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A Rare Case of Mixed Gonadal Dysgenesis with Malignant Mixed Germ Cell Tumor

Mamatha Basavaraju, Dhiraj K Balaji

Pediatric Surgery Department, Vydehi Institute of Medical Sciences and Research Centre, Whitefield, Banagalore, India

 

Correspondence:

Mamatha Basavaraju

Pediatric Surgery Department

Vydehi Institute of Medical Sciences and Research Centre

Whitefield, Banagalore, 560066, India

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Abstract

Mixed gonadal dysgenesis (MGD) comprises a heterogeneous group of diverse chromosomal, gonadal, and phenotypic abnormalities. MGD with 46 XO/XY mosaicism usually has a male phenotype(90%). We present a child with a rare case of XO/XY mosaicismreared as female. The child had abdominal distension and an abdominal mass for 2 years but was neglected until she developed features of intestinal obstruction. She had a prominent clitoris since birth butit was not of concern to the family untilit grewsignificantly at puberty. Though initially we attributed the clitoromegaly to be due to virilization from mixed germ cell tumor, later on further evaluation with karyotyping and intraoperative inspection we confirmed the diagnosis of mixed gonadal dysgenesis. The patient was successfully managed with neoadjuvent chemotherapy and excision of residual tumor.

Keywords: mixed gonadal dysgenesis, mixed germ cell tumor, intestinal obstruction

 

Introduction

Mixed gonadal dysgenesis (MGD) is usually diagnosed during evaluation for infertility, hypospadias or cryptorchidism in males or virilisation in females. One third of the patients with mixed gonadal dysgenesis have the risk to develop gonadoblastoma and another 1/3 of these gonadoblastomas are associated with malignant germ cell tumors such as germinoma, endodermal sinus tumor, immature teratoma, embryonal carcinoma, or choriocarcinoma [1, 2]. We present a rare case of mixed gonadal dysgenesis diagnosed when the child was admitted with advanced stage malignant tumor of the abdomen andwho was not evaluated for ambiguous genitalia until she developed bowel obstruction due to the tumor.

Case report

A 12 year old child,reared asfemale, presented to the pediatric emergency unit with a history of abdominal pain and gradual distention in the last 2 years. The parents also reported loss of weight and poor appetite for 1 month and bilious vomiting for 2 days. There was a history of a prominent clitoris since birth and a sudden increase in size noticed 2 years ago.

On physical examination a solid mass could be palpated occupying almost 2/3 of the abdomen.The child had clitoromegaly (stretched length of 8 cm), labia minorawas not well developed, the urethral opening and vaginal opening seen as 2 separate orifices - Prader stage 2 (Fig. 1).

Figure 1: Local exam showing clitoromegaly, underdeveloped labia minora, urethral opening and a vaginal opening as 2 separate orifices (Prader stage 2)

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Computer tomography (CT) of the abdomen and pelvis showed a left ovarian solid/ cysticmass of 87/149/158 mm extending superiorly up to the pancreas, displacing the uterus and bowel to the right, with features of partial bowel obstruction and “omental cake” (Fig. 2 A and 2B).

Figure 2A and 2 B: CT of the abdomen and pelvis showing the left ovarian mass

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Ultrasonography-guided (USG) fine needle aspiration cytology (FNAC) showed features suggestive of immature teratoma or mixed germ cell tumor (Fig.3). Blood tests showed elevated ß- hCG- 209 m IU/ml (normal value 0.5- 2.9mIU/ml) and alpha-fetoprotein (AFP)>3,000 ng/ml (normal value < 9 ng/ml) suggesting a probable mixed germ cell tumor. She was simultaneously evaluated for clitoromegaly and found to have an elevated testosterone level 108ng/dl (normal value15-70ng/ dl) however ACTH and17-hydroxyprogesterone were normal. Karyotype showed XO/XY mosaicism and an extra copy of Y chromosome translocation to chromosome 14.

 

Figure 3: Fine needle aspiration cytology (FNAC) from tumor – mature polygonal cells with eosinophilic cytoplasm along with columnar and cuboidal cells. Many atypical cells distributed in papillary and acinar-like structures with marked nuclear pleomorphism and high N:C ratio.

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She was started immediatelyonbleomycin, etoposide, cisplatin (BEP) chemotherapy due to the voluminous mass with features of subacute intestinal obstruction and probable omental involvement. After the 1st cycle of chemotherapy, the obstruction resolved. CT scan was repeated after 3 cycles but there was no further resolution in size of the mass.

The patient was taken to surgery and was operated under epidural anesthesia. One hundred percent oxygen was avoided since it can precipitate pulmonary damage in patients who have received preoperative bleomycine chemotherapy. At laparotomy a large ovarian tumor with 15/18cm in size was noted with 2 turns of torsion and extensive adhesion to the greater omentumand colon (Fig. 4). Left salphingo-oophorectomy was done along with excision of the greater omentum and release of the colonic adhesions.

 

Figure 4: Large ovarian tumor at laparotomy with 2 turns of torsion and extensive adhesion to greater omentum and colon.

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Uterus appeared rudimentary with streak right gonadalfeatures (Fig. 5). She underwent clitoroplasty during the same surgical intervention.Histopathologic exam of the left ovarian mass showed extensive necrosis witha mature cystic teratomatous component (Fig. 6). Para aortic lymph nodes, peritoneal washings and omentum were free of any metastasis. During follow-up period testosterone , AFP and ß-hCG were normal.

Figure 5: Rudimentary uterus and right streak gonad.

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Figure 6: Histopathological exam - fibromyxoid areas, hair follicles, glandular elements and squamous lined epithelium with no malignant changes, large areas of necrosis and features consistent with mature cystic teratoma

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Discussion

Our female patient came from a remote area witha history of gradual abdominal distension and palpable abdominal mass for 2 years but who was neglected until she developed features of intestinal obstruction. She was known to have a prominent clitoris since birth which became significantly enlarged only at puberty. For these reasons, she was evaluatedfor ambiguous genitalia only when she developed an abdominal tumor causing intestinal obstruction. Mixed gonadal dysgenesis comprises a heterogeneous group of diverse chromosomal, gonadal, and phenotypic abnormalities.

External genitalia in mixed gonadal dysgenesis can have a phenotype ranging from female to male [3],depending on the presence or absence of the testis-determining SRY gene, on the degree of mosaicism and the tissue distribution of the 45,X cell line[4]. Ninety percent of XO/XY mosacism have normal male genitalia, 5 % have female phenotype and 5% have ambiguous genitalia with hypertrophy of clitoris or hypospadias and cryptorchidism.

Internal genitalia may have remnants of the Müllerian duct structure, rudimentary uterus, and fallopian tube because of the anti-Müllerian hormone (AMH)deficiency or the paramesonephric ducts which do not respond to normal AMH.XO/XY mosaics presenting with ambiguous genitalia like our child usually have dysgenetic testis on one side and a contralateral streak gonad. The various combinations are:(a) testis plus contralateral streak gonad, (b) testis and contralateral gonadal agenesis, (c) hypoplastic gonads with tubules in one gonad or (d) streak gonad with contralateral tumor[5]. Dysgenetictestes aremore prone to neoplastic transformation than the streak gonad[6].

The risk for gonadoblastoma is low in those with a complete male phenotype and high in those with ambiguous genitalia and XO/XY mosaics with female phenotype(30%). Gonadoblastomaby itself is not malignant but 30% of gonadoblastomas are associated with more malignant germ cell tumors, such as germinoma, endodermal sinus tumor, immature teratoma, embryonal carcinoma, or choriocarcinoma[1, 2]. Hence, bilateral gonadectomy is recommended as soon as possible in individuals with MGD and female phenotype containing Y-chromosome material like in our case. In this case it is important that bilateral gonadectomy to be performed before the patient reaches puberty, not only to prevent the development of malignant tumors, but also to avoid virilization if the patient is to be raised as a female. Removal of gonad in MGD with a male phenotype is controversial, but since they can still have dysgenetic testis it will require regular follow-up with ultrasound and testicular biopsies [7]. Our child had a very voluminous mass and features of intestinal obstruction - Children's Oncology Group (COG) staging 3 so we decided to start her on neoadjuventchemotherapy. National Guideline Clearinghouse states that neoadjuvant chemotherapy can be considered for patients with extensive intra-abdominal disease, when initial debulking surgery is not an option.She was operated after 3 cycles of chemotherapy.

The histopathological exam of the specimen showed extensive necrosis and a mature teratomatous component, which may be attributed to chemotherapy-related changes. There are very few studies describing the chemotherapy induced changes and its prognosis in malignant germ cell tumors. The histological appearances of post chemotherapy residual mass may be heterogeneous with a mixture of fibrosis, necrosis, mature teratoma and residual malignant tissue [8]. Donohue et al. [9] studied the histological changes induced by chemotherapy in 73 patients with advanced non-seminomatous germ cell tumors of the testis which showed that 22% had histological evidence of residual tumor, 44% differentiated (mature) teratoma and 34% fibrosis and/or necrosis. Kesler et al. [10] found that complete necrosis in the residual mass predicted excellent survival compared toevidence of mature teratoma.

Hyperoxic exposure during general anesthesia after receiving bleomycin treatment is supose to potentiate bleomycin-induced pulmonary toxicity especially if operating within 6 months of receiving chemotherapy. After oxygen exposure, ferrous bleomycin compounds can induce reactive oxygen-free radicals and cause cell damage. Maintaining a FiO2 < 30% during surgery is considered safe [11]. This is the reason our child was operated under epidural anesthesia avoiding hyperoxia. Our patient has been on close follow-upfor 1 year and is disease free. She will require contralateral gonadectomy and estrogen replacement in future.

Conclusion

Mixed germ cell tumors withvirilisation are rare and in such cases, potential disorders of sexual differentiation must be evaluated . Mixed germ cell tumors in a case of mixed gonadal dysgenesis presenting in advanced stage can be managed successfully with neoadjuvant chemotherapy and excision of residual tumor.



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