Lymphadenectomy and Survival
The stage distribution for the 22 patients with lymphadenectomy was as follows: 12 stage I, 4 stage II, 4 stage III, and 2 stage IV. Nine of them had a grossly enlarged lymph node. Lymph node metastasis was found in 2 patients (9.1%, 2/22). The lymph node metastasis rate for patients with clinical stage III or IV disease was 33.3% (2/6). None of the patients with clinical stage I or II disease (clinically no gross extrapelvic metastasis) in whom lymphadenectomy was performed had lymph node metastases. The 5-year survival rates for patients with and without node dissection were 86.4% and 86.0%, respectively (P > 0.05).
Omentectomy and Survival
The stage distribution for the 55 patients with omentectomy was as follows: 29 stage I, 7 stage II, 14 stage III, and 5 stage IV. Thirty-seven of them had no gross lesions on the omentum. The postoperative pathology showed that only 1 patient (2.7%, 1/37) had tumor metastasis microscopically. The 5-year survival rates were 88.9% and 100.0% for stage I or II patients with and without omentectomy, respectively (P > 0.05).
Overall Survival and Other Prognostic Factors
The overall 5-year survival rate was 86.0%. For stages I, II, III, and IV patients, the 5-year survival rates were 94.2%, 75.0%, 77.4%, and 71.4%, respectively (Table 3). Optimal surgery was defined as surgery with no macroscopic residual disease. Satisfactory postoperative AFP decline was defined as normalization of AFP after the first or second cycles of postsurgery chemotherapy. All 65 patients received postoperative adjuvant chemotherapy. EP (etoposide, cisplatin), VBP (vincristine, bleomycin, cisplatin), and EBP (etoposide, bleomycin, cisplatin) regimens were administered to 4, 27, and 31 patients, with a median of 4, 5, and 5 cycles, respectively. Univariate analysis revealed that stage (P = 0 .022, Fig. 1A), age (P = 0.001 Fig. 1B), residual tumor (P = 0.036, Fig. 1C), and satisfactory AFP decline (P = 0.006 Fig. 1D) were significant prognostic factors (Table 3).
Multivariate Cox proportional hazard regression analysis was performed to determine the independent prognostic factors. The results revealed that AFP decline was an independent significant prognostic factor for OS (P = 0.028), whereas International Federation of Gynecology and Obstetrics stage, age, and residual tumor were not.
Preoperative Neoadjuvant Chemotherapy and Treatment Outcomes
Among the 6 patients receiving neoadjuvant chemotherapy (NACT), partial response was observed in 5 patients who received a BEP or VBP regimen for 1 to 4 cycles; no response was seen in the one who received 1 cycle of 5-fluorouracil plus carboplatin. After NACT, the optimal cytoreduction rate was 83.3% (5/6) compared with that of 50.0% (7/14) in stages III and IV patients without NACT. The 5-year survival rates in patients with or without NACT were 66.7% and 85.7%, respectively (P = 0.293).
Uterus-Sparing Surgery and Fertility Outcomes
Regular menstruations returned after discontinuation of chemotherapy in 39 patients (95.1% [39/41]) who had regular menstrual cycles before treatment. The recovery time of regular menses was 2 to 12 months (median, 4 months) after the cessation of chemotherapy. Fourteen of the 17 patients who attempted conception gave birth to normal children, resulting in 20 live births. Twelve cases conceived naturally, and 2 required in vitro fertilization.
Recurrence and Salvage Therapy
The median follow-up time was 70.0 months (range, 7.0–236.0 months). The median recurrent time was 9.3 months (range, 6.9–10.7 months). The recurrent rates for stage I, II, III, and IV disease were 5.3% (2/38), 0% (0/8), 20.0% (3/15), and 25.0% (2/8), respectively. The recurrent rates for patients 14 years or younger, 14 to 50 years, and 50 years or older were 23.5% (4/17), 4.5% (2/44), and 20.0% (1/5), respectively (Table 4). Of the 7 patients with recurrence, 3 were successfully salvaged and alive at 38.0, 102.6, and 45.2 months after initial diagnosis, whereas the other 4 patients failed and eventually died of the disease.
Ovarian YSTs are a rare germ cell tumor. In this study, we provide a detailed description of the clinical features of 66 patients with ovarian YST. To our knowledge, we first evaluate the therapeutic significance of omentectomy in patients with clinically early-stage disease without grossly visible lesions in the omentum, which is frequently performed in clinical practice in the treatment of ovarian YST. This study is one of the largest series about ovarian YST in the literature.
Recently, the diagnostic (for staging purpose) and therapeutic significance of omentectomy in clinically apparent early-stage epithelial ovarian cancer has been doubted.8,9 The significance of omentectomy in clinical early-stage ovarian YST has not been demonstrated in the literature, either. Many authors performed fertility-preserving comprehensive staging surgery for patients with early-stage disease in which omentectomy was also included.1,3,6 Recently, the justification for comprehensive staging surgery in malignant germ cell tumors has been questioned; patients may not benefit more from comprehensive staging surgery than from unilateral adnexectomy.5 Omentum is an important abdominal organ that can limit peritoneal bacteria infection and prevent adhesions of intestine to anterior abdominal wall following surgery. Most patients with ovarian YST had early-stage disease and a normal omentum. Theoretically, removing a grossly normal omentum may not be of therapeutic benefit for patients with early-stage disease. One may argue that a macroscopically normal omentum may have occult metastasis, which can be detected only microscopically. However, even if occult metastasis is present in the unremoved omentum, postoperative chemotherapy is likely to control the disease because ovarian YST is highly sensitive to chemotherapy. In our study, the occult metastatic rate of omentum is 2.7%. The 5-year survival rate was not significantly different for patients with or without omentectomy (89.2% vs 100.0%), and the survival results even favored those without omentectomy. Our data suggest that occult metastasis in the omentum is not common and that removing the grossly normal omentum might not confer benefit to patients with clinically apparent stage I-II disease. Although a definite conclusion could not be obtained based on a small number of data, those were interesting and promising data that justified further investigation, especially randomized trial.
In ovarian malignant germ cell tumors, dysgerminoma and malignant teratoma tend to spread to the retroperitoneal lymph node.10 For ovarian YST, few data are available about lymph node metastasis rate and the importance of lymphadenectomy. Two studies have shown that lymph node metastasis may be uncommon in this disease and that lymphadenectomy may not affect prognosis. In 1 study, lumbar-aortic lymph node dissection was performed in 11 patients, and lymph node metastasis was found in only 2 stage IIIC patients with bulky peritoneal disease and was not present in all clinical stage I patients whose tumors were grossly confined to the ovary.3 In another study, lymph node dissection was performed in 3 patients with stage II-IV disease, but lymph node involvement was not found in all cases.7 In our study, the pathological lymph node metastatic rate was 9.1% (2/22) for all patients who underwent lymphadenectomy and 33.3% (2/6) for those with stage III or IV disease. These results may indicate that the lymph node metastatic rate is very low for clinical stage I or II patients and higher for patients with advanced-stage disease. Of the 7 patients with recurrence, 4 (57.1%) had lymph node metastasis, and 3 of them had initial advanced disease, which also suggested that patients with advanced disease more easily develop lymph node metastasis. Thus, it is especially important to carefully inspect the lymph node status during operation for patients with advanced disease and remove the enlarged lymph node if the intraperitoneal lesion has been optimally removed. Although the 5-year survival rates for patients with and without node dissection were not significantly different (86.4% vs 86.0%) based on the small number of cases, the survival benefit and necessity for patients receiving lymphadenectomy with different disease stages can be further analyzed.
In the literature, the reported prognostic factors of ovarian YST are tumor stage,1,7,11 the volume of ascites,3,7 high level of serum AFP12,13 or postoperative serum AFP declining rate,3 residual tumor,7,11,14 cisplatin-based chemotherapy in advanced disease,14 and chemotherapy with a BEP regimen.3,15 In our study, univariate analysis showed that age, tumor stage, AFP decline, and residual tumors affect the prognosis. Multivariate Cox analysis revealed that only satisfactory postoperative AFP decline was an independent significant prognostic factor for 5-year survival rate. This is similar to the result of a previous report. That study showed that the serum half-life of AFP was significantly predictive of patient OS.3 Patients with a serum half-life of AFP of more than 10 days had lower 5-year OS than patients did with half-life of 10 days or less (59% vs 92%).3 AFP decline rate may help clinicians distinguish patients with low or high risk of recurrence and determine the number of chemotherapy cycles. For patients with satisfactory AFP decline, 2 more cycles of chemotherapy after normalization of AFP may be enough no matter the stage of disease. This situation is similar to that in patients with stage IA disease after the tumor has been removed. de la Motte et al3 suggested that patients with stage IA disease may need only 2 cycles of BEP chemotherapy. This point needs to be evaluated in a well-organized perspective study. For patients with unsatisfactory AFP decline, intense treatment may be necessary, such as more cycles of chemotherapy, or new treatment regimen may need to be investigated.
As of the impact of AFP level on patient survival, the results of previous studies were inconsistent. In some literature, high level of serum AFP was reported to be a prognostic factor,12,13 but in other articles, the AFP level did not significantly affect the prognosis.7,14 In our study, patients with high pretreatment AFP level tend to have poor survival (P = 0.07). The inconsistency between studies may be due to the small number of cases. What is more, pretreatment AFP level is related to tumor burden, which depends on tumor size and extent of tumor spread (tumor stage). Patients with early-stage disease may have a large-size tumor and high AFP level but good outcome; patients with late-stage disease may have small-volume tumor and low AFP level but poor outcome.
Studies showed that residual tumor decreased patient OS.7,11,14,16 For example, in the study of Nawa et al,7 the 5-year survival rate was 78% for patients with residual tumor of 2 cm or less and 29.2% for those with residual tumor of larger than 2 cm, respectively. However, there were 2 obvious drawbacks in previous studies. First, stage I patients were included in the group with no or less residual tumor.7,11,14,16 Actually, the term residual tumor is supposed to be used in advanced-stage disease with spread tumor in peritoneal cavity that cannot be removed. Second, mixed germ cell tumor was included in some studies, which has different characteristics compared with pure YST.7,14,16 In our study, we included only stage II-IV patients to evaluate the impact of residual tumor on survival. Univariate analysis showed that residual tumor is a significant prognostic factor, but multivariate analysis did not. However, the 5-year OS tends to favor the group without residual tumor (92.9% vs 60.0%). These data suggest that more aggressive surgery may render patients more survival benefit. What is more, whether there is survival difference between patients without residual tumor and those with only small residual tumors less than 1 or 2 cm remains to be further evaluated. Because YST tumor is highly sensitive to BEP chemotherapy, small residual tumors less than 1 or 2 cm may be diminished by postoperative chemotherapy.
Although cisplatinum-based chemotherapy dramatically improved the prognosis of ovarian YST, a few patients may still relapse, and rare data are available regarding salvage chemotherapy in the literature. High-dose chemotherapy combined with autologous stem cell transplantation may provide an opportunity for complete tumor remission.3,17,18 In our study, 1 patient had a para-aortic lymph node recurrence at 6 months after discontinuation of the BEP regimen and 10.7 months after the initial diagnosis. She was successfully salvaged with another 4 cycles of BEP regimen. Another patient had lung recurrence after BEP regimen and achieved complete remission on chemotherapy with paclitaxel plus cisplatin. A tumor reappearing in the lung also had complete remission after chemotherapy with epirubicin plus nedaplatin, which suggests that the 2 regimens, paclitaxel plus cisplatin and epirubicin plus nedaplatin, may be another option for salvage chemotherapy. Four of the 7 patients lived 3 years or more, and 2 patients lived even longer than 5 years after recurrence. These data demonstrate that salvage treatment with a combined modality may render long-term survival possible in some patients.
In patients with recurrence, patient 3 had brain metastasis following her lung metastasis (Table 4). To our knowledge, this is the first case of brain metastasis reported in an ovarian YST patient. She received radiation therapy for brain metastasis but failed and died of the disease 87.7 months after the initial diagnosis.
One should be aware of the limitations of this study. This study is retrospective and is subject to the limitations of this type of study. The number of cases was small. The treatment information in 2 of the recurrent cases is not available. The results of the study must be interpreted with caution.
In conclusion, postsurgery satisfactory AFP decline was an independent significant prognostic factor for patient survival. Omentectomy may not be necessary for clinical stage I or II patients. Recurrent patients may obtain long-term survival, and proper salvage treatments need further study.
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Keywords:© 2016 by the International Gynecologic Cancer Society and the European Society of Gynaecological Oncology.
AFP decline; Chemotherapy; Omentectomy; Ovarian yolk sac tumor