Gonadoblastoma Overgrown by Dysgerminoma in Women with 46,XX Karyotype -A Report of Two Cases

Home , Dysgerminoma, Embryonal carcinoma, Seminoma

대한병리학회지: 제 37 권제1 호 2003 The Korean Journal of Pathology. 2003; 37: 66-70

Gonadoblastoma Overgrown by Dysgerminoma in Women with 46,XX Karyotype -A Report of Two Cases-

Mi-Jung Kim∙Hee-Jeong Ahn1 Gonadoblastoma is a neoplasm containing an intimate mixture of germ cells and elements Ji-Young Kim1∙ Kyu-Rae Kim resembling immature granulosa or Sertoli cells. It has been considered as in situ germ cell malignancy that can be overgrown by more malignant germ cell neoplasms. The tumor has been reported to almost exclusively develop in various types of gonadal maldevelopment syn- Department of Pathology, University of dromes containing the Y chromosome, such as in pure or mixed gonadal dysgenesis and, less Ulsan College of Medicine, Asan commonly, in male hermaphroditism. However, occurrences in phenotypically and chromoso- Medical Center, Seoul, Korea; mally normal, menstruating women are exceptionally rare. We report two cases of gonadoblas- 1Department of Pathology, Bundang Hospital, College of Medicine Pochon toma overgrown by dysgerminoma occurring in the ovaries of phenotypically and cytogeneti- Cha University, Seongnam, Korea cally normal menstruating women. One of the two cases showed an area composed of granulosa cell tumor-like elements. This type of combination has been very rarely described, and exemplified that gonadoblastoma may progress to sex cord-stromal tumors as well as to the malignant germ cell tumors. Received : June 28, 2002 Accepted : November 6, 2002

Corresponding Author Kyu-Rae Kim, M.D. Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, 388-1 Pungnap-dong, Songpa-gu, Seoul 138-736, Korea Tel: 02-3010-4514 Fax: 02-472-7898 Key Words : Gonadoblastoma-Dysgerminoma-Sex Cord-Stromal Tumor-Gonadal Dysgen- E-mail: [email protected] esis, 46,XX

In 1953, Scully described gonadoblastoma as a separate enti- gonadoblastomas in the phenotypically and cytogenetically nor- ty. It was defined histologically by the occurrence of discrete mal menstruating women and a rare case in which the gonadoblas- aggregates composed of germ cells and sex cord elements resem- toma, the malignant germ cell neoplasia and the sex cord-stromal bling immature Sertoli or granulosa cells.1,2 The incidence of tumor coexist in a same tumor. gonadoblastoma is high in patients with various gonadal maldevelopment syndromes containing the Y chromosome.3,4 It is found in 25-30% of patients with XY gonadal dysgenesis, in CASE REPORT 15-20% of 45,X/46,XY individuals,5,6 and rarely in 46,XY male hermaphroditism patients.7,8 A small fraction of gonadoblas- Case 1 tomas, however, develops in 46,XX females with no evidence of Y chromosomal DNA,9,10 in patients with histories of normal A 33-year-old unmarried woman was admitted to the hospi- pregnancies or menstruation,2,11 and in phenotypically normal men tal for evaluation of a low abdominal mass. The patient had with undescended testes.12,13 We report two cases of gonadoblas- received an evaluation for secondary amenorrhea one year before tomas associated with dysgerminoma that occurred in phenotypi- and was found to have bilateral cystic ovarian masses with mul- cally and cytogenetically normal menstruating women. The tiple leiomyomas of the uterus. Her family history and past significance of this report is that it describes the rare cases of medical history were unremarkable. On physical examination,

66 Gonadoblastoma in 46,XX 67

A B

Fig. 1. (A) The cut surface of the ovary shows an ill-defined 1.8× 1.1×1 cm sized solid nodule in the cystic wall. The oligolocular cyst shows a hemorrhagic inner surface. (solid arrows: gonadoblastomatous area). (B) The gonadoblastomatous area (lower half) is overgrown by a typical dysgerminomatous area (upper half). The gonadoblastomatous area is composed of germ cells and smaller epithelial cells resembling immature Sertoli or granulosa cells forming Call-Exner like hyaline bodies. (C) Sex cord-stromal elements in the connective tissue stroma have a trabecular or cord- like arrangement. The cells have angulated nuclei with inconspic- C uous nuclear grooves.

the patient’s height was 160 cm and her weight was 90 kg. were multiple small subserosal leiomyomas in the uterus. The Breast development, pubic hair, and external genitalia were right ovary, the left ovarian cyst and the uterine myomas were normal. A pelvic examination revealed an enlarged uterus with removed. The right ovary was composed of an oligolocular cyst. bilateral pelvic masses. She had had normal menstruation until The inner surface of the right ovarian cyst was hemorrhagic and one year prior to the examination revealing the pelvic masses. shaggy, and the thickness of the wall ranged from 0.2 to 0.7 Her menstruations were moderate in amount, and they occurred cm. There was an ill-defined firm, solid grayish yellow nodule, at regular intervals. She had not been pregnant and denied hav- measuring 1.8×1.1×1 cm within the ovarian parenchyme ing had any gynecological problems. An ultrasonography revealed (Fig. 1A). The left ovary was cystic and had been ruptured pre- septated multilocular cystic ovarian masses on both adnexa. viously. The inner surface of the left ovarian cyst showed red to Multiple small uterine leiomyomas were also identified. brown patches without solid area. An exploratory laparotomy revealed a 9.5×5×2 cm cystic Microscopically, bilateral ovaries showed the typical features right ovarian mass and a 5×4×4 cm left ovarian mass. There of endometriotic cysts composed of an endometrial-type epithe- 68 Mi-Jung Kim∙Hee-Jeong Ahn∙Ji-Young Kim, et al.

A B

Fig. 2. (A) The cut surface of the ovary, measuring 8.5×7×5 cm, is mostly replaced by a solid pink gray colored and focally hemorrhagic tumor. Normal ovarian tissue (arrows) remains as a thin rim beneath the surface. (B) The gonadoblastomatous area is composed of cellular nests showing a mixture of germ cells and sex cord-like elements. (C) The dysgerminomatous area is composed of sheets or nests of germ cells and mature lymphocytes in fibrous C septa. lium, stroma, and hemosiderin-laden macrophages. The solid cytoplasm. A minor focus of sex cord-stromal components was nodule in the right ovary was composed of three different histo- seen at the periphery of the nodule, and the cells formed a tra- logical features. There were gonadoblastomatous and dysger- becular or cord-like arrangement (Fig. 1C). The nuclei of these minomatous areas (1.4 cm and 1.3 cm in greatest dimension, cells were oval or angulated; however, the grooves were incon- respectively) and a minor focus of a sex cord-stromal compo- spicuous, and significant pleomorphism and mitosis were absent. nent (Fig. 1B). In the gonadoblastomatous area, discrete cellu- These cells surrounded circular spaces filled with eosinophilic lar nests were composed of intimately admixed germ cells and hyaline materials and formed Call-Exner bodies. smaller epithelial cells resembling immature Sertoli or granu- Immunohistochemical staining for placental alkaline phos- losa cells. The latter formed Call-Exner-like hyaline bodies. The phatase (PLAP: 1:200, DAKO, Glostrup, Denmark) showed a germ cell components within the nests were similar to dysger- strong positive reaction in the dysgerminomatous component minoma which have large, round and vesicular nuclei, often with and in the germ cell components of the gonadoblastomatous prominent nucleoli as well as abundant and clear, or eosinophilic, area. The sex cord-stromal elements resembling Sertoli or gran- Gonadoblastoma in 46,XX 69

ulosa cells in the gonadoblastoma were immunonegative for attend her regular follow-up visits. PLAP, but positive for inhibin (1:50, Serotec, Oxford, U.K.). The Chromosomal analyses were performed with peripheral lym- Ki-67 (1:200, DAKO) proliferation index was high in the germ phocytes using conventional G-banding techniques. Both cases cell components, but not in the sex-cord stromal elements. revealed normal 46, XX karyotypes (Fig. 3). The patient was treated with combination chemotherapy. Eighteen months later, she is well without evidence of recur- rence or metastasis. DISCUSSION

Case 2 Neoplasms composed of germ cells and sex cord derivatives consist of two distinctive types: the gonadoblastoma and the A 30-year-old woman visited the emergency room because of unclassified type of mixed germ cell sex cord-stromal tumor. abdominal pain. She had experienced normal menstruation with These two types have different histopathologic, genetic and regular intervals, normal durations, and amount of blood. Her endocrine features and different clinical and biological behaviors. family history and past medical history were unremarkable. She Gonadoblastoma arises almost exclusively in the dysgenetic gonads had borne a healthy male baby two years before admission, and of patients with a Y chromosome. The most common karyotypes she had received dilatation and evacuation for artificial abortion of these patients are 46,XY and 45,X/46,XYmosaicism. It has several times after the last delivery. She was found to have a right been considered as in situ germ cell malginancy that commonly ovarian mass. A right salpingo-oophorectomy was performed. progresses to invasive germinoma or another type of malignant The ovarian mass measured 8.5×7×5 cm and the pedicle was germ cell tumor, or rarely regresses with hyalinization and cal- distorted, resulting in a partly hemorrhagic parenchyme. The cification. On the other hand, the mixed germ cell sex cord-stro- cut surface was mostly occupied by a well demarcated, pinkish mal tumor usually occurs in phenotypically and cytogenetically gray colored solid mass, and there was a thin layer of normal normal females without any evidence of developmental abnor- appearing ovarian tissue beneath the surface (Fig. 2A). The fal- malities affecting the gonads, the external genitalia, or body flu- lopian tube was essentially normal. ids. These two types of neoplasms are sufficiently distinctive and The histologic findings in case 2 showed the typical features usually do not coexist. In case 1, the tumor in which gonadoblas- of gonadoblastoma overgrown by dysgerminoma. Most areas of toma was overgrown by dysgerminoma was accompanied by an the mass were replaced by dysgerminoma, with the gonadoblas- area showing a proliferation of sex cord-stromal elements. This tomatous areas mainly identified at the periphery of dysgermi- feature is usually not seen in the gonadoblastoma or dysgermino- noma located beneath the surface of the ovary (Fig. 2B, C). After ma. A combination of this type has very rarely been descri- surgical treatment, we lost contact with her because she did not bed,14,15 exemplifying that gonadoblastoma may be overgrown by the sex cord-stromal tumor as well as by the invasive germ cell tumors. Both of the patients’ovaries in case 1 were severely deformed with adhesions due to the endometriosis. Even though the char- A B acteristic features of the polycystic ovary were not observed and 12 345 the serum levels of the luteinizing hormone (LH) and follicular C stimulating hormone (FSH) were not measured prior to the oper-

6 7 8 9 10 11 12 X ation, the secondary amenorrhea in case 1 might have been caused by the hormonal disorder associated with her obesity. D E 13 14 15 16 17 18 Phenotypic females with dysgenetic gonads and a Y chromosome are known to have an increased risk for gonadoblastoma and F G 19 20 21 22 Y other malignant germ cell tumors. A minute Y-derived marker chromosome occasionally found in patients with gonadoblastoma suggests that there is a pathogenetic relationship between a gene Fig. 3. Chromosomal analysis using peripheral lymphocytes by 3 conventional G-banding techniques reveals normal 46,XX kary- on the Y chromosome and gonadoblastoma. The gene involved otypes. in the pathogenetic mechanism of gonadoblastoma is currently 70 Mi-Jung Kim∙Hee-Jeong Ahn∙Ji-Young Kim, et al.

unknown, but GBY (gonadoblastoma locus on Y-chromosome) ma associated with 46,XY pure gonadal dysgenesis. A case report. J and TSPY (testis-specific protein, Y-encoded) have been postu- Korean Med Sci 1993; 8: 380-4. lated to be candidate genes for the development of gonadoblas- 5. Schellhas HF. Malignant potential of the dysgenetic gonad. I . Obstet toma. The GBY gene, which is supposed to be distinct by loca- Gynecol 1974; 44: 298-309. tion and function from the sex-determining region of the Y 6. Schellhas HF. Malignant potential of the dysgenetic gonad. II. Obstet chromosome (SRY), has been putatively suggested to be locat- Gynecol 1974; 44: 455-62. ed either adjacent to the centromere or on the proximal part of 7. Szokol M, Kondrai G, Papp Z. Gonadal malignancy and 46,XY kary- the long arm of the Y chromosome.3 The gene is postulated to otype in a true hermaphrodite. Obstet Gynecol 1977; 49: 358-60. have an undefined physiological function in normal males. In 8. Park IJ, Pyeatte JC, Jones HW, Woodruff JD. Gonadoblastoma in a female, it is said to predispose dysgenetic gonads to develop true hermaphrodite with 46,XY genotype. Obstet Gynecol 1972; 40: malignant tumors.16-18 The pathogenetic mechanism for the fre- 466-72. quent evolution of dysgerminoma in the background of gona- 9. Letterie GS, Page DC. Dysgerminoma and gonadal dysgenesis in a doblastoma also remains to be clarified. We could not perform 46,XX female with no evidence of Y chromosomal DNA. Gynecol DNA studies for the GBY gene in our cases, but the SRY genes Oncol 1995; 57: 423-5. of both patients were not demonstrated by polymerase chain 10. Troche V, Hernandez E. Neoplasia arising in dysgenetic gonads. reaction. Obstet Gynecol Surgery 1986; 41: 74-9. Dysgerminoma and gonadal dysgenesis in a 46,XX female 11. De Bacalao EB, Dominguez I. Unilateral gonadoblastoma in a preg- with no evidence of Y chromosomal DNA have rarely been nant woman. Am J Obstet Gynecol 1969; 105: 1279-81. described.2,9-11 Cytogenetically normal patients who have gona- 12. Talerman A, Delemarre JFM. Gonadoblastoma associated with doblastoma may have the GBY gene on the X chromosome or embryonal carcinoma in an anatomically normal male. J Urol 1975; on the autosomes. However, comprehesive research regarding 113: 355-9. the pathogenetic mechanism of gonadoblastoma occurring in 13. Hughesdon PE, Kumarasamy T. Mixed germ cell tumors (gona- phenotypically normal women is difficult to perform because doblastomas) in normal and dysgenetic gonads. Virchows Arch the cases are very rare. Therefore, the centralization and collab- (Pathol Anat) 1970; 349: 258-80. orative study of the rare cases may be necessary in the future. 14. Nomura K, Matsui T, Aizawa S. Gonadoblastoma with proliferation resembling Sertoli cell tumor. Int J Gynecol Pathol 1999; 18(1): 91-3. 15. Bhathena D, Haning RV, Shapiro S, Hafez GR. Coexistence of a REFERENCES gonadoblastoma and mixed germ cell-sex cord stroma tumor. Pathol Res Pract 1985; 180: 203-6. 1. Scully RE. Gonadoblastoma. A gonadal tumor related to the dys- 16. Page DC. Hypothesis: a Y-chromosomal gene causes gonadoblas- germinoma (seminoma) and capable of sex-hormone production. toma in dysgenetic gonads. Development 1987; 101(Suppl): 151-5. Cancer 1953; 6: 455-63. 17. Hidenbrand R, Schroden W, Brude E, et al. Detection of TSPY pro- 2. Scully RE. Gonadoblastoma. A review of 74 cases. Cancer 1970; 25: tein in a unilateral microscopic gonadoblastoma of a Turner mosa- 1340-56. ic patient with a Y-derived marker chromosome. J Pathol 1999; 189: 3. Petrovic V, Nasioulas S, Chow CW, Voullarie L, Schmidt M, Dahl 623-6. H. Minute chromosome derived marker in a child with gonadoblas- 18. Tsuchiya K, Reijo R, Page DC, Disteche CM. Gonadoblastoma: toma: cytogenetic and DNA studies. J Med Genet 1992; 29: 542-6. molecular definition of the susceptibility region on the Y chromo- 4. Kim SK, Sohn IS, Kim JW, et al. Gonadoblastoma and dysgermino- some. Am J Hum Genet 1995; 57: 1400-7.