec. Brit. Cwlth. 78, IOll-1083 (1971)
Dysgerminoma in Turner's Syndrome· 259 Dominguez, C. J., and Greenblatt, R. B.: Dysgerminoma of the ovary in a patient with Turner's syndrome. Amer. ]. Obstet. Gynec. 83,674-677 (1962) Fathalla, M. F., Rashad, M. N., and Kerr, M. G.: The relationship between ovarian tumours and intersex states with special reference to the dysgerminoma and arrhenoblastoma.]. Obstet. Gynaec. Brit. Cwlth. 73, 8I2-820 (1966) Frasier, S. D., Bashore, R. A., and Mosier, H. D.: Gonadoblastoma associated with pure gonadal dysgenesis in monozygous twins. ]. Pediatrics 64, 740-745 (1964) Hughesdon, P. E., and Kumarasamy, T.: Mixed germ cell tumours (gonadoblastomas) in normal and dysgenetic gonads. Vir chows Arch. Abt. A Path. Anat. 349, 258-280 (197 0 )
]irasek, ]. E.: Nadory gonad obsahujid zarodecne builky: dysgerminom, dysgeneticky dysgerminom, gonadoblastom. Cs. Gynekologie 37, 146-149 (1972) Khudr, G., and Benirschke, K.: Quinacrine fluorescence microscopy of formalin-fixed tissues, Stain Techn. 48, 193-197 (1973) Morris, ]. M.: The syndrome of testicular feminization in male pseudohermaphrodites. Amer.]. Obstet. Gynec. 65,1192-1211 (1953) Ohno, S.: Major regulatory genes for mammalian sexual development. The Cell (in print). Philip, ]., and Teter, ].: Significance of chromosomal investigation of somatic cells to determine the genetic origin of gonadoblastoma. Acta path. microbiol. scand. 61, 543-55 0 (19 6 4)
Salet, ]., de Gennes, ]. L., de Grouchy, J., Musset, R., Pelissier, Cl., Yaneva, H., Sebaoun, M., and Netter, A.: A propos d'un cas de gonadoblastome 46,XX. Ann. Endocrinol. 3 1,9 27-93 8 (197 0 )
Scully, R. E.: Gonadoblastoma. A gonadal tumour related to the dysgerminoma (seminoma) and capable of sex-hormone production. Cancer 6, 445-463 (1953) Scully, R. E.: Gonadoblastoma. A review of 74 cases. Cancer 25, 1340-1356 (1970) Talerman, A., Huyzinga, W. T., and Kuipers, T.: Dysgerminoma, clinicopathological study of 22 cases. Obstet. Gynec. 41, 137-147 (1973) Teter, J.: A new concept of classification of gonadal tumours arising from germ cells (gonocytoma) and their histogenesis. Gynaecologia (Basel) 150, 84-102 (1960) Teter, ].: Prognosis, malignancy and curability of the germ cell tumors occurring in dysgenetic gonads. Amer. ]. Obstet. Gynec. 108, 894-900 (1970) Teter, ]., and Boczkowski, K.: Occurrence of tumors in dysgenetic gonads. Cancer 20, 1301-1310 (19 67)
Wachtel, St. S., Ohno, S., Koo, G. c., and Boyse, E. A.: Possible role for H-Y antigen in the primary determination of sex. Nature 257, 235-236 (1975) Dr. Helga Rehder, Abteilung fur Pathologie der Medizinischen Hochschule, Ratzeburger Allee 160, D-2400 Lubeck Dr. Thomas Melcher, Abteilung fur Gynakologie und Geburtshilfe der Medizinischen Hochschule, Ratzeburger Allee 160, D-2400 Lubeck
Abteilung fur Pathologie (Leiter: Prof. Dr. med. A. Gropp) and Abteilung fUr Gynakologie und Geburtshilfe (Leiter: Prof. Dr. med. F. Oberheuser) der Medizinischen Hochschule Lubeck
Dysgerminoma in Turner's Syndrome Dysgerminom bei Turner-Syndrom HELGA REHDER and TH. MELCHER With 4 Figures' Received June 19, 1975 . Accepted in revised form January 7, 1976
Key words: Turner's syndrome - Gonadal dysgenesis - Dysgerminoma - Gonadoblastoma - Gonadal tumour
Summary The importance of the Y-chromosome for the germ cell tumour development in gonadal dysgenesis has been emphasized many times. In contrast, only two cases of dysgerminoma or gonadoblastoma had been published so far in the XO-Turner's syndrome. With this report, another case of Turner's syndrome developing a dysgerminoma in a gonadal streak is presented. No Y-chromosome containing stem line could be detected in the patient nor in the tumour. A primary genetic etiology or a mechanism related to early secondary regression or dysgenesis of the gonad are discussed as causative factors in germ cell tumour development within gonadal streaks.
The high incidence of gonadal germ cell tumours in inters exes and in gonadal dysgenesis has been emphasized in numerous publications (Teter and Boczkowski, 1967; Teter, 1970; Scully, 1970; Hughesdon and Kumarasamy, 1970; Talerman et aI., 1973). In almost all of these cases karyotypes with a Y-chromosome were found. The tumour rate quoted for gonadal dysgenesis ranges from 37.5% in cases with an 46,XY karyotype (Barr et aI., 1967) to 17.6% in cases with a mosaic karyotype 45,XO/46,XY (van Campenhout et aI., 1968). Other forms of male pseudohermaphroditism including testicular feminization syndrome obviously bear a lower tumour risk of 10% and less (Morris, 1953; Dewhurst
25 2 .
H. Rehder and Th. Melcher
et aI., 1971) depending on the grade of differentiation and on the position of the gonad. So far few cases of gonadoblastoma or dysgerminoma have been observed in females with abnormal gonadal development, whose karyotype, however, does not include a Y-chromosome. Thus, only two cases of such tumours have been reported in association with Xo-Turner's syndrome (Dominguez and Greenblatt, 1962; Jirasek, 1972) and one case of gonadoblastoma in XX-gonadal dysgenesis (Salet et aI., 1970). Two further observations of gonadoblastoma, one occurring in a patient with 46,XX/ 45,XO mosaicism (Patel and Prentice, 1972), the other in a pregnant woman with 46,XX karyotype, reported to have been suffering from severe oligmenorrhea prior to pregnancy (Bergher de Bacalao and Dominguez, 1969), have to be considered as doubtful with regard to the published karyotypes.
Fig.
1.
Patient with clinical features of Turner's syndrome.
Dysgerminoma in Turner's Syndrome . 253
This communication presents another patient with clinical and cytogenetical evidence of XO-Turner's syndrome, who developed a germ cell tumour in the gonadal streak.
Case report The observation concerns a 38 year old woman, who displayed typical features of Turner's syndrome (Fig. I): a broad neck, resembling a webbed neck, an extremely low posterior hairline, a shieldlike chest and far apart nipples as well as scarce axillary and pubic hair. Only her height of 156 cms exceeded slightly the average height of Turner women. However, she mentioned that her family members were all extremely tall, her brother being more than 190 cms and her sister 180 cms tall. She consulted the gynaecologist first at the age of 28 years because of primary amenorrhea. Slight menstrual bleedings could be provoked during a six years period of therapeutic hormonal substitution with Primosiston, a compound of estrogenes and gestagenes. With the cessation of hormonal treatment the menstrual bleedings stopped. But after four more years of amenorrhea, genital bleedings recurred. The histological examination of
Fig.
2.
Dysgerminoma in the gonadal streak. HE; X
200.
254 . H. Rehder and Th. Melcher
uterine curettage material displayed abortive proliferative changes, suggesting hormonal stimulation of an atrophic mucosa. Subsequently a leftsided adnexal tumour was diagnosed and removed together with the uterus and the contralateral adnexa. Gonadotrophin- and estrogene levels had not been examined before removal of the gonadal tumour.
Morphological findings Grossly the tumour seemed to be well encapsulated, measuring 16 X 10 X 6 cms in diameter. Its cut surface was grey, soft and friable with areas of hemorrhage and extensive focal necrosis resulting in cyst formation. Histologically the tumour showed in some parts solid and alveolar arrangements of large clear germ cells and a delicate fibrous stroma with scattered lymphocytes (Fig. 2). In other parts of the tumour, tubular and papillary structures prevailed, which were difficult to interpret but in view of the fact that the tumour was rather necrotic, the tubular pattern
x
Fig. 3.
The patient's karyotype-45, XO. Giemsa banding technique.
Dysgerminoma in Turner's Syndrome. 255
Fig. 4 a
Fig. 4 b
Fig. 4. Y-body fluorescence (Quinacrine-dihydrochloride), X 2,250. a) negative fluorescence in the nuclei of the dysgerminoma, b) positive fluorescence (control) in male testicular tissue (see text).
was interpreted to be an artefact and to result from shrinking of tumour cells pulling away from the stroma. Thus, the diagnosis was dysgerminoma. No ovarian tissue was found near the tumour. On the contralateral side the adnexa consisted of the Fallopian tube only. A tiny white spot at the back of the ligamentum latum could be identified histologically as fibrotic dysgenetic gonadal tissue.
Cytogenetical findings The pathomorphological finding of a germ cell tumour in gonadal dysgenesis prompted a chromosome analysis of the patient. From two subsequent lymphocyte cultures, the evaluation of 60 metaphases confirmed the previously made tentative assumption of a 45,XO karyotype (Fig. 3). No Barr-body was seen in the nuclei of hair root cells. All attempts to demonstrate an F-body in nuclei of hair root cells, of buccal epithelium, in lymphocytes and in granulocytes of blood smear by Quinacrine fluor-
256 . H. Rehder and Th. Melcher
escence staining failed. Neither could an F-body (= Y-body) be identified in the nuclei of the gonadal tumour cells by the fluorescence method on paraffin sections following the procedure of Khudr and Benirschke (1973) (Fig. 4 a). A control section of paraffin embedded male testicular tissue was F-body positive with this technique (Fig. 4 b). The diagnosis of XO-Turner's syndrome without evidence of mosaicism involving a Y-chromosome was supported by the clinical findings.
Discussion The dysgerminoma in the gonadal dysgenesis and intersex state designates an undifferentiated gonadal germ cell tumour that can not be distinguished from the dysgerminoma of the ovary in the chromosomally normal female nor from the seminoma of the testis in the chromosomally normal male. Granulomatous and giant cell reactions, however, are quite rare (Scully, 1970)' Very often structural elements resembling gonadoblastoma are found within the tumour or on the contralateral side as well as calcifications that are frequent in the gonadoblastoma and normally do not occur in pure dysgerminoma. In fact, the "dysgenetic dysgerminoma" (Jid.sek, 1972) might be considered to have arisen from a gonadoblastoma. The gonadoblastoma, however, as it was first described by Scully (1953), is the most frequent tumour of the dysgenetic gonad. In addition to the germ cell elements it also contains constituents related to the cell types of the sexually differentiated gonadal parenchyma, Sertoli- or granulosa cells, and interstitial Leydig- or lutein cells, thus imitating testicular as well as ovarian structures and being capable of producing androgenes as well as estrogenes (Scully, 1953 and 1970; Borghi et aI., 1962; Griffiths et aI., 1966). This ambiguous morphological and endocrine behaviour has led to the definition "tumour of the undifferentiated gonad" for the gonadoblastoma, whereas the dysgenetic dysgerminoma is considered to be its malignant variant. Teter (1960) in his classification of the gonadal germ cell tumours preferred the designation "gonocytoma I-IV", referring to the number of different gonadal cell elements that participate in the tumour. The gonocytoma I, a pure germ cell tumour, thus stands for the dysgerminoma. The gonocytome II and III, showing in addition Sertolior granulosa cells in the first and Sertoli- or granulosa cells plus Leydig- or lutein cells in the latter case correspond to the "gonoblastoma of Scully". The gonocytoma IV again shows pure germ cell elements with an interstitial cell proliferation outside the tumour. Scully (1970) does not accept this classification, since he considers the appearance of interstitial cells within a germ cell tumour to depend on the stimulation by the pituitary gland after puberty.
Dysgerminoma in Turner's Syndrome . 257
In our patient, a germ cell tumour, resembling a dysgerminoma could be identified in the left gonadal streak. Yet, no gonadoblastoma structures were present in the numerous sections made. One may, however, presume that the dysgerminoma had overgrown a preexisting gonadoblastoma that had been hormonally active. This would explain the endometrial proliferation and episodes of bleeding in our patient. Dysgerminoma developing in the gonadal streak of a patient with Turner's syndrome is certainly a rare condition. Compared with the high risk of gonadal tumour development in patients with XY-gonadal dysgenesis and related mosaics, it seems rather surprising that a different situation should exist in XO-gonadal dysgenesis, i.e. in Turner's syndrome. In histological sections the gonadal streaks look completely alike in both conditions. Both, the XY- and the XO-gonadal dysgenesis patients display an increased gonadotrophin (FSH) blood level, which has been discussed as a possible promoting factor of tumour development or tumour growth (Frasier et aI., 1964), considering the fact that germ cell tumours are most often described as occuring after puberty. It looks, however, from the majority of the cases, as if a Y-chromosome in at least one stemline is responsible for the origin of a gonadal tumour. This could imply that the directly or indirectly Y-linked mutant gene responsible for preventing gonadal differentiation in XY-gonadal dysgenesis may at the same time enhance gonadal tumour development. However, it has to be emphasized that an XY-containing stemline could not be ascertained in our patient, neither in lymphocytes and in nuclei of hair root cells and buccal epithelial cells, nor in the gonadal tumour, in the latter case by the use of the technique of Khudr and Benirschke (1973). It should be mentioned here that a Y-body can very well be demonstrated in dysgerminoma cells of a patient with XY-gonadal dysgenesis (own observation).
On the other hand, the pathogenetic process of gonadal dysgenesis itself may represent a causative factor of gonadal tumour development preferentially in XY-gonadal dysgenesis. It is known that in Turner's syndrome ovarian differentiation is primarily induced and then continued until secondary regression occurs, mostly in later embryonic life. In contrast, gonadal differentiation does not take place primarily in XY-gonadal dysgenesis. Thus, if gonadoblastoma or "dysgenetic dysgerminoma" is to be considered a tumour of the undifferentiated gonad, XY-gonadal dysgenesis may bear a greater tumour risk, while the Xo-Turner's syndrome falls into this category only if gonadal regression starts early. Some authors consider dysgerminoma of the intersex state as well as gonadoblastoma to be tumours of the testes (Philip and Teter, 1964;
258 . H. Rehder and Th . Melcher
Fathalla et al., I966). They believe, that an inCIpIent and almost abortive testicular differentiation occurring in very early embryonic development might explain the findings of these tumours in XY-gonadal dysgenesis. We must, however, presume, that the male determining gene product of the Y-chromosome, probably a histocompatibility Y-antigen (HY-antigen), bound to the cell surface and functioning as a marker for testicular differentiation is missing in XY-gonadal dysgenesis (Wachtel et al., 1975; Ohno, in print). The existence of this HY -antigen, for example, has already been ascertained in the XX-male syndrome. On the other hand, a hypothesis for gonadal tumour development in gonadal dysgenesis, basing on an abortive testicular differentiation can not be applied to Turner's syndrome, while the conditions brought about by an early onset of ovarian degeneration could well represent a causative factor of the development of a germ cell tumour as in the patient described in this report. There is no indication, whatsoever, that the hormonal treatment, which the patient received for six years, induced the gonadal tumour. Certainly, many cases of Turner's syndrome get hormonal treatment, and a coincidence of steroid hormone treatment and development of ovarian germ cell tumour is not known.
Zusammenfassung Die Bedeutung des Y-Chromosoms bei der Entstehung von Keimzelltumoren in dysgenetischen Gonaden erscheint unumstritten. Dagegen sind Dysgerminome oder Gonadobias tome beim XO-Turner-Syndrom nur in zwei Eillen beschrieben. Ober einen weiteren Fall eines Turner-Syndroms mit Dysgerminom im Bereich der linken Gonadenleiste wird hier berichtet. Primar chromosomal-genetische oder sekundar pathogenetische Ursachen in Zusammenhang mit der genetisch determinierten Regression der Gonadenanlage konnten bei der Entstehung derartiger Gonadenleistentumoren eine Rolle spielen.
References Barr, M. L., Carr, D. H., Plunkett, E. R., Soltan, H. c., and Wiens, R. G.: Male pseudohermaphroditism and pure gonadal dysgenesis in sisters. Amer. J. Obstet. Gynec. 99, 1047- 10 55 (19 6 7) Bergher de Bacalao, E., and Dominguez, J.: Unilateral gonadoblastoma in a pregnant woman. Amer. J. Obstet. Gynec. 105,. 1279-1281 (1969) van Campenhout, J., Lord, J., Vauclair, R., Lanthie, A., and Berard, M.: The phenotype and gonadal histology in XO/XY mosaic individuals: report of two personal cases. ]. Obstet. Gynaec. Brit. Cwlth. 76, 631-639 (1969) Dewhurst, C. J., Ferreira, H. P., and Gillett, P. G.: Gonadal Malignancy in XY females. J. Obstet. Gynaec. Brit. Cwlth. 78, IOll-1083 (1971)
Dysgerminoma in Turner's Syndrome· 259 Dominguez, C. J., and Greenblatt, R. B.: Dysgerminoma of the ovary in a patient with Turner's syndrome. Amer. ]. Obstet. Gynec. 83,674-677 (1962) Fathalla, M. F., Rashad, M. N., and Kerr, M. G.: The relationship between ovarian tumours and intersex states with special reference to the dysgerminoma and arrhenoblastoma.]. Obstet. Gynaec. Brit. Cwlth. 73, 8I2-820 (1966) Frasier, S. D., Bashore, R. A., and Mosier, H. D.: Gonadoblastoma associated with pure gonadal dysgenesis in monozygous twins. ]. Pediatrics 64, 740-745 (1964) Hughesdon, P. E., and Kumarasamy, T.: Mixed germ cell tumours (gonadoblastomas) in normal and dysgenetic gonads. Vir chows Arch. Abt. A Path. Anat. 349, 258-280 (197 0 )
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