Introduction

Malignant germ cell tumors (MGCTs) are rare tumors that account for 2–3% of all ovarian cancers. They generally occur in adolescents and young women of the reproductive age group. The median age at diagnosis is 16–20 years with the 15–19-year-old group having the highest incidence [1]. The prognosis of patients with GCT has improved drastically in the last few decades after the introduction of platinum-based chemotherapy [2, 3]. Fertility-sparing surgery (preservation of one ovary and uterus) whenever feasible with or without adjuvant chemotherapy is the standard treatment approach for young patients with malignant ovarian germ cell tumor (MOGCT) [4, 5]. Approximately 30–40% of patients with malignant germ cell tumor ovary are diagnosed at an advanced stage [1, 6]. Upfront fertility-sparing surgery may not be feasible in these women due to poor performance status, large tumor load, bilateral ovarian disease, or large tumors infiltrating the uterus. Neoadjuvant chemotherapy (NACT) followed by conservative surgery might be considered for such patients [1, 2, 7, 8]. This study aimed to analyze the feasibility and pattern of fertility-sparing surgery in patients who received NACT for advanced malignant germ cell tumor ovary and to assess the menstrual and reproductive function in such patients.

Materials and Methods

This is a retrospective study of patients who underwent surgery following neoadjuvant chemotherapy for advanced germ cell tumor of the ovary from January 2008 to March 2019. Demographic data, clinical manifestations, tumor markers, imaging, FIGO stage, histology, details of chemotherapy, surgical procedure, and reproductive function including menstrual status and pregnancy after fertility-sparing surgery were collected from medical records. The diagnosis of malignant germ cell tumor of the ovary was made based on clinical features, tumor markers, and cytology or biopsy from the tumor. Computerized tomography (CT) scan of the chest, abdomen, and pelvis was done in all patients to assess the extent of the disease. Patients with poor performance status, extensive peritoneal deposits not amenable to primary surgery, and tumors adherent to the uterus were treated with 3–4 courses of Bleomycin, Etoposide, and Cisplatin (BEP) regimen. After completing chemotherapy, the disease status was reassessed by tumor marker assay and CT scan of the pelvis, abdomen, and chest. All patients underwent surgery. After treatment, they were followed up with clinical examination and tumor markers every 3 months during the first 2 years, every 6 months for the next 3 years and then yearly. Abdominal and pelvic ultrasound was done every 6 months and CT was done when clinically indicated. Follow-up data were collected from hospital records. The study was approved by the institutional review board.

Results

Twenty-eight patients with MOGCT underwent surgery following NACT at our department during this period and were included in this study. The median follow-up period was 76 months (range: 7–133 months). The median age was 16.5 years (range 7-31 years). Twenty-one (75%) patients were post-menarcheal and none of them reported any menstrual irregularities at the time of presentation. Four patients were parous. The most common presenting symptom was abdominal pain (67.8%) followed by abdominal distension (42.8%). Ten patients had massive ascites and nine patients had pleural effusion. Twelve patients (42.8%) had yolk sac tumor, ten (35.7%) had dysgerminoma and six (21.5%) had mixed germ cell tumor with four of them having yolk sac component. The patient characteristics are shown in Table 1.

Table 1 Characteristics of 28 patients with malignant ovarian germ cell tumor
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One patient had extensive disease at laparotomy and fertility preservation was not feasible, for which she was sent for NACT. The rest of the patients had clinical and radiological evidence of extensive disease and underwent NACT after cytology or guided biopsy from the tumor. Twenty-three (82.2%) patients received four cycles of NACT and four patients (14.3%) received three cycles. One patient (3.5%) received one cycle at a local hospital for extensive-stage III disease. CT done at our center showed good interval response and she was taken for cytoreduction. None of the patients had progressive disease while on chemotherapy. CT scan done following NACT showed near total treatment response and all patients underwent cytoreductive surgery. Among them, 24 patients (85.8%) underwent fertility-sparing surgery- unilateral salpingo-oophorectomy, two patients had bilateral salpingo-oophorectomy with preservation of the normal uterus and the remaining two patients had a total hysterectomy and bilateral salpingo-oophorectomy. The details of the surgery are shown in Table 2. Both the patients who underwent hysterectomy with bilateral salpingo-oophorectomy were not keen on fertility preservation as they had completed their family, even though fertility preservation was feasible. Among patients who wanted to retain fertility, fertility-sparing surgery was feasible in 92.3% (24/26) patients. Two patients who underwent bilateral salpingo-oophorectomy had bilateral ovarian disease at presentation and persistent large residual masses in both ovaries at laparotomy. During surgery, extensive tumor deposits were noted in seven patients (25%). But optimal cytoreduction could be achieved in all. Final pathological examination showed a complete pathological response in 25 (89.3%) patients. Two patients with mixed germ cell tumors had elements of mature teratoma in the final pathology specimen. A tiny focus of residual tumor was noted in the ovary in three patients. One of them had received only one cycle of NACT and received three cycles of adjuvant chemotherapy after surgery. The other two patients had completed four cycles of NACT and were kept under close follow-up. They are disease-free seven years and one year after surgery. Three of our patients who had received three cycles of NACT each before surgery received one cycle of adjuvant chemotherapy with Etoposide and Cisplatin (EP).

Table 2 Details of surgery
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Twenty-five patients (89.2%) are under regular follow-up. One patient lost to follow-up was 6 months pregnant at the time of the last follow-up. She had been coming for regular follow-up visits for six years until her pregnancy. One patient, who initially presented with stage IV dysgerminoma died due to disease recurrence. The patient had presented in poor general condition with bilateral adnexal masses, extensive peritoneal deposits, massive pleural effusion, and metastatic left supraclavicular node. She received neoadjuvant chemotherapy and underwent surgery after three cycles as she responded well to NACT. During surgery, she was found to have residual disease only in her ovaries and underwent bilateral salpingo-oophorectomy as both the ovaries were completely replaced by tumor. This was followed by one cycle of adjuvant chemotherapy. Six months later she presented with multiple recurrences in the peritoneal cavity and with pleural effusion. She was started on second-line chemotherapy with Paclitaxel, Ifosfamide, and Cisplatin (TIP). While on second-line chemotherapy, she had progressive disease and succumbed to the disease.

Of the 21 patients who had fertility-sparing surgery and are currently under follow-up, 16 (76.1%) reported resumption of regular menstrual cycles with a normal flow while one patient complained of irregular menstrual cycles following chemotherapy. Two of our patients had a history of primary amenorrhea before their malignancy and two are still premenarcheal. Three patients attained menarche within 2 years of completion of treatment. All the patients regained their menstrual function within 6 months of completing chemotherapy. Two patients who underwent fertility-sparing surgery were diagnosed with a benign cyst of the retained ovary during follow-up. One of them proceeded to have a hysterectomy and salpingo-oophorectomy as she had completed her family and the other patient is currently under follow-up and is disease-free.

In this study, three patients tried for pregnancy and had a total of four pregnancies. Two patients wanted to delay their pregnancy and 13 are not yet married. All three patients conceived spontaneously and none of them reported any abortions. One woman became pregnant twice and had two live births. One patient got lost to follow-up during pregnancy and the other patient delivered a term baby. All three babies are healthy and reported no anomalies. Details of menstrual function after chemotherapy and pregnancy in patients who underwent fertility-sparing surgery are given in Table 3.

Table 3 Menstrual function and pregnancy in patients who underwent fertility-sparing surgery
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Discussion

Even though MOGCTs are rare tumors, they mostly occur during adolescence and early adulthood and have an enormous impact on the reproductive outcome of these patients. Before the introduction of chemotherapy, most of these patients used to undergo radical surgeries and had a very poor prognosis. Over the last three decades, the highly chemosensitive nature of these tumors has been proven by various studies [2, 3]. With the reported 5-year overall survival rate of 100% for dysgerminomas and 85% for non-dysgerminomas, the reproductive outcome of these patients following treatment is considered important [4].

The median age of the patients in our study was 16.5 years which is similar to other studies and preservation of fertility is of utmost importance to these patients [7, 9]. Twelve (43%) patients in our study had yolk sac tumor of the ovary with a median AFP of 3.3 × 104 and another four patients had mixed germ cell tumor with yolk sac components. Yolk sac tumors are highly aggressive malignancies with around 30–40% presenting in the International Federation of Gynecology and Obstetrics (FIGO) stage III or IV [10]. Patients with yolk sac tumor often have tumor infiltrating the uterus and adjacent structures and their general condition is often too poor to tolerate primary surgery [11]. None of our patients had a diagnosis of pure immature teratoma based on pre-chemotherapy tumor marker levels and biopsy. Various studies suggest that patients with pure immature teratoma of the ovary present early and can be treated by primary surgery with or without adjuvant chemotherapy [12, 13]. In the study by Alwazzan et al. [12] among 27 patients, 25 presented with either stage I or stage II disease. Primary surgery could be done on all patients.

Neoadjuvant chemotherapy is being increasingly used in patients with bulky MOGCTs to increase the chance of successful fertility preservation and to minimize the extent of surgery required to achieve maximal cytoreduction [1]. In the study by Talukdar et al., the efficacy of NACT followed by fertility-preserving surgery in patients with advanced or bulky MOGCT was compared with standard treatment [7]. They reported comparable survival outcomes between the two groups. Lu et al. studied the role of NACT in patients with advanced ovarian Yolk sac of the tumor [11]. They reported that NACT followed by cytoreductive surgery resulted in better optimal cytoreduction, less perioperative morbidity and similar progression-free survival compared to patients who underwent primary surgery. These studies show that NACT followed by surgery might be a reasonable option for patients with advanced malignant germ cell tumor of the ovary having an extensive intraabdominal disease where fertility preservation might not be possible or where the poor general condition of the patient precludes primary surgery. All our patients had received NACT because of advanced-stage disease. They showed good responses to chemotherapy and the majority of them could undergo fertility-sparing surgery. In the study by Husaini et al. among 65 patients with ovarian dysgerminomas who underwent primary surgery, bilateral oophorectomy \(\pm \) hysterectomy had to be done in 18.4% of patients while in our study, 92% of patients who wished to preserve fertility could undergo fertility-sparing surgery [14].

Various studies have shown that patients who undergo primary fertility-preserving surgery followed by adjuvant chemotherapy have a good reproductive function after treatment [15,16,17,18]. In the study by Tamuchi et al. among 105 patients with malignant germ cell tumor of the ovary who underwent fertility-sparing treatment, 42 of 45 patients who desired children became pregnant and had a total of 65 pregnancies [19]. Our study showed that patients who receive NACT followed by fertility-preserving surgery can regain menstrual function and maintain fertility after treatment. Excluding two patients who were diagnosed with primary amenorrhea before the diagnosis of malignancy and two patients who are still premenarcheal, all our patients who underwent fertility-sparing surgery have resumed menstruation within 6 months following completion of chemotherapy. In our study, there are too few patients who attempted pregnancy, but all three patients who tried conceived naturally without any assisted reproductive techniques. In the study by Talukdar et al., 18 of 21 patients who received NACT resumed regular menstruation and ten patients became pregnant which was comparable to the standard treatment group in their study [7].

In conclusion, when fertility preservation is not feasible, NACT followed by cytoreductive surgery might be considered in patients with advanced malignant germ cell tumor of the ovary. NACT followed by surgery can result in complete cytoreduction, with a high chance of fertility preservation and good menstrual and reproductive outcome. This requires a multidisciplinary approach considering the age of the patient and future fertility wishes after proper oncofertility counseling.