Retrospective Analysis of Pure Ovarian Immature Teratoma in Patients Aged 15

Abstract

Purpose:

To evaluate the clinicopathological characteristics and surgical outcomes in patients with pure ovarian immature teratomas (POITs).

Materials and Methods:

In this multicenter study, a retrospective review was made of the databases of six Gynecology Oncology Departments in Turkey to identify patients with POITs who had undergone surgery between 1993 and 2019.

Results:

Evaluation was made of 48 patients with a median age at diagnosis of 22.5 years (range, 15–37 years). In 40 (83%) patients, stage I was determined and in eight patients, an advanced stage (IIIB, IIIC, and IVB) was determined. Tumors were found to be grade I in 17 (35.4%) cases, grade II in 12 (25%), and grade III in 19 (39.6%). Fertility-sparing surgery was applied to 42 (87.5%) patients and radical surgery to 6 (12.5%). The median follow-up was 60 months (range, 3–246 months). Recurrence was seen in seven patients, all with grade III tumors. In the final pathological examination of recurrent tumors, mature teratoma was reported in five patients, and immature teratoma in one patient. Salvage surgery was not performed in one patient as the tumor was unresectable and so a regimen of bleomycin, etoposide, and cisplatin (BEP) was administered.

Conclusion:

POITs are rare tumors seen at a young age, and benign or malignant relapse can be seen in these tumors. In this cohort, the malignant recurrence rate was 4.1%, and the benign recurrence rate was 10.4%. All the recurrences were in grade III tumors. Benign recurrences can be treated with surgery alone and the malignant group should be treated with surgery followed by chemotherapy.

Introduction

Malignant ovarian germ cell tumors (MOGCTs) constitute ∼5% of all ovarian tumors.¹ Pure ovarian immature teratomas (POITs) are a rare subtype, accounting for <1% of all ovarian tumors, and ∼35.7% of all MOGCTs.^2,3 POITs are composed of three germ layers: endoderm, ectoderm, and mesoderm. Histological grading is applied according to the tissue amount containing immature neural elements.⁴ POITs differ from teratomas in other regions in terms of genetic, endocrinological, and peritoneal spread, and recurrences may occur as POIT, malignant germ cell tumor, mature teratoma, or gliomatosis.⁵ Studies have been conducted on factors other than grade and stage, which determine oncological outcome and recurrence but these have been limited by small sample sizes.

As they are rare tumors, there is no clear consensus in the literature on optimal surgery and adjuvant therapy for the management of POITs. The postoperative treatment approach is different in pediatric patients and young adults.^6,7 Fertility preservation is important in the management of such cases, and approaches have been based on retrospective studies involving a small number of patients. In studies conducted after 1970, adjuvant chemotherapy has been observed to increase survival.⁸ Follow-up is recommended for grade IA stage I patients, whereas the use of adjuvant chemotherapy in other early-stage (stage IA; grade II–III, IB, and IC) cases is controversial.⁹ There has been no previous comprehensive study on the extent of surgery in patients with advanced immature teratoma.

The aim of this multicenter study was to determine the clinicopathological characteristics and surgical outcomes of patients with POITs.

Materials and Methods

IRB approval number: 2019-20/5.

Study design and patient enrollment

This retrospective multicenter study was carried out using the databases of six Gynecology Oncology Departments in Turkey. The data were retrieved from these databases of a total of 48 consecutive patients between the age of 15 and 39 years, who were diagnosed with POIT between January 1993 and December 2019. All the study procedures were applied in compliance with the Declaration of Helsinki. Approval for the study was granted by the Local Ethics Committee of Etlik Zübeyde Hanım Women's Health Research Hospital. After careful evaluation, patients aged of >39 years were excluded from the study. Patients with any other histological type of ovarian tumors such as mixed germ cell tumors, sex cord-stromal tumors, or epithelial tumors, were also excluded from the study.

The clinicopathological patient data were collected from the patient files, pathology reports, and hospital registry of each participating center. Data including age, tumoral features (tumor size, grade, and laterality), tumor markers (Ca125, alpha-fetoprotein [AFP], and human chorionic gonadotropin [hCG]), stage at diagnosis, type of surgical procedure, the presence of ascites, lymph node status, chemotherapy after surgery, and clinical status at follow-up were evaluated.

Descriptions

Patients treated before 2014 were restaged according to the 2014 FIGO staging criteria using surgical and pathological assessment. Histological grading was described according to the Norris criteria.⁴ Postoperative adjuvant chemotherapy decisions were made by the tumor board in all participating centers. Routine follow-up was performed every 3 months for the first 2 years, every 6 months for the following 3 years, and annually thereafter.

All operations were performed by gynecology oncologists with the aim of obtaining complete cytoreduction. Maximal cytoreduction was defined as no visible tumor after primary surgery; optimal and suboptimal cytoreduction were used for patients with residual tumor ≤1 cm and >1 cm, respectively. The surgical procedures were conservative or radical, and ± additional staging surgery, including peritoneal cytology, peritoneal biopsy, omentectomy, or omental biopsy, with or without lymph node dissection. Radical surgery consisted of hysterectomy, bilateral salpingo-oophorectomy, retroperitoneal lymphadenectomy, omentectomy, appendectomy, peritoneal biopsies, and abdominal washing. Preservation of uterus and at least one ovary was defined as a conservative surgery. The conservative group included patients who underwent fertility-sparing surgery. The fertility-sparing approach was defined as the preservation of the uterus and a portion of at least one ovary and ± staging surgery, including exploration of the peritoneal surfaces with multiple biopsies, cytology, omentectomy, appendectomy, and retroperitoneal lymphadenectomy, was applied to this procedure. All pathology specimens were reported by pathologists specialized in gynecological oncology at each institution.

Statistical analysis

Statistical analysis was performed using IBM SPSS Statistics for Windows, Version 23.0 software (Armonk, NY). The demographic features of the patients and disease characteristics were assessed with descriptive statistics. Continuous variables were presented as median, minimum-maximum values, and categorical variables as number and percentage.

Results

The median age of patients at diagnosis was 22.5 years (range, 15–37 years) and POIT prevalence was calculated as 25% (12/48) in women aged ≤19 years and as 37.5% (18/48) in women aged 20–25 years. Tumor size was mean 17.5 cm (range, 4–35 cm). A total of 40 (83%) patients were at stage I and 8 patients were at an advanced stage (IIIB, IIIC, and IVB). In the histological grading, 17 (35.4%) tumors were grade I, 12 (25%) were grade II, and 19 (39.6%) were grade III tumors. A concurrent mature cystic teratoma involving the opposite ovary was determined in eight (16.6%) patients. Data related to Ca 125 level were available for 30 patients and the relevant median level was 65 IU (range, 10–7778), which was determined to be elevated in 20 patients. AFP level was available for 21 patients, and the median level was 46.5 ng/mL (range, 1–10,000) with values higher than 10 ng/mL seen in 12 patients. The most common clinical symptoms on presentation were abdominal pain in 62.5% and abdominal mass/distension in 31.3%. The median duration of follow-up was 60 months (range, 3–246 months).

Ascites were present in eight (16.7%) patients, two of whom had malignant cytology. Fertility-sparing surgery was applied to 42 (87.5%) patients and radical surgery to 6 (12.5%). In 30 (62.5%) patients, staging surgery was performed. Surgical outcomes were reported as maximal debulking in 25 (52.1%) patients, optimal debulking in 4 (8.3%) patients, and suboptimal debulking in 1 (2.1%) patient. In 18 (37.5%) patients, the surgical outcomes were not reported. Lymphadenectomy was applied to 30 (62.5%) patients and lymph node metastasis was detected in 3 (6.3%) patients.

Postoperative adjuvant chemotherapy was applied to 30 (62.5%) patients. With the exception of 16 stage IA and 2 stage I grade II patients, adjuvant chemotherapy was applied to all the other stage IA grade II–III, stage IC, and stage III–IV cases. The chemotherapy regimen was BEP (bleomycin, etoposide, and cisplatin) in 26 (54.1%) patients, VBP (vinblastine, bleomycin, and cisplatin) in 2 (4.2%), VEB (vinblastine, etoposide, and cisplatin) in 1 (2.1%), and EP (etoposide and cisplatin) in 1 (2.1%) patient. The median number of chemotherapy cycles was 4 (range 3–6). None of the patients was given neoadjuvant chemotherapy. The clinical, surgical, and pathological characteristics of the patients are presented in Table 1.

Table 1.

Patients' Characteristics

Age (years), median (range)	22.5 (15–37)
PTD, median (range), cm	17.5 (4–35)
Tumor markers, median (range)
CA 125	65 (10–7778)
AFP	46.5 (1–10,000)
Beta—hCG	0.8 (0.15–7.1)
Stage, n (%)
IA	34 (70.8)
Grade I	16 (47)
Grade II	9 (26.5)
Grade III	9 (26.5)
IC1	2 (4.2)
IC2	2 (4.2)
IC3	2 (4.2)
IIIB	3 (6.3)
IIIC	3 (6.3)
IVB	2 (4.2)
Grade, n (%)
I	17 (35.4)
II	12 (25)
III	19 (39.6)
Laterality, n (%)
Unilateral	47 (97.9)
Bilateral	1 (2.1)
Ascites
Yes	8 (16.7)
No	40 (83.3)
Type of surgery
Unilateral cystectomy	3 (6.3)
Bilateral cystectomy+staging	1 (2.1)
USO	11 (22.9)
USO+contralateral cystectomy	1 (2.1)
USO+staging	23 (47.9)
USO+ contralateral cystectomy+staging	3 (6.3)
TAH+USO	2 (4.2)
TAH+BSO+staging	4 (8.3)
Fertility sparing surgery
Yes	42 (87.5)
No	6 (12.5)
Lymph node involvement, n (%)
Negative	27 (56.2)
Positive	3 (6.3)
Not performed	18 (37.5)
Surgical outcome, n (%)
Suboptimal	1 (2.1)
Optimal	4 (8.3)
Maximal	25 (52.1)
Not reported	18 (37.5)
Chemotherapy
BEP	26 (54.1)
VBP	2 (4.2)
VEB	1 (2.1)
EP	1 (2.1)
Not received	18 (37.5)
Recurrence
Yes	7 (14.6)
No	41 (85.4)
Follow-up, median (range), month	60 (3–246)

AFP, alpha-fetoprotein; BEP, Bleomisin+Etoposide+Cisplatin; BSO, bilateral salpingo-oophorectomy; EP, Etoposide+Cisplatin; hCG, human chorionic gonadotropin; TAH, total abdominal hysterectomy; USO, unilateral salpingo-oophorectomy; VBP, Vinblastin+Bleomisin+Cisplatin; VEP, Vinblastin+Etoposide+Cisplatin.

During the follow-up period, recurrence developed in seven (14.6%) patients at median 9 months (range, 6–21 months). All recurrent patients had received four cycles of BEP chemotherapy after the initial surgery. Of the seven patients with recurrence, three had stage IA, one had stage IC1, and the other three had stage IIIB, IIIC, and IVB, respectively. All the recurrences were in grade IIII tumors. In one patient, unresectable tumor was detected in the upper abdomen from elevated tumor marker values and imaging methods, so surgery was not performed and the BEP regimen was administered. With the exception of this patient, salvage cytoreductive surgery was performed in all other patients with recurrence. The final pathological examination of recurrent tumors was reported as mature teratoma in five patients (Table 2), and immature teratoma in one patient (Table 3). Benign recurrences were treated with surgery alone, and the malignant group was treated with surgery followed by chemotherapy. All recurrent patients became disease-free.

Table 2.

Clinicopathologic Characteristics of Women with Benign Recurrent Disease

No.	Age	Stage	Grade	Initial surgery	Adjuvant treatment	Site of relapse	Treatment of relapse	Recurrence pathology	Time to relapse (m)	Outcome F/U (m)
(1)	27	IC3	III	LeftUSO+right cystectomy+LND+Omx	4 cyc. BEP	Right ovary	Surgical excision	Mature teratoma	9	48 NED
(2)	14	IA	III	Right USO+ left cystectomy+LND	4 cyc. BEP	Liver	Surgical excision	Mature teratoma	8	60 NED
(3)	28	IA	III	Left USO	4 cyc. BEP	Omentum, right ovary	Surgical excision	Mature teratoma	12	60 NED
(4)	30	IIIB	III	TAH +USO+LND+Omx	3 cyc. BEP	Liver	Surgical excision	Mature teratoma	12	36 NED
(5)	34	IA	III	TAH+BSO+staging	4 cyc. BEP	Diafragma	Surgical excision	Mature teratoma	8	61 NED

CT, chemotherapy; cyc, cycle; LND, lymph node dissection; M, month; NED, no evidence of disease; Omx, omentectomy.

Table 3.

Clinicopathologic Characteristics of Women with Malign Recurrent Disease

No.	Age	Stage	Grade	Initial surgery	Adjuvant treatment	Site of relapse	Treatment of relapse	Recurrence pathology	Time to relapse (m)	Outcome F/U (m)
(1)	20	IIIC	III	TAH+USO+Omx	4 cyc. BEP	Liver	Surgery+CT (EP, 3 cyc.)	Immature teratoma	21	24 NED
(2)	22	IVB	III	TAH+USO+tumoral debulking	4 cyc. BEP	Upper abdomen	CT (BEP, 4 cyc.)	NA	6	12 NED

NA, not available.

Discussion

POITs are rare tumors and due to the lack of studies with large cohorts, the prediction of the clinical outcome is challenging. Since it is mostly seen at a young age and diagnosed at an early stage, data concerning advanced stage POITs are limited. Furthermore, most previous studies have included combinations of different malignant germ cell tumors.

The most common presenting symptoms of POITs is abdominal distension and they are nearly always seen unilaterally.^10,11 In this study, the most common clinical symptoms on presentation were abdominal pain (62.5%) and abdominal mass/distension (31.3%) and only one (2.1%) case had bilateral tumoral involvement. Similarly, Pavone et al. reported that the most common presenting symptom was abdominal pain, and precocious puberty was not observed in any pubertal cases.¹¹

Ovarian neoplasia is rarely seen in pediatric and adolescent cases. Although rare, malignant tumors may be encountered as much as benign tumors in adnexal masses determined in these age groups. If malignant ovarian tumor is suspected at this age, differential diagnosis is important to confirm the diagnosis and to be able to recommend the appropriate treatment to protect fertility. Therefore, clinical findings, elevated serum tumor marker levels, and differentiating radiological findings are important. Elevated tumor markers according to the tumor type may be helpful in the diagnosis of malignancy, but tumor markers are positive in only 54% of malignant cases. Thus, the imaging findings may also be helpful in diagnosis. On radiological imaging, there is an appearance of a solid cystic mass.¹²

It has been reported that preoperative Ca 125 and AFP may increase in these tumors.¹⁰ In the current study, Ca 125 level data were available for 31 patients, of which 20 were seen to have values >35 IU, and the AFP level data were available for 21 patients, of which 12 had values >10 ng/mL.

The standard treatment for young patients with stage I immature teratomas except for stage IA grade I is unilateral salpingo-oophorectomy with complete staging surgery followed by platinum-based chemotherapy.^13,14 However, the use of chemotherapy following surgery at an early stage is a controversial issue, especially for patients with stage I grade II–III.⁹ In a study that reported the role of postoperative adjuvant chemotherapy for stage I immature teratomas, it was suggested that chemotherapy be used only for recurrences, and that surgical treatment should be applied to all patients at stage I regardless of the grade.⁹ In the multicenter analysis by Bergamini et al., no difference was determined between adult and postpubertal stage IA–C, grade II–III cases receiving or not receiving adjuvant chemotherapy in respect of malignant relapse (grade II–III immature teratoma), disease-free survival, and overall survival.¹⁵

In a study conducted on a pediatric patient group, adjuvant chemotherapy after surgery was observed not to reduce the risk of recurrence.⁶ Pavone et al. evaluated pediatric ovarian immature teratoma and reported that of 13 cases with tumor rupture, 5 had received adjuvant chemotherapy, and the other 8 had not, and no recurrence was observed in any of these cases, including those with grade tumors.¹¹ In the current study, with the exception of stage IA grade I patients, only two stage I grade II patients did not receive adjuvant therapy after surgery. During follow-up, recurrence was not observed in any grade II patients.

Although the National Comprehensive Cancer Network (NCCN) guideline recommends adjuvant chemotherapy for all cases other than stage IA grade I, no superiority of adjuvant chemotherapy over the option of follow-up has been found in the controversial group of stage IA–C grade II–III cases.^9,14,15 There is a need for further multicenter studies to support these retrospective study findings.

However, previous studies have shown that the fertility-sparing approach appears to have excellent survival outcomes in young women with MOGCT, even in advanced stages.^16,17 In the current study, the fertility-preserving approach was not applied in advanced-stage patients. The majority of patients with preserved fertility were stage I patients, and also grade I–II patients were in this group.

Immature teratomas are generally unilateral tumors. Bilateral immature teratoma is a rare condition with an incidence of 1.7%, more likely to be associated with an advanced stage.¹⁸ In the current study, bilateral IT was observed in one (2.1%) case and this was at an advanced stage. This may have resulted from performing radical surgery in advanced cases in this study. Routine contralateral ovarian biopsy is not recommended due to the rare involvement of contralateral ovaries. In some studies, the rate of mature teratoma in the contralateral ovary has been reported as 5.1%–19%.^4,10 In the current study, eight (16.6%) patients had a concurrent mature cystic teratoma in the contralateral ovary. All these findings support the application of fertility-sparing surgery at early stages.

Due to the significance of the stage of disease, 30 (62.5%) patients underwent staging surgery. The current guideline provides no clear consensus on this issue for early-stage patients. The most controversial procedure of complete staging surgery is routine lymphadenectomy. While the NCCN guideline recommends performing omentectomy and lymphadenectomy in malignant germ cell tumors, the European Society for Medical Oncology guidelines recommend omentectomy, not lymphadenectomy.^14,19 Several studies have reported that lymphadenectomy and omentectomy have no effect on disease-free survival.^20,21 In the current study, lymphadenectomy was performed in 30 (62.5%) patients, three (6.3%) of whom had lymph node involvement. Omental involvement was seen in four patients. The fact that these rates are higher than other studies may be due to the higher number of advanced stage and grade III patients in this study.

A previous study reported the recurrence rate in the early stage to be 5.3%,¹⁴ and the MITO study declared that rate to be 21.45%.⁹ The recurrence rate at stage I varies among studies, which may stem from different grades of disease in each study. In the current study, the recurrence rate was determined as 10% at stage I. Recurrence was observed in only four patients, three of whom were stage IA, grade III, and IC3, grade III. Similarly, Vicus et al. reported the recurrence rate to be 9.4% in stage I disease.¹³ However, in the current study, the pathology at stage I of all the recurrences was benign histology as mature teratoma.

Pathology in recurrence of immature teratoma might be in the form of POIT, malignant germ cell tumor, mature teratoma, and progression of gliomatosis. Since the treatment differs for each, the histological type of relapse should be evaluated.⁵ The recurrence rate in the current study was 14.6%. None of the patients with grade I or II had recurrences regardless of the stage. All the recurrent cases were grade III, although the stages were stage IA in three cases, stage IC3 in one case, IVB in one case, and IIIB and IIIC in the others. The recurrence pathology was immature teratoma for the patient with stage IIIC, and in all the other cases, the recurrence pathology was reported as a mature teratoma. These findings show that grade is an important factor for recurrence, and these results are consistent with the findings of previous studies.^6,7 Several studies have reported that increased grade leads to an increased mortality rate and the grade of the primary tumor is the most important factor determining extraovarian spread.^4,22

Ovarian immature teratoma contains mature and immature tissues originating from all three germ layers at varying amounts. Although the amount of neuroepithelium is important to determine grade I, immunohistochemical studies may be helpful for diagnosis in some situations. Salla-4, OCT-3/4, and SOX-2 are widely used markers. OCT-4 in particular has been shown to be a promising biomarker, which could be used in the diagnosis of cases of malignant immature teratoma as it is expressed in high-grade immature teratoma. In addition, it may be differentiated from other mixed germ cell tumors with the absence of chromosome 12p amplification.²³

The effect of maximal cytoreduction on the oncology outcomes is insufficient due to the limited number of patients with advanced MOGCT. In advanced disease, the role of aggressive cytoreduction for the achievement of no visible disease is not well established. Better survival has been reported in patients with advanced MOGCT maximal cytoreduction in various studies in the literature.^16,24 Park et al. reported residual tumor size to be an independent prognostic factor for recurrence and survival in stage I–IV MOGCT.¹⁶ Another study confirmed the suggestion that in grade III stage III patients, event-free survival was better following complete resection.⁶ Williams et al. reported that better survival could be provided with platinum-based chemotherapy when the minimal residual disease was achieved.²⁴ All these results emphasize that obtaining minimal residual tumor improves survival in MOGCT. In the present study, maximal and optimal debulking was performed in 29 (60.4%) patients.

Another controversial issue is chemotherapy in POITs. With the use of postoperative chemotherapy after the 1970s, an increase in survival rates was observed.⁸ Various platinum-based regimens have been used and these are generally preferred. Currently, BEP is the most commonly used regimen. The number of chemotherapy cures varies between 3 and 4 according to the risk groups.²⁵ In the current study, the median number of chemotherapy cycles was 4, and the BEP regimen was used in 54.1% of patients. In some studies, increased survival rates have been reported with the use of postoperative adjuvant chemotherapy.^8,10

There were some limitations to this study. First, a central pathology review could not be performed due to the retrospective nature of the study. Second, as the data were obtained from six different institutions, there may have been potential differences in clinical and surgical management. Despite these limitations, retrospective studies make significant contributions to the literature by reflecting the real-life data of the patients. In this study, the clinicopathological characteristics of all the patients with disease recurrence were presented, and although this is a rare tumor type, the sample size was large.

In conclusion, POITs are rare tumors seen at a young age and benign or malignant recurrence of these tumors may be seen. In this cohort, the malignant recurrence rate was 4.1%, and the benign recurrence rate was 10.4%. All the recurrences were in grade III tumors. Benign recurrences can be treated with surgical excision. However, the BEP regimen should be applied after secondary cytoreductive surgery in malignant recurrences. POITs are rare tumors and further prospective studies are required for optimal management of the disease.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

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Retrospective Analysis of Pure Ovarian Immature Teratoma in Patients Aged 15–39 Years: A Turkish Multicenter Study