Malignant germ cell tumor (MGCT) is a rare entity in the female genital system. Ovarian malignant germ cell tumors (MOGCTs) are highly malignant, rapidly growing, and have a peak incidence in women under the age of 20 years [1]. MOGCTs account for 5% of all ovarian malignancies in Western countries, but may represent approximately 15% of ovarian cancers in Asians and in blacks [2]. However, Surveillance, Epidemiology, and End Results (SEER) data (1973 to 2002) demonstrated lower rates of MOGCTs in blacks than whites and other nonwhites, and an increased incidence for Asian/Pacific Islanders and Hispanics [3]. The relatively low frequency of advanced-stage disease, together with their excellent sensitivity to contemporary platinum-based chemotherapy, has resulted in favorable cure rates for MOGCT patients [4]. Additionally, the predominant unilaterality of these tumors allows for fertility-sparing surgery as initial treatment of choice, and the minimal recommended approach is unilateral oophorectomy [5]. Because this disease affects adolescent and young women of childbearing age and has much less aggressive surgical extent but better curability than epithelial ovarian cancer, the correct evaluation, treatment, and regular follow-ups are of the highest importance for these patients. Tumors arising primarily from the vagina comprise 3% to 8% of all MGCTs [6], and endodermal sinus tumor/ yolk sac tumor is the most common histological subtype at that site [7]. Although the cisplatin, etoposide and bleomycin (PEB) chemotherapy regimen without surgery has achieved complete remission (CR) in some early cases [8], the proper diagnosis and appropriate initial treatment remains unsolved challenges, and long-term surveillance information is limited due to the rarity of this malignancy in the pediatric population [9]. In addition, disorder of sex development (DSD) has been recognized as one of the main risk factors for the development of germ cell tumors [10]. Therefore, we retrospectively analyzed and prospectively followed a cohort of 230 Chinese women diagnosed with MGCT in the genital system, including 17 DSD females (social gender) with concomitant MGCTs. The objective was to summarize our 10-year experience towards the optimal management of MGCTs and to explore the key factors affecting the relapse and prognosis of these tumors.

We herein collected a total of 230 female patients with MGCTs in the genital system, who were either initially admitted or subsequently transferred to Peking Union Medical College Hospital (PUMCH) between September 2004 and September 2014 (end date of the study). Paraffin-embedded tissue section specimens of the transferred patients were reviewed, and their diagnosis confirmed by experienced pathologists at PUMCH or other tertiary referral hospitals. The histological diagnosis followed the ICD-O-3 (International Classification of Disease for Oncology) criteria that recognize pure dysgerminoma (9060–9061 [n=44]) and non-dysgerminoma (9070–9071 [n=74], 9073 [n=4], 9080–9084 [n=68], 9091 [n=7], and 9100 [n=6]) (Table 1). Moreover, another 27 tumors had at least two malignant components, thus defined as mixed MGCTs. The clinical information was retrieved from the medical record database, including the patient’s age at diagnosis, ethnic group, primary tumor site, histological subtype, extent of disease and operation, International Federation of Gynecology and Obstetrics (FIGO) stage when a comprehensive staging procedure was performed, and chemotherapy regimen. Specifically, the extent of the disease was categorized into local (disease confined to the ovaries) and metastatic disease, the latter comprising regional spread in the pelvis and distant metastases. Fertility-sparing surgery with unilateral salpingo-oophorectomy was the standard practice, and radical cytoreductive strategy was applied for advanced disease based upon the experience with epithelial ovarian cancer, especially for those without child-bearing requirement. The initial treatment, consisting of surgery with or without standardized platinum-based chemotherapy (≤6 courses), was considered to be effective if the neoplasm was excised satisfactorily and the surveillance indicators (tumor markers, imaging, and physical examinations) were all negative for at least 4 weeks after completion of therapy. Potential impact factors for the treatment efficiency were simultaneously analyzed. Long-term surveillance and survival outcomes were obtained through either the Outpatient Surveillance System of PUMCH or telephone interviews with patients and relatives. The overall survival (OS) and disease-free survival (DFS) of patients with germ cell cancer were evaluated, with an emphasis on recurrent cases, and clinical prognostic factors were reviewed. Categorical variables were described with proportions, and continuous variables with median and range. The impact factors for therapeutic response were also analyzed, and differences were compared by chi-square or Fisher exact test. The observation time for OS ranged from the date of diagnosis to the date of death or study end date, whichever occurred first. While the endpoint for DFS was either the date of first recurrence or last follow-up, starting from the end of the first effective treatment. Potential clinical parameters for survival outcome were evaluated univariatly using the Kaplan-Meier method with log-rank tests accessing the differences between groups, and the 95% CI were calculated. Multivariate analysis was performed using Cox regression model. A p<0.050 (two-sided) was considered statistically significant. Statistical analysis was performed using SPSS ver. 20.0 (IBM Co., Armonk, NY, USA). This study was approved by the Institutional Review Board at the PUMCH, Beijing, China (ZS-834). Written informed consent was obtained from all patients at admission to PUMCH.

Without limitation to the ovary, our study included MGCTs of other sites of origin in the female genital system. The results demonstrated that neither short-term therapeutic effect nor long-term survival outcome was different among the groups. Regardless of the primary tumor sites, patients had an excellent prognosis after similar treatment with appropriate surgery combined with platinum-based chemotherapy. Germ cell malignancies are neoplasms derived from primitive germ cells of the embryonic gonad [11], but the exact cause is still unknown. It is worth mentioning that all vaginal MGCTs in our cohort were yolk sac tumors, and occurred in infants. Excluding the infantile population, no significant association of tumor origin sites with histology and age was demonstrated, indicating a probably unique etiology for vaginal MGCTs. Five percent of dysgerminoma occur in phenotypically normal females with dysgenetic gonads, which is linked to Y-chromosome material with karyotypes 46XY (pure gonadal dysgenesis and complete androgen insensitivity) or mosaic 45X/46XY (mixed gonadal dysgenesis) [12]. Because half of the patients with dysgenetic gonads and Y-chromosome in their karyotype will develop malignancy [13], early bilateral gonadectomy was performed for all the DSD patients (7.39%) in our study.

One important finding of this study is the adverse impact of more aggressive surgery on both OS and DFS, with consideration of both the patients’ demographic characteristics and other clinical parameters. Modern principles recommend that conservative fertility-sparing surgery is the initial treatment of choice, and this type of surgery is feasible even with extensive and metastatic disease [14]. In accordance with this, we found that the extent of disease did not affect either the remission or OS rates by multivariate analysis. In particular, though 8 patients with childbearing requirement had their fertility deprived for persistent disease, three of them eventually died of uncontrolled ovarian cancer. Although a retrospective study reported that patients after incomplete resection of the tumor had a higher recurrence rate (68% vs. 28%) and lower DFS (34% vs. 65% at a median of 5 years) compared with completed resection of tumor [15], our study revealed that surgical thoroughness was unrelated to excision extension, OS and DFS, though the disease could be more rapidly under control in the short-term. Hence, although optimal debulking is the standard recommendation in advanced stage disease, judgment must be exercised to weigh the benefit of aggressive cytoreductive surgery against the chemosensitivity of MGCT. Moreover, no pathologically positive lymph note was detected after comprehensive staging in 56 patients, nor did the staging procedure improve the curability or prognosis according to our data. Therefore, staging is not required, especially when debulking is already satisfactorily achieved.

Stage IA dysgerminoma and stage IA, grade 1 immature teratoma are treated adequately with surgery alone, and all other patients are advised to have postoperative chemotherapy. A combination of PEB is the standard regimen [16]. Our results demonstrated that instead of regimen options, timely initiation of chemotherapy (within 7 days after surgery) was the key to enhance the therapeutic effect, but the OS and DFS were not influenced. In other words, anti-neoplastic medicine is of significant value as complementary treatment, and should be applied whenever risk factors are identified. Additionally, institutions lacking experience of treating MGCTs should refer these patients to higher-level hospitals (Chinese Tertiary Medical Centers) where standard chemotherapy can be given. Although three cycles of PEB are adequate for patients with completely resected stage IB–III disease [17], the optimal number of cycles of chemotherapy in incompletely resected or stage IV disease is uncertain. Remission has been realized in many of our patients with four to six cycles of chemotherapy depending on the decline of the serum tumor markers, and the bulkiness of residual disease. Thus, the number of courses may be flexible and individualized.

Approximately 20% of the patients will be resistant to treatment or experience relapse [18], in our study 34 patients (14.78%) had persistent malignancy at first and 14 (6.09%) recurrent tumors at a later stage. Additionally, our study revealed most recurrences occurred within the first 2 years after the end initial treatment, and salvage therapy had made most relapses remitted. Therefore, patients must be followed at gradually prolonged intervals if no abnormality has been detected. Monitoring of tumor markers (e.g., human chorionic gonadotropin, alpha fetal protein, etc), abdominal and pelvic imaging is of importance for timely recognition of recurrence. Although the role of surgery in the management of recurrent and refractory disease is not well defined [19], secondary cytoreductive surgery combined with chemotherapy was preferred in our hospital. As a result, more than half of these patients achieved remission under long-term surveillance. Histological type and stage are the most important prognostic factors, with dysgerminoma having the best survival in other researches [20]. Additionally, a large population-based (2,541 cases) study addressed the prognostic role of age on cause-specific survival in MOGCT [21]. However, our study identified the extent of disease and surgery, together with the level of hospital as the independent impact factor on DFS, while controlling other variables (e.g., age at diagnosis, extent of disease, histological subtype, performance of staging, and postoperative chemotherapy).

We acknowledge that our study has several limitations. Due to the large proportion of transferred patients lacking detailed medical records, some key factors cannot be fully analyzed, such as the extent of residual disease. The median surveillance duration to observe the effect on fertility or teratogenicity after fertility-sparing surgery and chemotherapy for MGCT is relatively short. During follow-up, only 28 patients declared recent desire for fertility, and 14 of them had a healthy baby, with another two patients were diagnosed with definitive infertility. Hence, a longer period of follow-up in a larger multicentral population is needed for more accurate evaluation, and fertility-related quality of life need to be monitored.

In conclusion, our study identified that there was no significant association of the primary tumor sites with the therapeutic response and prognosis in MGCT. The initial surgical option should be chosen with caution, because neither comprehensive staging nor aggressive debulking improves the patients’ DFS or OS. The short-term remission rate and long-term survival outcome should be balanced. Additionally, the preservation of fertility needs to be managed, if a patient so desires and her condition allows the option. Finally, standard but individualized chemotherapy should be supplemented in time, when necessary.