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Germ cell tumors associated with XY gonadal dysgenesis
Germ cell tumors associated with XY gonadal dysgenesis HELMUT JOSE FELIX ANN
M.
SCHELLHAS,
TRUJILLO, N.
CORK,
Houston,
In
F.
M.D.* M.D.
RUTLEDGE,
M.D.
M.A.
Texas
5 phenotypic
female
patients germ cell tumors were found associated with One of these patients developed a gonadal choriocarcinoma 9 years after a gonadoblastoma had been removed in the contralateral ovary. Two patients were found to have gonadoblastomas with metastatic dysgerminomatous components. The last two patients had dysgerminomas. These findings are bf clinical interest because the gonadoblastoma was thought to be of low-grade malignancy and for this reason treated conservatively in most reports.
XY gonadal dysgenesis.
T H E S I M U L T A N E 0 U S occurrence Of germ cell tumors and intersex has been described in the literature since the beginning of this century. The possibility to study the chromosomal constitution of these patients by the modern methods of cytogenetics furnishes more detailed information about the developmental disorder and may assist in determining the histogenesis of the germ cell tumor.
Most patients with ovarian tumors were referred to this institution after an exploratory laparotomy had been performed in another hospital. Because the clinical! information often is incomplete and because of the possibility that advanced tumor growth could have masked a developmental abnormality, all patients with ovarian germ cell tumors seen in a 2 year period were screened for chromosomal abnormalities. Material
From the Gynecology Service, Department of Surgery and the Cytogenetic and Immunology Laboratories, Department of Clinical Pathology, The University of Texas, M. D. Anderson Hospital and Tumor Institute. Supported Research National Maryland.
methods
Patients with the diagnosis of an ovarian germ cell tumor seen at the M. D. Anderson Hospital Gynecology Service, Department of Surgery, from July, 1968, to June, 1970, were screened for chromosomal abnormalities in collaboration with the Department of Clinical Pathology, Cytogenetic Laboratory. Examined were 14 patients followed for dysgerminoma, 9 patients with embryonal carcinoma, 3 patients with malignant teratoma, and one patient with choriocarcinoma. In the latter patient a gonadoblastoma had been removed 9 years earlier. The clinical
by Public Health Service Grant CA 06939-05 from the Cancer Institute, Bethesda.
Presented at the Thirtv-eighth Annual Meeting of the Central Association of Obstetricians and Gynecologists, Chicago, Illinois, Sept. 24-26, 1970.
-
and
*Present address: Department of Obstetrics and Gynecology, University of Cincinnati, Cincinnati General Hospital.
1197
1198
Schellhas
et al.
records of these patients were reviewed and the diagnosis of anatomic abnormalities was established on the basis of the operative reports furnished by the referring physicians. The histologic diagnosis of the tumors was provided by the Department of Anatomical Pathology of this institute. Most tissue sections were submitted from outside laboratories. The sex chromatin pattern of the patients was determined from buccal smears fixed in 3 per cent acetic acid in 95 per cent ethanol and stained with aceto0rcein.l In all patients peripheral blood cultures stimulated with phytohemagglutinin were utilized for cytogenetic studies. Standard cytogenetic techniques were applied throughout for harvesting the cultures, for slide preparations, and for metaphase analysis with a minimum
of 30 to 50 metaphases analyzed in every successful culture. In cases of special interest, the peripheral blood cultures were repeated and chromosome studies were performed on fibroblast cultures derived from skin biopsies. Results All patients with the history of normal menstrual function prior to the manifestation of their disease were found to have normal female karyotypes 46,Xx and buccal smears positive for sex chromatin. This includes 7 patients with the diagnosis of embryonal carcinoma, 3 patients with malignant teratoma, and 6 patients with dysgerminoma. In one patient with embryonal carcinoma no mitotic cells could be obtained on three different occasions as she was undergoing chemotherapy. In the group of 10 patients without spontaneous
Table I. Sex chromosome
complement and physical findings in a group of patients with germ cell tumors Status
of gonads
No.
and
genitals
1 Total
-
3
3
1
1
2:
T
2:
22
5
27
malformation
Table II. Germ Case No.,
cell tumors
Age
initials Case No. N. T.
1,
Case No. D. A.
2,
Case No. M. D.
3,
Case No. C. D.
4,
Case No. D. F.
5,
and menstrual history
chromosomes
of patients I46,XY
Total
associated
5
menstruation,
and
were
14
were
sex
chromatin
posi-
with
The 5 patients older than 14 years without spontaneous menstruation were found to have a male 46,XY chromosomal pattern in the peripheral blood lymphocytes and in fibroblasts from skin cultures and were sex chromatin negative.
XY
gonadal
Height
dysgenesis-clinical Sex
5’5%”
Primary
Normal external vestige, right
18 amenorrhea
5’8”
Primary
External pubertal genitals, infantile vestige, left tube cordlike, right gonadal mass, small breasts
23 menses
6’1”
Induced
Normal right
18 menses
5’8”
Induced
Normal external genitals, infantile and tube, right tube attached small breasts
15 (one
5’1%”
Spotting
Normal left
external gonadal
data
characteristics
19 amenorrhea
time)
patients
years of age or younger when their disease was found. All 5 patients had XX sex tive.
46,Xx
Unilateral gonadal vestiges Unilateral absent gonad Blind vagina No
April 15, 1971 J. Obstet. Gynec.
Amer.
genitals, normal-sized uterus, left gonadal gonad resembling normal ovary, small breasts uterus,
genitals, infantile uterus, mass, small breasts uterus, to right
external genitals, infantile gonad, right gonadal mass,
left
tube attached
uterus, breasts
left
gonadal
to right
gonadal
absent gonadal
streak,
left gonad mass,
normal-appearing not developed.
Volume Number
109 8
Germ cell tumors and XY gonadal
Review of the clinical data of all examined patients (Table I) revealed the following developmental abnormalities at the time of laparotomy : 3 patients with unilateral gonadal vestiges, one patient with unilateral absent gonad, and one patient with a blind vagina. In the latter patient the pelvic reproductive organs could not be identified because of tumor extension. The 4 patients with known gonadal abnormalities had primary amenorrhea. The patient with the blind vagina was prepubertal. The 4 patients with dysgenetic or absent unilateral gonads were found to have 46,XY karyotypes and to be sex chromatin negative. The patient with the blind vagina had a 46,Xx karyotype on repeated examinations and was sex chromatin positive. There was only one patient, 15-year-old, D. F., in whom no developmental abnormalities were noted; however, she had a 46,XY chromosomal constitution and was sex chromatin negative. Except for a short period of vaginal spotting, she had never menstruated. The clinical details of the 5 patients with 46,XY chromosomal constitution are summarized in Tables II and III. All 5 patients had exploratory laparotomy and surgical
Table III.
Germ
cell tumors
associated
with
dysgenesis
1199
procedures as listed before their referral to this institution. Only a limited number of slides, referred from other institutions, were available of each tumor for microscopic examination. The tissue of Patient N. T. revealed a typical gonadoblastoma with sertoli and granulosa cell elements, clusters of germ cells, nests of Leydig cells, and multiple calcifications. This case is in preparation for publication in detail by H. Steven Gallagher. The microscopic sections of the tumors from the other 4 patients were shown to have in common extensive areas with a typical dysgerminomatous pattern. In the ovarian tumor of Patient D. A., however, numerous foci of calcifications were found close to the tumor capsule. The calcified bodies were round and laminated and often confluent. They were encapsulated by annular fibrous tissue often lined by layers of granulosa-like cells. In addition nests of granulosa cells with hyaline foci and small calcifications could be seen (Figs. 1 and 2). Similar structures were found in the tissue of the ovarian tumor of Patient M. D. In both cases the initial diagnosis of dysgerminoma was revised to gonadoblastoma. The tumors of Pa-
XY
gonadal
dysgenesis
pathologic
findings Case No., initials
Tumor
extension
and
diagnosis
mass, 27 cm. diameter, to right iliac, para-aortic, nodes
3,500 and
IV
Bilat. S&O, radical NED 14 yr.
left gonadal streak metastases in right
IIB
TAH, bilat. S&O, XRT pelvis & abdomen, NED 5 yr.
IA
Right S&O, radical NED 2 yr.
XRT,
III
Right S&O, NED 2%
XRT,
2,
Right solid gonadal grams, metastatic left supraclavicular Dx : Gonadoblastoma
Case No. M. D.
3,
Large right gonadal with microscopic broad ligament Dx : Gonadoblastoma
mass, tumor,
Case No. C. D.
4,
Right gonadal tumor Dx: Dysgerminoma
10 x 5 x 5 cm.
Case No. D. F.
5,
gonad
with
small
Right gonadal tumor 2,250 grams, ascites, enlarged para-aortic nodes Dx: Dysgerminoma radical XRT: irradiation Salpingo-oophorect0my; of disease;
and
TAH:
follow-up
Left
Case No. D. A.
no evidence
and
IA
Left rudimentary Dx : Gonadoblastoma
*S&O:
Therapy*
mass
1,
NED:
Stage tumor
Case No. N. T.
total
abdominal
malignant
to pelvis, hysterectomy.
abdomen,
S&O, developed lethal choriocarcinoma of right ovary 9 yr. post-op., metastatic to abdomen and lungs
mediastinum,
and
radical yr. left
XRT,
supraclavicular
to
area;
200
Schellhas
Fig. hyaline
et al.
1. Case D. A. Gonadoblastoma foci and calcifications.
Amer.
of the
tients D. F. and C. D. showed the patterns of pure dysgerminoma except for the occasional occurrence of calcified foci and the frequent appearance of giant cell-like structures. Sections of extragonadal metastatic tumor in Patients D. A. and M. D. represented pure dysgerminoma.
right
gonad.
Nests
of granulosa-like
April 15, 1971 J. Obstet. Gym.
cells
with
Comment Four of the patients with XY sex chromosomes (D. A., M. D., C. D., and N. T.) revealed similar characteristics : ( 1) female phenotype with underdeveloped secondary sex characteristics, (2) normally developed hypoplastic Miillerian duct derivatives, (3)
Volume Number
109 8
Fig. foci.
Germ
cell
2. Case D. A. Gonadoblastoma. Nests of granulosa-like Encapsulated calcifications in lower half.
rudi .mentary or absent gonads, (4) absent spor uaneous menarche, and (5) 46,XY chroomal constitution. This entity is recognizeld as XY gonadal dysgenesis. The large size of the gonadal tumors in our patients conezealed the original gonadal forms and the histologic structure of the contralateral
tumors
and
XY gonadal
cells with
germ
dysgenesis
cells and
1201
hyaline
ovaries is not well documented. In the Patient D. F. no anatomic abnormality was recognized in the tumor-free gonad. h she had all of the other characteristic :s in common with the group of patients with XY gonadal dysgenesis, we will also include : her in this group.
1202
Schellhas
et al. Amer.
Gonadal dysgenesis has been found associated in patients with X0, XY, and XX sex chromosomes and with a variety of mosaic forms. Teter and Boczkowski17 observed that a Y chromosome was always present in cases of germ cell tumors in dysgenetic gonads. Several exceptions to this rule were reported. One case of 45,X0 gonadal dysgenesis (Turner’s syndrome) has been found associated with a dysgerminoma.61 8 A case of a unilateral gonadoblastoma in a pregnant woman with a normal 46,Xx karyotype was published by Bergher De Bacalao and Dominguez.2 However, analysis of the published karyotype by our cytogenetic laboratory suggests that in this latter case an X isochromosome may have been present. McDonough and associates9 described a case of X0/X fragment sex chromosomes in which the fragment could possibly represent a Y chromosome, and MillerlO reported a case of XO/XM mosaicism in which an abnormal minute metacentric chromosome was found. The latter 2 cases were associated with a gonadoblastoma. The gonadoblastoma was described by scullyll in 1953. Malignant germ cells and immature sex cord derivatives (granulosa and sertoli cells) are intimately mixed in this tumor. Leydig-like cells are sometimes found and are thought to be associated with the occurrence of virilization. Foci of calcifications, usually with tubular structures, are characteristic and can often be seen on x-ray. Most gonadoblastomas reported were small tumors. Scully x2>I3 has recently reviewed 70 cases of gonadoblastomas from his own material and the literature. He observed that about one quarter of all tumors were found in gonadal streaks, one-fifth in cryptorchid testes and the others in gonads of unknown nature. Most authorsl*l I31 15-17 consider the gonadoblastoma to be a more differentiated tumor than the dysgerminoma. The histologic pattern of a gonadoblastoma was never found in any tumor metastases. No case of metastatic dysgerminoma associated with a gonadoblastoma and so far no tumor recurrences or deaths due to gonadoblastoma have
April 15, 1971 J. Obstet. Gynec.
been reported. Scullyl*~ I3 emphasized, however, that the follow-up has been inadequate in most instances. Contrary to these reports, a more malignant tumor potential is evident in the M. D. Anderson Hospital group of patients. Two patients with the diagnosis of gonadoblastoma with dysgerminomatous overgrowth had metastases of the dysgerminomatous component. The development of a fatal choriocarcinoma in the same dysgenetic gonadal condition, from which a gonadoblastoma arose 9 years earlier, underlines the detrimental capabilities of the maldeveloped gonadal tissue. Additional evidence is provided by the report of Caffrey and Casey4 of a patient in whom biliateral gonadoblastomas were associated with a fatal embryonal carcinoma and by the report of Teter and Boczkowski17 of a patient in whom traces of choriocarcinoma were found in a dysgerminoma. Clinically, XY gonadal dysgenesis or its mosaic variations should be recognized as early as possible. Signs of virilization are often caused by a gonadoblastoma and should be an indication for screening the young patient with buccal smears, and, ideally, with cytogenetic studies. Primary amenorrhea is a manifestation of gonadal dysgenesis and should be an additional signal to karyotype the postpubertal patient. Hormonal induction of menses is possible in these patients and should not distract from further evaluation. The patient with a female phenotype and an XY sex chromosome complement or other sex chromosomal alterations should be surgically explored, if gonadal dysgenesis is suspected, and abnormal gonads removed. An exception presents the pure Turner syndrome (X0 gonadal dysgenesis) in which germ cell tumors are extremely uncommon. Family members should also be screened, since familial occurrence of XY gonadal dysgenesis with or without germ cell tumors has been found.3* 5p 7* l4 Conversely, intersex should be suspected in all patients with germ cell tumors and with signs of virilization and/or with primary amenorrhea. Recognition of an intersex sta-
Volume 109 Number 8
tus could eliminate therapeutic restrictions devised for the preservation of fertility in germ cell tumor patients.
Germ
cell
tumors
and
XY gonadal
dysgenesis
1203
The authors express their appreciation to Dr. H. Steven Gallagher for his suggestions.
REFERENCES
1. Atkin, N. B.: Acta Cytol. 11: 453, 1967. 2. Bergher De Bacalao, E., and Dommguez, I.: AMER. J. OBSTET. GYNEC. 105: 1279, 1969. 3. Brogger, A., and Strand, A.: Acta Endocr. 48: 490, 1965. 4. Caffrey, R. J., and Casey, C. H.: J. A. M. A. 202: 279, 1967. 5. Cohen, M. M., and Shaw, M. W.: New Eng. J. Med. 272: 1084, 1965. 6. Dominguez, C. J., and Greenblatt, R. B.: AMER. J. OBSTET. GYNEC. 83: 674, 1962. 7. Frazier, S. D., Bashore, B. A., and Mosier, H. D.: J. Pediat. 64: 740, 1964. 8. Greenblatt, R. B., Byrd, k. J., McDonough, P. G.. and V. B.: AMER. Y1. OBSTET. GYNE~. 98: Mahesh.1967. 151, 9. McDonough, P. G., Greenblatt, R. B., Byrd: J. R., and Hastings, E. V.: Obstet. Gynec. 29: 54, 1967.
10. Miller, 0. J.: AMER. J. OBSTET. GYNEC. 90: 1078, 1964. 11. Scully, R. E.: Cancer 6: 445, 1953. 12. Scully, R. E.: In Sturgis, S. H., and Taymor, M. L., editors: Meigs and Sturgis: Progress in Gynecology, New York and London, 1970, Grune & Stratton, Inc., vol. IV. 13. Scully, R. E.: Hum. Path. 1: 73, 1970. 14. Sternberg. W. H.. Barclav. D. L.. and Kloeofer, H. -W.: New Eng. ‘J. Med. 278: 695, 1968. 15. Taylor, H., Barter, R. H., and Jacobson, C. B.: AMER. J. OBSTET. GYNEC. 96: 816, 1966. 16. Teilum, G.: In Gent& F., and Jungueira, A. C., editors: UICC Monography Series, Berlin, 1968, Springer-Verlag, vol. II. 17. Teter, J., and Boczkowski, K.: Cancer 20: 1301, 1967.
Discussion DR. CARL J. PAUERSTEIN, San Antonio, Texas. Dr. Schellhas and his colleagues have presented 5 patients with ovarian tumors and XY gonadal dysgenesis. I would like to focus this discussion upon the diagnosis of the tumors. Since the pathologist diagnosed ovarian tumors by considering both the histology and the clinical picture, let us apply this classic approach to the cases under consideration. With regard to the histology, Scully8 originally described tumors that “were in part dysgerminomas, but elsewhere were composedof cells of sex cord and mesenchyme origin.” If this is the typical picture, what may we accept as less typical, but sufficient to be diagnostic? For example, in Teter’sa series a tumor containing dysgerminoma, syncytiotrophoblast, and calcified concretions was diagnosed as “dysgerminoma.” Was this an atypical dysgerminoma, or an incompletely developed gonadoblastoma? Although Scully described scattered calcific foci in the stroma of his original two cases, I agree with the essayists that calcification alone is insuf&ient reason to diagnose a tumor that is predominantly a dysgerminoma as “gonadoblastoma.” The tumor originally removed from the left gonad of Patient N. T. clearly satisfied Scully’s criteria for gonadoblastoma. Two additional Pa-
tient’s, D. A. and M. D., had tumors which were predominantly dysgerminoma, but which contained some elements seen in the gonadoblastoma. The last 2 patients, C. D. and D. F., showed occasional calcified foci, and frequent giant celllike structures in otherwise typical dysgerminomas. Thus the histology presented a problem only in D. A. and M. D. With regard to the clinical picture, none of these patients was virilized. Starting with Scully’s original 2 cases, most patients with gonadoblastoma reported upon in the literature have been virilized.*~ 3p5 Although some patients with dysgerminoma have also been virilized,l* 5 classically the pure dysgerminoma does not produce androgen. The absence of virilization in Dr. Schellhas’ patients suggests that either the tumors were not typical gonadoblastoma, or that the classic description of the gonadoblastoma needs modification. Finally, the dysgerminoma is considered a malignant tumor, which warrants radical therapy, whereas the gonadoblastoma is thought of as relatively benign. Taylor, Barter, and Jacobson4 concluded that postoperative irradiation was not necessary for patients with gonadoblastoma because neither recurrences nor metastases has been reported. In his discussion of that paper, Woodruffs cautioned that any lesion which contained
M.
SCHELLHAS,
TRUJILLO, N.
CORK,
Houston,
In
F.
M.D.* M.D.
RUTLEDGE,
M.D.
M.A.
Texas
5 phenotypic
female
patients germ cell tumors were found associated with One of these patients developed a gonadal choriocarcinoma 9 years after a gonadoblastoma had been removed in the contralateral ovary. Two patients were found to have gonadoblastomas with metastatic dysgerminomatous components. The last two patients had dysgerminomas. These findings are bf clinical interest because the gonadoblastoma was thought to be of low-grade malignancy and for this reason treated conservatively in most reports.
XY gonadal dysgenesis.
T H E S I M U L T A N E 0 U S occurrence Of germ cell tumors and intersex has been described in the literature since the beginning of this century. The possibility to study the chromosomal constitution of these patients by the modern methods of cytogenetics furnishes more detailed information about the developmental disorder and may assist in determining the histogenesis of the germ cell tumor.
Most patients with ovarian tumors were referred to this institution after an exploratory laparotomy had been performed in another hospital. Because the clinical! information often is incomplete and because of the possibility that advanced tumor growth could have masked a developmental abnormality, all patients with ovarian germ cell tumors seen in a 2 year period were screened for chromosomal abnormalities. Material
From the Gynecology Service, Department of Surgery and the Cytogenetic and Immunology Laboratories, Department of Clinical Pathology, The University of Texas, M. D. Anderson Hospital and Tumor Institute. Supported Research National Maryland.
methods
Patients with the diagnosis of an ovarian germ cell tumor seen at the M. D. Anderson Hospital Gynecology Service, Department of Surgery, from July, 1968, to June, 1970, were screened for chromosomal abnormalities in collaboration with the Department of Clinical Pathology, Cytogenetic Laboratory. Examined were 14 patients followed for dysgerminoma, 9 patients with embryonal carcinoma, 3 patients with malignant teratoma, and one patient with choriocarcinoma. In the latter patient a gonadoblastoma had been removed 9 years earlier. The clinical
by Public Health Service Grant CA 06939-05 from the Cancer Institute, Bethesda.
Presented at the Thirtv-eighth Annual Meeting of the Central Association of Obstetricians and Gynecologists, Chicago, Illinois, Sept. 24-26, 1970.
-
and
*Present address: Department of Obstetrics and Gynecology, University of Cincinnati, Cincinnati General Hospital.
1197
1198
Schellhas
et al.
records of these patients were reviewed and the diagnosis of anatomic abnormalities was established on the basis of the operative reports furnished by the referring physicians. The histologic diagnosis of the tumors was provided by the Department of Anatomical Pathology of this institute. Most tissue sections were submitted from outside laboratories. The sex chromatin pattern of the patients was determined from buccal smears fixed in 3 per cent acetic acid in 95 per cent ethanol and stained with aceto0rcein.l In all patients peripheral blood cultures stimulated with phytohemagglutinin were utilized for cytogenetic studies. Standard cytogenetic techniques were applied throughout for harvesting the cultures, for slide preparations, and for metaphase analysis with a minimum
of 30 to 50 metaphases analyzed in every successful culture. In cases of special interest, the peripheral blood cultures were repeated and chromosome studies were performed on fibroblast cultures derived from skin biopsies. Results All patients with the history of normal menstrual function prior to the manifestation of their disease were found to have normal female karyotypes 46,Xx and buccal smears positive for sex chromatin. This includes 7 patients with the diagnosis of embryonal carcinoma, 3 patients with malignant teratoma, and 6 patients with dysgerminoma. In one patient with embryonal carcinoma no mitotic cells could be obtained on three different occasions as she was undergoing chemotherapy. In the group of 10 patients without spontaneous
Table I. Sex chromosome
complement and physical findings in a group of patients with germ cell tumors Status
of gonads
No.
and
genitals
1 Total
-
3
3
1
1
2:
T
2:
22
5
27
malformation
Table II. Germ Case No.,
cell tumors
Age
initials Case No. N. T.
1,
Case No. D. A.
2,
Case No. M. D.
3,
Case No. C. D.
4,
Case No. D. F.
5,
and menstrual history
chromosomes
of patients I46,XY
Total
associated
5
menstruation,
and
were
14
were
sex
chromatin
posi-
with
The 5 patients older than 14 years without spontaneous menstruation were found to have a male 46,XY chromosomal pattern in the peripheral blood lymphocytes and in fibroblasts from skin cultures and were sex chromatin negative.
XY
gonadal
Height
dysgenesis-clinical Sex
5’5%”
Primary
Normal external vestige, right
18 amenorrhea
5’8”
Primary
External pubertal genitals, infantile vestige, left tube cordlike, right gonadal mass, small breasts
23 menses
6’1”
Induced
Normal right
18 menses
5’8”
Induced
Normal external genitals, infantile and tube, right tube attached small breasts
15 (one
5’1%”
Spotting
Normal left
external gonadal
data
characteristics
19 amenorrhea
time)
patients
years of age or younger when their disease was found. All 5 patients had XX sex tive.
46,Xx
Unilateral gonadal vestiges Unilateral absent gonad Blind vagina No
April 15, 1971 J. Obstet. Gynec.
Amer.
genitals, normal-sized uterus, left gonadal gonad resembling normal ovary, small breasts uterus,
genitals, infantile uterus, mass, small breasts uterus, to right
external genitals, infantile gonad, right gonadal mass,
left
tube attached
uterus, breasts
left
gonadal
to right
gonadal
absent gonadal
streak,
left gonad mass,
normal-appearing not developed.
Volume Number
109 8
Germ cell tumors and XY gonadal
Review of the clinical data of all examined patients (Table I) revealed the following developmental abnormalities at the time of laparotomy : 3 patients with unilateral gonadal vestiges, one patient with unilateral absent gonad, and one patient with a blind vagina. In the latter patient the pelvic reproductive organs could not be identified because of tumor extension. The 4 patients with known gonadal abnormalities had primary amenorrhea. The patient with the blind vagina was prepubertal. The 4 patients with dysgenetic or absent unilateral gonads were found to have 46,XY karyotypes and to be sex chromatin negative. The patient with the blind vagina had a 46,Xx karyotype on repeated examinations and was sex chromatin positive. There was only one patient, 15-year-old, D. F., in whom no developmental abnormalities were noted; however, she had a 46,XY chromosomal constitution and was sex chromatin negative. Except for a short period of vaginal spotting, she had never menstruated. The clinical details of the 5 patients with 46,XY chromosomal constitution are summarized in Tables II and III. All 5 patients had exploratory laparotomy and surgical
Table III.
Germ
cell tumors
associated
with
dysgenesis
1199
procedures as listed before their referral to this institution. Only a limited number of slides, referred from other institutions, were available of each tumor for microscopic examination. The tissue of Patient N. T. revealed a typical gonadoblastoma with sertoli and granulosa cell elements, clusters of germ cells, nests of Leydig cells, and multiple calcifications. This case is in preparation for publication in detail by H. Steven Gallagher. The microscopic sections of the tumors from the other 4 patients were shown to have in common extensive areas with a typical dysgerminomatous pattern. In the ovarian tumor of Patient D. A., however, numerous foci of calcifications were found close to the tumor capsule. The calcified bodies were round and laminated and often confluent. They were encapsulated by annular fibrous tissue often lined by layers of granulosa-like cells. In addition nests of granulosa cells with hyaline foci and small calcifications could be seen (Figs. 1 and 2). Similar structures were found in the tissue of the ovarian tumor of Patient M. D. In both cases the initial diagnosis of dysgerminoma was revised to gonadoblastoma. The tumors of Pa-
XY
gonadal
dysgenesis
pathologic
findings Case No., initials
Tumor
extension
and
diagnosis
mass, 27 cm. diameter, to right iliac, para-aortic, nodes
3,500 and
IV
Bilat. S&O, radical NED 14 yr.
left gonadal streak metastases in right
IIB
TAH, bilat. S&O, XRT pelvis & abdomen, NED 5 yr.
IA
Right S&O, radical NED 2 yr.
XRT,
III
Right S&O, NED 2%
XRT,
2,
Right solid gonadal grams, metastatic left supraclavicular Dx : Gonadoblastoma
Case No. M. D.
3,
Large right gonadal with microscopic broad ligament Dx : Gonadoblastoma
mass, tumor,
Case No. C. D.
4,
Right gonadal tumor Dx: Dysgerminoma
10 x 5 x 5 cm.
Case No. D. F.
5,
gonad
with
small
Right gonadal tumor 2,250 grams, ascites, enlarged para-aortic nodes Dx: Dysgerminoma radical XRT: irradiation Salpingo-oophorect0my; of disease;
and
TAH:
follow-up
Left
Case No. D. A.
no evidence
and
IA
Left rudimentary Dx : Gonadoblastoma
*S&O:
Therapy*
mass
1,
NED:
Stage tumor
Case No. N. T.
total
abdominal
malignant
to pelvis, hysterectomy.
abdomen,
S&O, developed lethal choriocarcinoma of right ovary 9 yr. post-op., metastatic to abdomen and lungs
mediastinum,
and
radical yr. left
XRT,
supraclavicular
to
area;
200
Schellhas
Fig. hyaline
et al.
1. Case D. A. Gonadoblastoma foci and calcifications.
Amer.
of the
tients D. F. and C. D. showed the patterns of pure dysgerminoma except for the occasional occurrence of calcified foci and the frequent appearance of giant cell-like structures. Sections of extragonadal metastatic tumor in Patients D. A. and M. D. represented pure dysgerminoma.
right
gonad.
Nests
of granulosa-like
April 15, 1971 J. Obstet. Gym.
cells
with
Comment Four of the patients with XY sex chromosomes (D. A., M. D., C. D., and N. T.) revealed similar characteristics : ( 1) female phenotype with underdeveloped secondary sex characteristics, (2) normally developed hypoplastic Miillerian duct derivatives, (3)
Volume Number
109 8
Fig. foci.
Germ
cell
2. Case D. A. Gonadoblastoma. Nests of granulosa-like Encapsulated calcifications in lower half.
rudi .mentary or absent gonads, (4) absent spor uaneous menarche, and (5) 46,XY chroomal constitution. This entity is recognizeld as XY gonadal dysgenesis. The large size of the gonadal tumors in our patients conezealed the original gonadal forms and the histologic structure of the contralateral
tumors
and
XY gonadal
cells with
germ
dysgenesis
cells and
1201
hyaline
ovaries is not well documented. In the Patient D. F. no anatomic abnormality was recognized in the tumor-free gonad. h she had all of the other characteristic :s in common with the group of patients with XY gonadal dysgenesis, we will also include : her in this group.
1202
Schellhas
et al. Amer.
Gonadal dysgenesis has been found associated in patients with X0, XY, and XX sex chromosomes and with a variety of mosaic forms. Teter and Boczkowski17 observed that a Y chromosome was always present in cases of germ cell tumors in dysgenetic gonads. Several exceptions to this rule were reported. One case of 45,X0 gonadal dysgenesis (Turner’s syndrome) has been found associated with a dysgerminoma.61 8 A case of a unilateral gonadoblastoma in a pregnant woman with a normal 46,Xx karyotype was published by Bergher De Bacalao and Dominguez.2 However, analysis of the published karyotype by our cytogenetic laboratory suggests that in this latter case an X isochromosome may have been present. McDonough and associates9 described a case of X0/X fragment sex chromosomes in which the fragment could possibly represent a Y chromosome, and MillerlO reported a case of XO/XM mosaicism in which an abnormal minute metacentric chromosome was found. The latter 2 cases were associated with a gonadoblastoma. The gonadoblastoma was described by scullyll in 1953. Malignant germ cells and immature sex cord derivatives (granulosa and sertoli cells) are intimately mixed in this tumor. Leydig-like cells are sometimes found and are thought to be associated with the occurrence of virilization. Foci of calcifications, usually with tubular structures, are characteristic and can often be seen on x-ray. Most gonadoblastomas reported were small tumors. Scully x2>I3 has recently reviewed 70 cases of gonadoblastomas from his own material and the literature. He observed that about one quarter of all tumors were found in gonadal streaks, one-fifth in cryptorchid testes and the others in gonads of unknown nature. Most authorsl*l I31 15-17 consider the gonadoblastoma to be a more differentiated tumor than the dysgerminoma. The histologic pattern of a gonadoblastoma was never found in any tumor metastases. No case of metastatic dysgerminoma associated with a gonadoblastoma and so far no tumor recurrences or deaths due to gonadoblastoma have
April 15, 1971 J. Obstet. Gynec.
been reported. Scullyl*~ I3 emphasized, however, that the follow-up has been inadequate in most instances. Contrary to these reports, a more malignant tumor potential is evident in the M. D. Anderson Hospital group of patients. Two patients with the diagnosis of gonadoblastoma with dysgerminomatous overgrowth had metastases of the dysgerminomatous component. The development of a fatal choriocarcinoma in the same dysgenetic gonadal condition, from which a gonadoblastoma arose 9 years earlier, underlines the detrimental capabilities of the maldeveloped gonadal tissue. Additional evidence is provided by the report of Caffrey and Casey4 of a patient in whom biliateral gonadoblastomas were associated with a fatal embryonal carcinoma and by the report of Teter and Boczkowski17 of a patient in whom traces of choriocarcinoma were found in a dysgerminoma. Clinically, XY gonadal dysgenesis or its mosaic variations should be recognized as early as possible. Signs of virilization are often caused by a gonadoblastoma and should be an indication for screening the young patient with buccal smears, and, ideally, with cytogenetic studies. Primary amenorrhea is a manifestation of gonadal dysgenesis and should be an additional signal to karyotype the postpubertal patient. Hormonal induction of menses is possible in these patients and should not distract from further evaluation. The patient with a female phenotype and an XY sex chromosome complement or other sex chromosomal alterations should be surgically explored, if gonadal dysgenesis is suspected, and abnormal gonads removed. An exception presents the pure Turner syndrome (X0 gonadal dysgenesis) in which germ cell tumors are extremely uncommon. Family members should also be screened, since familial occurrence of XY gonadal dysgenesis with or without germ cell tumors has been found.3* 5p 7* l4 Conversely, intersex should be suspected in all patients with germ cell tumors and with signs of virilization and/or with primary amenorrhea. Recognition of an intersex sta-
Volume 109 Number 8
tus could eliminate therapeutic restrictions devised for the preservation of fertility in germ cell tumor patients.
Germ
cell
tumors
and
XY gonadal
dysgenesis
1203
The authors express their appreciation to Dr. H. Steven Gallagher for his suggestions.
REFERENCES
1. Atkin, N. B.: Acta Cytol. 11: 453, 1967. 2. Bergher De Bacalao, E., and Dommguez, I.: AMER. J. OBSTET. GYNEC. 105: 1279, 1969. 3. Brogger, A., and Strand, A.: Acta Endocr. 48: 490, 1965. 4. Caffrey, R. J., and Casey, C. H.: J. A. M. A. 202: 279, 1967. 5. Cohen, M. M., and Shaw, M. W.: New Eng. J. Med. 272: 1084, 1965. 6. Dominguez, C. J., and Greenblatt, R. B.: AMER. J. OBSTET. GYNEC. 83: 674, 1962. 7. Frazier, S. D., Bashore, B. A., and Mosier, H. D.: J. Pediat. 64: 740, 1964. 8. Greenblatt, R. B., Byrd, k. J., McDonough, P. G.. and V. B.: AMER. Y1. OBSTET. GYNE~. 98: Mahesh.1967. 151, 9. McDonough, P. G., Greenblatt, R. B., Byrd: J. R., and Hastings, E. V.: Obstet. Gynec. 29: 54, 1967.
10. Miller, 0. J.: AMER. J. OBSTET. GYNEC. 90: 1078, 1964. 11. Scully, R. E.: Cancer 6: 445, 1953. 12. Scully, R. E.: In Sturgis, S. H., and Taymor, M. L., editors: Meigs and Sturgis: Progress in Gynecology, New York and London, 1970, Grune & Stratton, Inc., vol. IV. 13. Scully, R. E.: Hum. Path. 1: 73, 1970. 14. Sternberg. W. H.. Barclav. D. L.. and Kloeofer, H. -W.: New Eng. ‘J. Med. 278: 695, 1968. 15. Taylor, H., Barter, R. H., and Jacobson, C. B.: AMER. J. OBSTET. GYNEC. 96: 816, 1966. 16. Teilum, G.: In Gent& F., and Jungueira, A. C., editors: UICC Monography Series, Berlin, 1968, Springer-Verlag, vol. II. 17. Teter, J., and Boczkowski, K.: Cancer 20: 1301, 1967.
Discussion DR. CARL J. PAUERSTEIN, San Antonio, Texas. Dr. Schellhas and his colleagues have presented 5 patients with ovarian tumors and XY gonadal dysgenesis. I would like to focus this discussion upon the diagnosis of the tumors. Since the pathologist diagnosed ovarian tumors by considering both the histology and the clinical picture, let us apply this classic approach to the cases under consideration. With regard to the histology, Scully8 originally described tumors that “were in part dysgerminomas, but elsewhere were composedof cells of sex cord and mesenchyme origin.” If this is the typical picture, what may we accept as less typical, but sufficient to be diagnostic? For example, in Teter’sa series a tumor containing dysgerminoma, syncytiotrophoblast, and calcified concretions was diagnosed as “dysgerminoma.” Was this an atypical dysgerminoma, or an incompletely developed gonadoblastoma? Although Scully described scattered calcific foci in the stroma of his original two cases, I agree with the essayists that calcification alone is insuf&ient reason to diagnose a tumor that is predominantly a dysgerminoma as “gonadoblastoma.” The tumor originally removed from the left gonad of Patient N. T. clearly satisfied Scully’s criteria for gonadoblastoma. Two additional Pa-
tient’s, D. A. and M. D., had tumors which were predominantly dysgerminoma, but which contained some elements seen in the gonadoblastoma. The last 2 patients, C. D. and D. F., showed occasional calcified foci, and frequent giant celllike structures in otherwise typical dysgerminomas. Thus the histology presented a problem only in D. A. and M. D. With regard to the clinical picture, none of these patients was virilized. Starting with Scully’s original 2 cases, most patients with gonadoblastoma reported upon in the literature have been virilized.*~ 3p5 Although some patients with dysgerminoma have also been virilized,l* 5 classically the pure dysgerminoma does not produce androgen. The absence of virilization in Dr. Schellhas’ patients suggests that either the tumors were not typical gonadoblastoma, or that the classic description of the gonadoblastoma needs modification. Finally, the dysgerminoma is considered a malignant tumor, which warrants radical therapy, whereas the gonadoblastoma is thought of as relatively benign. Taylor, Barter, and Jacobson4 concluded that postoperative irradiation was not necessary for patients with gonadoblastoma because neither recurrences nor metastases has been reported. In his discussion of that paper, Woodruffs cautioned that any lesion which contained