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Gonadoblastoma-Associated Mixed Gonadal Germ Cell Tumor with Dysgerminoma and Hepatoid Yolk Sac Tumor Components in 46XY Gonadal Dysgenesis
Case Report Gonadoblastoma-Associated Mixed Gonadal Germ Cell Tumor with Dysgerminoma and Hepatoid Yolk Sac Tumor Components in 46XY Gonadal Dysgenesis Daniele M. Losada MD 1,*, Cristina L. Benetti-Pinto MD, PhD 2, Liliana A.L.A. Andrade MD, PhD 1 1 2
~o Paulo, Brazil Department of Anatomic Pathology, University of Campinas, Campinas, Sa ~o Paulo, Brazil Department of Obstetrics and Gynecology, University of Campinas, Campinas, Sa
a b s t r a c t Background: Disorders of sex development are congenital conditions with atypical chromosomal, gonadal, or anatomical sex development. Gonadal dysgenesis in patients containing a Y chromosome have a high risk of developing germ cell tumors with potential for malignant transformation. Case: We present the case of a 17-year-old phenotypic female with primary amenorrhea and 46,XY complete gonadal dysgenesis. Pelvic ultrasound showed a solid cystic lesion in the right gonad. Pathology showed a gonadoblastoma-associated mixed gonadal germ cell tumor with dysgerminoma and hepatoid yolk sac tumor. Summary and Conclusion: To our knowledge, this mixed neoplasm association has not been previously reported and this case illustrates the challenges for the diagnosis of gonadal dysgenesis-associated tumors, emphasizing its recognition and prognostic implications. Key Words: disorders of sex development, 46,XY gonadal dysgenesis, Gonadoblastoma, Dysgerminoma, Yolk sac tumor, Primary amenorrhea
Introduction
Disorders of sex development are defined by congenital conditions in which development of chromosomal, gonadal, or genital sex is atypical. They can be classified as: (1) sex chromosome-related; (2) 46,XX-related; or (3) 46,XYrelated.1 Gonadal developmental disorders are congenital conditions with discordance between phenotype, genotype, and hormonal profile.2,3 Gonadal dysgenesis, a form of gonadal developmental disorder, is a condition in which gonadal development is interrupted leading to gonadal dysfunction and encompasses a wide spectrum of phenotypes.3 In gonadal dysgenesis, the presence of a Y chromosome or Y-chromosome material renders the patient at increased risk for developing gonadal tumors that can reach up to 50% in 46, XY genotypes.2 These gonadal neoplasms are mainly germ cell tumors such as gonadoblastoma or carcinoma in situ, with the potential for malignant transformation to dysgerminoma. To prevent the development of malignancy in patients with XY gonadal dysgenesis, gonadectomy is typically recommended. The management of patients with disorders of sex development requires a coordinated and multidisciplinary approach and there is still no consensus regarding the appropriate timing for gonadectomy.3
The authors indicate no conflicts of interest. * Address correspondence to: Daniele M. Losada, MD, Departamento de Anatomia gica, Universidade Estadual de Campinas (UNICAMP), Rua Tess Patolo alia Vieira de Camargo, 126 e Cidade Universit aria Zeferino Vaz CEP 13083-887, Campinas, S~ ao Paulo, Brazil; fax: þ55 19 3421 9306 E-mail address: [email protected] (D.M. Losada).
Some studies correlate gonadal neoplasm in patients with female phenotype, primary amenorrhea, lack of sex chromatin pattern, and presence of Y chromosome. Histopathological analysis is crucial for the diagnosis, because normal pelvic ultrasound or normal magnetic resonance imaging do not rule out neoplasm in patients with gonadal dysgenesis and Y chromosome.4 These cases are challenging for clinicians and pathologists and their correct resolution has important therapeutic and prognostic implications. Herein we describe, to the best of our knowledge, the first case in the literature of gonadoblastoma-associated mixed gonadal germ cell tumor with dysgerminoma and hepatoid yolk sac tumor (YST) components in 46,XY complete gonadal dysgenesis. Case
A 17-year-old, female phenotype (Tanner III breasts, pubis Tanner IV), in primary amenorrhea investigation, with elevated follicle stimulating hormone (102 mIU/mL) and luteinizing hormone (42 mIU/mL). The patient was 160 cm height, 48 kg weight, and the physical examination showed normal female genitalia with visible vaginal orifice, urethral orifice, and a normal size clitoris. The karyotype was 46,XY, with diagnosis of complete gonadal dysgenesis. Pelvic ultrasound showed a small uterus and a solid-cystic lesion with a 2.5-cm diameter in the right ovary; the left ovary was not seen. The patient was submitted to elective gonadectomy. Histologically, the right gonad was heterogeneous presenting undifferentiated gonadal tissue and nests of primitive germ cells involved by sex cord cells, hyaline basal membrane, and microcalcifications, corresponding to
1083-3188/$ - see front matter Ó 2019 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. https://doi.org/10.1016/j.jpag.2019.05.014
D.M. Losada et al. / J Pediatr Adolesc Gynecol 32 (2019) 558e560
559
Fig. 1. Histological features (hematoxylin and eosin stain). (A) Gonadoblastoma: low-power magnification showing nests of primitive germ cells involved by sex cord cells, hyaline basal membrane material, and micro calcification. (B) Dysgerminoma: proliferation of uniform primitive germ cells organized in solid arrangement surrounded by varying amounts of connective tissue stroma containing lymphocytes. (C) Hepatoid yolk sac tumor: eosinophilic, large, polygonal, hepatocyte-like cells organized in solid or in glandular arrangements and hyaline globules.
gonadoblastoma (Fig. 1A). In other areas and mingling with gonadoblastoma, primitive germ cells were observed, with vesicular nuclei and evident nucleoli, clear cytoplasm in solid arrangement surrounded by varying amounts of connective tissue stroma containing lymphocytes, characteristic of dysgerminoma (Fig. 1B). Next to this, other areas exhibited glandular or solid arrangement with large, polygonal and eosinophilic hepatocyte-like cells with a round nuclei and prominent nucleoli and hyaline globules corresponding to YST hepatoid variant (Fig. 1C). The immunohistochemical reactions in gonadoblastoma and dysgerminoma components were OCT 3/4 (octamer binding transcription factor 3/4, primitive germ cell marker) positive and negative for b-human chorionic gonadotrophin, alpha fetoprotein, and CD30. The hepatoid YST expressed alpha
fetoprotein, glypican-3, and HepPar-1 and it was negative for b-human chorionic gonadotrophin and CD30 (Fig. 2). The final diagnosis was gonadoblastoma-associated mixed gonadal germ cell tumor with dysgerminoma and hepatoid YST components on the right gonad. The left gonad was composed of only fibrous tissue without germ cells (streak gonad). Because of the unexpected results of the anatomopathological report, defining the presence of the yolk sac component in the neoplasia, and its incomplete staging during surgery, computed tomography scans of the skull, thorax, and abdomen were performed after surgery. The patient then received 4 cycles of bleomycin (30.00 UI), etoposide (147.50 mg), and cisplatin (29.50 mg) and continues in follow-up in the past 20 months on our service with good clinical and laboratorial responses to the
Fig. 2. Immunohistochemical reactions. (A) Alpha-fetoprotein: granular cytoplasmic positivity in the hepatoid tumor yolk sac component. (B) Alpha-fetoprotein negative in the gonadoblastoma component. (C) Glypican-3: comparing the positive reaction in the hepatoid yolk sac tumor component (right) with the lack of expression in gonadoblastoma (left). (D) HepPar-1: higher-power magnification showing isolated cells exhibiting granular cytoplasmic positivity in the hepatoid yolk sac tumor component.
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D.M. Losada et al. / J Pediatr Adolesc Gynecol 32 (2019) 558e560
treatment, despite her psychological difficulties in accepting the diagnosis of tumor. Summary and Conclusion
Gonadal dysgenesis is classified as complete or partial, depending on gonadal morphology. Incidence of gonadal malignancy in patients with 46,XY complete gonadal dysgenesis range from 37.5% to 45%, in which dysgerminoma corresponds to 22%-66%.3 Immunohistochemical reaction for OCT 3/4, a transcription factor present in embryonic stem cells, is exclusively expressed in neoplasms with pluripotent capacity, such as dysgerminoma.5 In the reported case OCT 3/4 exhibited positive nuclear staining in gonadoblastoma and dysgerminoma components. However, this marker is not able to distinguish between dysgerminoma and embryonal carcinoma so, CD30 evaluation was necessary because it is frequently expressed in embryonal carcinoma but is absent in dysgerminoma.5 In the present case CD30 was negative pointing to the diagnosis of dysgerminoma. Although a standard prognostic system for germ cell tumors in gonadal dysgenesis is currently unavailable, some studies associate poor prognostic indicators including large size, unfavorable histological types, and advanced stage at presentation.6 Mixed germ cell tumors, which might show almost any combination of components, are common in the testis but rare in the ovary. The most common combination reported in ovary is dysgerminoma and YST (one-third of the cases). YST presents a morphological spectrum of neoplastic endodermal differentiation with heterogeneous histology exhibiting an overlapping immunophenotype. The YST hepatoid variant is characterized by the presence of large polygonal cells with abundant eosinophilic cytoplasm growing in compact masses separated by thin fibrous bands resembling hepatocellular carcinoma.7 The differential diagnosis of hepatoid variant of YST included hepatoid carcinoma, metastatic hepatocellular carcinoma, and embryonal carcinoma.8 Hepatoid carcinoma arises in
elderly individuals and in most cases shows elevated serum alpha-fetoprotein level.8 The possibility of metastatic hepatocellular carcinoma is ruled out with imaging studies and postoperative normalization of serum alpha fetoprotein. Embryonal carcinoma cells are more atypical than hepatoid YST, express CD30, and usually contains syncytiotrophoblastic giant cells, which were absent in the present case. Clinically, hepatoid YST occurs mostly in young adults generally associated with a high level of serum alphafetoprotein and poor prognosis. Microscopically these tumors show typical areas of YST associated with hyaline globules.8 Hepatoid YST cells are immunoreactive for alpha fetoprotein, a-1-antitrypsin, albumin, carcinoembryonic antigen, and epithelial membrane antigen, and occasionally produce bile in canalicular-like structures.8 In conclusion, the present case emphasizes the challenge for differential diagnosis and prognostic implications for patients with gonadal dysgenesis during the investigation of primary amenorrhea.
References 1. Hughes IA, Houk C, Ahmed SF, et al: Consensus statement on management of intersex disorders. J Pediatr Urol 2006; 2:148 2. Hennes E, Zahn S, Lopes LF, et al: Molecular genetic analysis of bilateral ovarian germ cell tumors. Klin Padiatr 2012; 224:359 3. McCann-Crosby B, Mansouri R, Dietrich JE, et al: State of the art review in gonadal dysgenesis: challenges in diagnosis and management. Int J Pediatr Endocrinol 2014; 2014:4 4. Ebert KM, Hewitt GD, Indyk JA, et al: Normal pelvic ultrasound or MRI does not rule out neoplasm in patients with gonadal dysgenesis and Y chromosome material. J Pediatr Urol 2018; 14:154.e1 5. Cossu-Rocca P, Jones TD, Roth LM, et al: Cytokeratin and CD30 expression in dysgerminoma. Hum Pathol 2006; 37:1015 6. Murugaesu N, Schmid P, Dancey G, et al: Malignant ovarian germ cell tumors: identification of novel prognostic markers and long-term outcome after multimodality treatment. J Clin Oncol 2006; 24:4862 7. Prat J, Bhan AK, Dickersin GR, et al: Hepatoid yolk sac tumor of the ovary (endodermal sinus tumor with hepatoid differentiation): a light microscopic, ultrastructural and immunohistochemical study of seven cases. Cancer 1982; 50:2355 8. Horie Y, Kato M: Hepatoid variant of yolk sac tumor of the testis. Pathol Int 2000; 50:754
~o Paulo, Brazil Department of Anatomic Pathology, University of Campinas, Campinas, Sa ~o Paulo, Brazil Department of Obstetrics and Gynecology, University of Campinas, Campinas, Sa
a b s t r a c t Background: Disorders of sex development are congenital conditions with atypical chromosomal, gonadal, or anatomical sex development. Gonadal dysgenesis in patients containing a Y chromosome have a high risk of developing germ cell tumors with potential for malignant transformation. Case: We present the case of a 17-year-old phenotypic female with primary amenorrhea and 46,XY complete gonadal dysgenesis. Pelvic ultrasound showed a solid cystic lesion in the right gonad. Pathology showed a gonadoblastoma-associated mixed gonadal germ cell tumor with dysgerminoma and hepatoid yolk sac tumor. Summary and Conclusion: To our knowledge, this mixed neoplasm association has not been previously reported and this case illustrates the challenges for the diagnosis of gonadal dysgenesis-associated tumors, emphasizing its recognition and prognostic implications. Key Words: disorders of sex development, 46,XY gonadal dysgenesis, Gonadoblastoma, Dysgerminoma, Yolk sac tumor, Primary amenorrhea
Introduction
Disorders of sex development are defined by congenital conditions in which development of chromosomal, gonadal, or genital sex is atypical. They can be classified as: (1) sex chromosome-related; (2) 46,XX-related; or (3) 46,XYrelated.1 Gonadal developmental disorders are congenital conditions with discordance between phenotype, genotype, and hormonal profile.2,3 Gonadal dysgenesis, a form of gonadal developmental disorder, is a condition in which gonadal development is interrupted leading to gonadal dysfunction and encompasses a wide spectrum of phenotypes.3 In gonadal dysgenesis, the presence of a Y chromosome or Y-chromosome material renders the patient at increased risk for developing gonadal tumors that can reach up to 50% in 46, XY genotypes.2 These gonadal neoplasms are mainly germ cell tumors such as gonadoblastoma or carcinoma in situ, with the potential for malignant transformation to dysgerminoma. To prevent the development of malignancy in patients with XY gonadal dysgenesis, gonadectomy is typically recommended. The management of patients with disorders of sex development requires a coordinated and multidisciplinary approach and there is still no consensus regarding the appropriate timing for gonadectomy.3
The authors indicate no conflicts of interest. * Address correspondence to: Daniele M. Losada, MD, Departamento de Anatomia gica, Universidade Estadual de Campinas (UNICAMP), Rua Tess Patolo alia Vieira de Camargo, 126 e Cidade Universit aria Zeferino Vaz CEP 13083-887, Campinas, S~ ao Paulo, Brazil; fax: þ55 19 3421 9306 E-mail address: [email protected] (D.M. Losada).
Some studies correlate gonadal neoplasm in patients with female phenotype, primary amenorrhea, lack of sex chromatin pattern, and presence of Y chromosome. Histopathological analysis is crucial for the diagnosis, because normal pelvic ultrasound or normal magnetic resonance imaging do not rule out neoplasm in patients with gonadal dysgenesis and Y chromosome.4 These cases are challenging for clinicians and pathologists and their correct resolution has important therapeutic and prognostic implications. Herein we describe, to the best of our knowledge, the first case in the literature of gonadoblastoma-associated mixed gonadal germ cell tumor with dysgerminoma and hepatoid yolk sac tumor (YST) components in 46,XY complete gonadal dysgenesis. Case
A 17-year-old, female phenotype (Tanner III breasts, pubis Tanner IV), in primary amenorrhea investigation, with elevated follicle stimulating hormone (102 mIU/mL) and luteinizing hormone (42 mIU/mL). The patient was 160 cm height, 48 kg weight, and the physical examination showed normal female genitalia with visible vaginal orifice, urethral orifice, and a normal size clitoris. The karyotype was 46,XY, with diagnosis of complete gonadal dysgenesis. Pelvic ultrasound showed a small uterus and a solid-cystic lesion with a 2.5-cm diameter in the right ovary; the left ovary was not seen. The patient was submitted to elective gonadectomy. Histologically, the right gonad was heterogeneous presenting undifferentiated gonadal tissue and nests of primitive germ cells involved by sex cord cells, hyaline basal membrane, and microcalcifications, corresponding to
1083-3188/$ - see front matter Ó 2019 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. https://doi.org/10.1016/j.jpag.2019.05.014
D.M. Losada et al. / J Pediatr Adolesc Gynecol 32 (2019) 558e560
559
Fig. 1. Histological features (hematoxylin and eosin stain). (A) Gonadoblastoma: low-power magnification showing nests of primitive germ cells involved by sex cord cells, hyaline basal membrane material, and micro calcification. (B) Dysgerminoma: proliferation of uniform primitive germ cells organized in solid arrangement surrounded by varying amounts of connective tissue stroma containing lymphocytes. (C) Hepatoid yolk sac tumor: eosinophilic, large, polygonal, hepatocyte-like cells organized in solid or in glandular arrangements and hyaline globules.
gonadoblastoma (Fig. 1A). In other areas and mingling with gonadoblastoma, primitive germ cells were observed, with vesicular nuclei and evident nucleoli, clear cytoplasm in solid arrangement surrounded by varying amounts of connective tissue stroma containing lymphocytes, characteristic of dysgerminoma (Fig. 1B). Next to this, other areas exhibited glandular or solid arrangement with large, polygonal and eosinophilic hepatocyte-like cells with a round nuclei and prominent nucleoli and hyaline globules corresponding to YST hepatoid variant (Fig. 1C). The immunohistochemical reactions in gonadoblastoma and dysgerminoma components were OCT 3/4 (octamer binding transcription factor 3/4, primitive germ cell marker) positive and negative for b-human chorionic gonadotrophin, alpha fetoprotein, and CD30. The hepatoid YST expressed alpha
fetoprotein, glypican-3, and HepPar-1 and it was negative for b-human chorionic gonadotrophin and CD30 (Fig. 2). The final diagnosis was gonadoblastoma-associated mixed gonadal germ cell tumor with dysgerminoma and hepatoid YST components on the right gonad. The left gonad was composed of only fibrous tissue without germ cells (streak gonad). Because of the unexpected results of the anatomopathological report, defining the presence of the yolk sac component in the neoplasia, and its incomplete staging during surgery, computed tomography scans of the skull, thorax, and abdomen were performed after surgery. The patient then received 4 cycles of bleomycin (30.00 UI), etoposide (147.50 mg), and cisplatin (29.50 mg) and continues in follow-up in the past 20 months on our service with good clinical and laboratorial responses to the
Fig. 2. Immunohistochemical reactions. (A) Alpha-fetoprotein: granular cytoplasmic positivity in the hepatoid tumor yolk sac component. (B) Alpha-fetoprotein negative in the gonadoblastoma component. (C) Glypican-3: comparing the positive reaction in the hepatoid yolk sac tumor component (right) with the lack of expression in gonadoblastoma (left). (D) HepPar-1: higher-power magnification showing isolated cells exhibiting granular cytoplasmic positivity in the hepatoid yolk sac tumor component.
560
D.M. Losada et al. / J Pediatr Adolesc Gynecol 32 (2019) 558e560
treatment, despite her psychological difficulties in accepting the diagnosis of tumor. Summary and Conclusion
Gonadal dysgenesis is classified as complete or partial, depending on gonadal morphology. Incidence of gonadal malignancy in patients with 46,XY complete gonadal dysgenesis range from 37.5% to 45%, in which dysgerminoma corresponds to 22%-66%.3 Immunohistochemical reaction for OCT 3/4, a transcription factor present in embryonic stem cells, is exclusively expressed in neoplasms with pluripotent capacity, such as dysgerminoma.5 In the reported case OCT 3/4 exhibited positive nuclear staining in gonadoblastoma and dysgerminoma components. However, this marker is not able to distinguish between dysgerminoma and embryonal carcinoma so, CD30 evaluation was necessary because it is frequently expressed in embryonal carcinoma but is absent in dysgerminoma.5 In the present case CD30 was negative pointing to the diagnosis of dysgerminoma. Although a standard prognostic system for germ cell tumors in gonadal dysgenesis is currently unavailable, some studies associate poor prognostic indicators including large size, unfavorable histological types, and advanced stage at presentation.6 Mixed germ cell tumors, which might show almost any combination of components, are common in the testis but rare in the ovary. The most common combination reported in ovary is dysgerminoma and YST (one-third of the cases). YST presents a morphological spectrum of neoplastic endodermal differentiation with heterogeneous histology exhibiting an overlapping immunophenotype. The YST hepatoid variant is characterized by the presence of large polygonal cells with abundant eosinophilic cytoplasm growing in compact masses separated by thin fibrous bands resembling hepatocellular carcinoma.7 The differential diagnosis of hepatoid variant of YST included hepatoid carcinoma, metastatic hepatocellular carcinoma, and embryonal carcinoma.8 Hepatoid carcinoma arises in
elderly individuals and in most cases shows elevated serum alpha-fetoprotein level.8 The possibility of metastatic hepatocellular carcinoma is ruled out with imaging studies and postoperative normalization of serum alpha fetoprotein. Embryonal carcinoma cells are more atypical than hepatoid YST, express CD30, and usually contains syncytiotrophoblastic giant cells, which were absent in the present case. Clinically, hepatoid YST occurs mostly in young adults generally associated with a high level of serum alphafetoprotein and poor prognosis. Microscopically these tumors show typical areas of YST associated with hyaline globules.8 Hepatoid YST cells are immunoreactive for alpha fetoprotein, a-1-antitrypsin, albumin, carcinoembryonic antigen, and epithelial membrane antigen, and occasionally produce bile in canalicular-like structures.8 In conclusion, the present case emphasizes the challenge for differential diagnosis and prognostic implications for patients with gonadal dysgenesis during the investigation of primary amenorrhea.
References 1. Hughes IA, Houk C, Ahmed SF, et al: Consensus statement on management of intersex disorders. J Pediatr Urol 2006; 2:148 2. Hennes E, Zahn S, Lopes LF, et al: Molecular genetic analysis of bilateral ovarian germ cell tumors. Klin Padiatr 2012; 224:359 3. McCann-Crosby B, Mansouri R, Dietrich JE, et al: State of the art review in gonadal dysgenesis: challenges in diagnosis and management. Int J Pediatr Endocrinol 2014; 2014:4 4. Ebert KM, Hewitt GD, Indyk JA, et al: Normal pelvic ultrasound or MRI does not rule out neoplasm in patients with gonadal dysgenesis and Y chromosome material. J Pediatr Urol 2018; 14:154.e1 5. Cossu-Rocca P, Jones TD, Roth LM, et al: Cytokeratin and CD30 expression in dysgerminoma. Hum Pathol 2006; 37:1015 6. Murugaesu N, Schmid P, Dancey G, et al: Malignant ovarian germ cell tumors: identification of novel prognostic markers and long-term outcome after multimodality treatment. J Clin Oncol 2006; 24:4862 7. Prat J, Bhan AK, Dickersin GR, et al: Hepatoid yolk sac tumor of the ovary (endodermal sinus tumor with hepatoid differentiation): a light microscopic, ultrastructural and immunohistochemical study of seven cases. Cancer 1982; 50:2355 8. Horie Y, Kato M: Hepatoid variant of yolk sac tumor of the testis. Pathol Int 2000; 50:754