Ovotesticular Mixed Germ Cell Tumor in a 46, XY/46, XX Hermaphrodite: A Case Report

We present a 27-year-old true hermaphrodite born with ambiguous genitalia, diagnosed to have an ovotesticular disorder of sexual development (OT-DSD) 46, XY/46, XX karyotype as a young adult. He presented with a 2-month history of an abdominal mass, accompanied by abdominal pain and narrow stools. Work-up was suspicious for a germ cell tumor, hence he underwent exploratory laparotomy, total abdominal hysterectomy, bilateral salphingo-oophorectomy, and bilateral lymph node dissection. Histopathology revealed a left ovarian mixed germ cell tumor: yolk sac tumor (60%) and immature teratoma WHO grade 2 (40%), and right testicular gonadoblastoma (40%) with seminoma (60%). Adjuvant treatment with bleomycin, etoposide, cisplatin for 2 cycles was administered and serial monitoring showed decreasing levels of serum beta-human chorionic gonadotropin and alpha-fetoprotein; however, new cervical and retroperitoneal masses developed. The patient declined surgery, hence second-line combination chemotherapy using paclitaxel, ifosfamide, and cisplatin was started. Due to acute kidney injury and new-onset neurologic symptoms while on treatment, the patient refused further work-up and treatment. Presently, he is on best supportive care. Ovotesticular disorder of sexual development is the rarest disorder of sexual differentiation. It requires the presence of both follicle-containing ovarian tissue and testicular tissue in an individual. Dysgenetic gonads may increase the risk for malignant transformation in 3-5% of cases. We discuss the genetics, gender assignment, pathophysiology, diagnostics, therapeutics and prognosis of such patients. A multi-disciplinary approach is emphasized for these individuals.


Introduction
Disorders of sexual development pertain to discordant genetic and phenotypic sex due to disordered development of the genitalia and gonads. Ovotesticular disorder of sexual development (OT-DSD) or true hermaphroditism is the rarest disorder of sexual differentiation, with an approximate of 500 reported cases worldwide and comprises less than 10% of all DSD [1]. The phenotypic spectrum may vary from normal male or female external genitalia to various degrees of ambiguity. The most common karyotype is 46,XX, followed by 46,XX/46,XY chimerism or mosaicism, and 46,XY [2]. Malignant transformation of dysgenetic gonads increases with the presence of the Y chromosome and has an estimated frequency of 3-5% [1,2]. Germ cell tumors (GCT) arise from primordial cells of the testes and ovaries and account for 5% of ovarian cancers and 95% of testicular cancers.
Diagnosis and management of OT-DSDvaries depending on the age of diagnosis, external and internal genital development, and reproductive capacity. True hermaphrodites also uniquely tackle ethical issues of gender assignment, reproductive, and psychosocial issues. Ovotesticular GCT warrants a multidisciplinary approach due to its rarity and complexity. The purpose of this paper is to present a case of an ovotesticular mixed GCT and to highlight its pathophysiology, diagnosis, treatment, and prognosis.

Case
Our patient is a true hermaphrodite, born full-term via spontaneous vaginal delivery,from a 29-year-old G4P1 (1020) mother with unremarkable prenatal history and non-consanguineous marriage. The patient was noted to have ambiguous genitalia at birth but was raised as a female per mother's decision. No further work-up was done. Developmental milestones, growth stature, and intelligence were normal for age. The patient was reared as a female and pubarche and thelarche occurred at 13 years old. However, delayed pubertal changes were observed and the patient's gender preference shifted to being a male attracted to females. Due to primary amenorrhea and features of masculinization, they sought genetic consult, and chromosomal analysis revealed a mosaic 46, XX/46, XY karyotype when he was age 21.
Six years later, at the age of 27, he sought to consult at our institution due to a two-month history of progressive hypogastric pain associated with a palpable abdominal mass, constipation, and narrow stools. Pertinent physical examination findings included non-dysmorphic facial features, absence of facial hair or acne, female pattern of axillary hair, tanner stage IV of the breast (Figure 1), presence of a palpable, non-tender abdominal mass, tanner stage IV of the pubic hair ( Figure Figure 18) and seminoma (60%, Figure   19). The uterus showed a disordered proliferative endometrium and the cervix had squamous metaplasia. Histopathology was negative for tumors in the right ovarian, fallopian tube, epididymis and seminal vesicle. The bilateral pelvic lymph nodes, omentum, and peritoneal fluid cytology were likewise negative for malignant cells.   The presence of yolk sac tumor in immature teratomas generally reflects a more aggressive behavior and a worse outcome [10].
Surgery is essential for diagnosis, staging, and treatment. Incorporations of platinum agents in both testicular and ovarian GCT is the current standard of care as adjuvant treatment. Cisplatin-based combination chemotherapy can cure patients even with disseminated GCTs [11]. Current category 1 adjuvant treatment regimen for both testicular and ovarian GCT is bleomycin, etoposide, cisplatin (BEP). Assessment of serial tumor markers (β-HCG and AFP) is important to monitor response to treatment wherein decreasing values represent an adequate tumor response; while a plateau or rise in marker levels indicate relapse or resistance to therapy. Typically, a good prognosis is observed in 90% of women with early-stage OGCTs, with up to 80% long term survivors. Good-risk NSGCTs have at least 80% relapse-free survival; however, up to 60% of intermediate or poor-risk NSGCTs relapse and require additional treatment [11].
Our patient had decreasing tumor marker levels after BEP but due to clinical progression, the regimen was shifted to paclitaxel, ifosfamide, cisplatin (TIP). The patient was advised regarding surgical removal of residual disease; however, he did not consent.
Patients with NSGCT may be complicated by the presence of a metastatic teratoma component which is insensitive to chemotherapy, and surgery is the only curative management. A growing teratoma should be considered when a mass grows during chemotherapy especially when serum tumor markers are declining [11].

Summary
Early detection and referral of a patient with ambiguous genitalia can provide improved quality of life, and prevent gender dysphoria and psychosocial dilemmas. Prophylactic removal of the dysgenetic gonad may prevent risk for malignant transformation. Patients with OT-DSDs have normal life spans, normal intelligence, and may have reproductive potentials. Ovotesticular mixed GCT requires individualized holistic treatment plans and entails a multidisciplinary approach which should include psychosocial support for optimal outcomes.