Song, Taejong MD; Choi, Chel Hun MD; Park, Hwang Shin MD; Kim, Min-Kyu MD; Lee, Yoo-Young MD; Kim, Tae-Joong MD; Lee, Jeong-Won MD; Bae, Duk-Soo MD, PhD; Kim, Byoung-Gie MD, PhD
Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Received November 23, 2010, and in revised form January 20, 2011.
Accepted for publication January 27, 2011.
Address correspondence and reprint requests to Byoung-Gie Kim, MD, PhD, Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-Dong, Gangnam-gu, Seoul 135-710, Korea. E-mail: firstname.lastname@example.org.
These 2 authors (T. S. and C. H. C.) contributed equally to this paper.
Disclosures: The authors have no conflicts of interest or financial ties to disclose.
Borderline ovarian tumors (BOTs), or low malignant potential tumors, account for 10% to 15% of all ovarian epithelial tumors.1 Borderline ovarian tumors share some of the histological features of malignant epithelial ovarian tumors but are characterized by the absence of identifiable destructive stromal invasion.1 Patients with BOTs exhibit the following characteristics: a younger age at time of diagnosis, an earlier stage at time of presentation, a longer survival rate, and late recurrences.1 The survival rate in patients with BOTs confined to the ovary is 98% to 100%.2 Because a high proportion of women with BOTs are young and the prognosis is excellent, the preservation of fertility is an important issue in the management of these tumors. It is therefore necessary to gather more information about the role for fertility-sparing surgery to provide information to help determine adequate management and to predict prognosis. We evaluated the oncological safety and reproductive outcomes in women treated with fertility-sparing surgery for BOTs and who were followed at our institution.
PATIENTS AND METHODS
After institutional review board approval for medical records and pathological slide reviews was obtained, we retrospectively identified patients with pathologically confirmed BOTs who were treated and followed between January 1997 and December 2009 at the Samsung Medical Center. Patients who did not receive primary treatment or follow-up care at Samsung Medical Center were excluded from analysis. The records were analyzed for demographic information for procedures of the surgery, the histological type of tumor, residual mass, implant invasiveness, surgical stage (as determined using the International Federation of Gynecology and Obstetrics system for ovarian cancer), adjuvant therapy, recurrence, treatment at the times of recurrence, and death. The pathological slides were reviewed by 2 experienced pathologists. Patients with any disagreement between the original and reviewed pathological report were excluded from study population. To evaluate the reproductive outcomes including menstruation and pregnancy, we attempted to have a telephone interview with all the patients who underwent fertility-sparing surgery.
The radicality of surgical management was determined on the basis of disease extent, patient age, and patient's desire to preserve fertility, after thorough preoperative counseling. The surgical procedure was considered fertility sparing when the uterus and at least part of 1 ovary were left in situ. Thus, unilateral salpingo-oophorectomy and unilateral ovarian cystectomy with/without contralateral ovarian cystectomy or wedge resection were all defined as fertility-sparing surgeries. Radical surgery was defined as a treatment without conservation of female reproductive potential. The standard radical treatment was hysterectomy and bilateral salpingo-oophorectomy. Peritoneal implants were divided histologically into noninvasive and invasive implants by the absence or presence of destructive stromal invasion into the underlying tissue.3,4 Recurrence was defined as the same tumor cell type detected after an apparent complete surgical resection. Recurrent tumors were subclassified into 2 forms: (1) recurrence as BOT, and (2) recurrence as invasive ovarian carcinoma (IOC). The surgical approach (laparoscopy vs laparotomy) was at the discretion of the attending surgeon but was not limited to a specific study period or a specific surgeon. Patients were treated with adjuvant platinum-based chemotherapeutic regimens at the discretion of their physician. After completion of primary treatment, patients were examined every 3 months during the first 2 years, every 6 months during the next 3 years, and yearly thereafter.
The tumor recurrence rate, progression to IOC rate, fertility outcome, and the number of pregnancies were analyzed. The recurrence-free survival time was calculated as the number of months from the date of surgery to the date of surgery or the date of disease recurrence of the date censored. The survival curves and rates were calculated using the Kaplan-Meier method. The differences in survival were assessed using the log-rank test. Frequency distributions were compared using χ2 and Fisher exact tests, and the mean and median values between groups were compared using Student t test and the Mann-Whitney U test. A P ≤ 0.05 in a 2-sided test indicated a significant difference. The statistical analysis was performed with SPSS software (version 12.0; SPSS, Inc, Chicago, Ill).
Two hundred ninety-eight patients with BOTs met our inclusion criteria. Of the 298 patients, 143 underwent radical surgery, and 155 underwent fertility-sparing surgery. Table 1 shows the characteristics of the study patients. The median patient age at the time of surgery was significantly lower in the fertility-sparing surgery group than the radical surgery group (49 years vs 29 years, P < 0.001). In the fertility-sparing surgery group, 106 (68.3%) women were nulliparous, and 8 (5.2%) were primiparous. The tumor size did not differ significantly between the 2 surgery groups. The proportion of patients with advanced stage disease (stages II and III) in the fertility-sparing group was significantly lower compared with that in the radical surgery group (3.2% vs 14.0%, P = 0.002), and the proportion of patients who underwent a laparoscopic surgical approach in fertility-sparing surgery group was significantly higher compared with that in the radical surgery group (32.2% vs 4.2%, P < 0.001). The proportion of additional surgical procedures was less frequently performed in the fertility-sparing surgery group than the radical surgery group, as follows: peritoneal cytology (97.9% vs 94.8%), omentectomy (66.0% vs 31.6%), and appendectomy (51.0% vs 14.8%). Of the 155 women in the fertility-sparing surgery group, 117 (75.4%) underwent unilateral salpingo-oophorectomy, and 38 (24.5%) underwent unilateral ovarian cystectomy. Adjuvant chemotherapy was administrated to 30 patients as platinum-based regimens: chemotherapy was mainly indicated for patients with advanced-stage disease and patients with massive ascites or tumors with micropapillary pattern, intraepithelial carcinoma, or microinvasion.
The median follow-up time was 54.4 months (range, 1.5-147.6 months) in the radical surgery group and 56.0 months (range, 0.6-155.9 months) in the fertility-sparing surgery group. The 5-year recurrence-free survival rates in the radical surgery group and the fertility-sparing surgery group were 95.2% and 93.8%, respectively. Nineteen patients had a recurrence after 10 to 77 months from initial surgery (median interval, 38 months). The rate of recurrence was higher among the fertility-sparing surgery group (7.7%) than the radical surgery group (4.9%); however, this difference was not statistically significant (P = 0.280). After excluding patients with advanced-stage disease, which is known as the most important prognostic factor of recurrence for patients with BOTs,5,6 recurrence-free survival did not differ significantly between the 2 surgery groups (Fig. 1) and between mucinous tumors and nonmucinous tumors (4.7% vs 6.9%, P = 0.548).
Table 2 shows the characteristics of patients with recurrences. Of the 19 patients, 15 had a BOT recurrence, and 4 had an IOC recurrence. All but 1 patient with a recurrence underwent secondary surgery with or without adjuvant chemotherapy. Of the 12 patients who developed recurrences of disease in the fertility-sparing surgery group, 8 underwent a radical surgery as the treatment at the recurrence, and 4 underwent a second round of fertility-sparing surgery; one had a second recurrence of a BOT in the remaining ovary, which was salvaged with radial surgery. In the fertility-sparing surgery group, the rate of recurrence did not differ significantly between unilateral salpingo-oophorectomy and ovarian cystectomy only (5.9% vs 13.2%, P = 0.110). In this group, the site of recurrence in all patients was the remaining ovary. The patients were successfully treated with surgical management and received no additional chemotherapy. In addition, univariate analysis was performed to identify prognostic factors for recurrence. Stage (hazard ratio [HR], 3.15; 95% confidence interval [CI], 1.24-8.04; P = 0.011), presence of invasive implants (HR, 9.00; 95% CI, 2.07-39.13; P < 0.001), and micropapillary pattern (HR, 5.9; 95% CI, 2.1-16.4; P = 0.004) were significant prognostic factors. However, multivariate analysis of these significant variables was not possible because of the relatively small number of recurrences. At the time of analysis, 1 patient had died of disease, 2 patients were alive with disease, and the remaining patients were alive with no evidence of disease.
Of 155 patients who underwent fertility-sparing surgery, 116 (74.4%) were contacted by telephone and were able to provide information related to their menstrual cycles and obstetric histories. Of the 116 patients, 108 (93.1%) had regular menstruation, 6 (5.6%) had irregular menstruation, and 2 (1.9%) had premature menopause. Of the 116 patients, 51 attempted to conceive, and 45 (88.2%) succeeded (48 singleton pregnancies, 3 twin pregnancies, 3 miscarriages, and 4 ongoing pregnancies); 40 conceived spontaneously, 3 of whom conceived after ovulation induction using clomiphene and 2 of whom conceived after in vitro fertilization treatment. The median time between the initial surgery and pregnancy was 28 months (range, 8-97 months). At the time of analysis, 54 healthy full-term babies had been born without congenital anomalies, and 4 women were in the second or third trimester of pregnancy. At the time of surgery, 4 patients were during the pregnancy: 3 patients underwent ovarian cystectomies at the second trimester, and 1 patient underwent a unilateral salpingo-oophorectomy at the first trimester. All 4 patients delivered healthy, full-term babies. To date, none of these patients has undergone radical surgery after completion of childbearing, with the exception of 1 patient who had stage IIc disease with invasive implants.
Borderline ovarian tumors occur in younger patients than IOC. In the current study, 157 patients (52.7%) were younger than 40 years, and 44.6% were nulliparous. In view of the relatively young age, fertility-sparing surgery (cystectomy or oophorectomy) is considered in managing these patients. Seventy percent of all serous BOTs and 90% of all mucinous BOTs are diagnosed as stage I disease, and because survival for stage I disease is excellent, today, there is a trend to treat them with conservative surgery.7 Our data confirm that fertility-sparing surgery for patients with BOTs is safe and can result in future pregnancies, suggesting that such surgery should be considered for young patients who wish to preserve fertility.
The main histological type in our study was mucinous (59.4%). Interestingly, although studies in Western countries have reported the serous type as the most common histology (serous, 59.4%-70.1%),8-12 studies in Eastern countries reported the mucinous type to be the most common (mucinous, 67.4%-68.1%).6,13,14 This discrepancy might be accounted for by genetic differences between these 2 groups, but the exact reason is not clear.
We compared the tumor recurrence rates and incidence of pregnancy in 143 patients who had undergone radical surgery with 155 patients who had undergone fertility-sparing surgery. There was no significant difference between the 2 groups in recurrence rates (4.9% vs 7.7%, P = 0.280), and this finding did not change when analyzing stage I disease only (3.3% vs 8.0%, P = 0.127). Based on literature (Table 3), the recurrence rate is somewhat higher (many studies) or similar (few studies) in the fertility-sparing group (rate, 6.5%-29.5%) than the radical surgery group (rate, 0%-8%).6-8,10-12,15 We suggest that the difference in recurrence rates is attributable to the different recurrence patterns between the 2 groups. Indeed, the main site of recurrence in the fertility-sparing surgery group was an isolated recurrence on the remaining ovary. In these women, the recurrence can be successfully salvaged with repeat surgery, and fertility-sparing surgery can be attempted if childbearing has not been completed.
In our series, only 2 (1.9%) of the 116 patients contacted by telephone had premature menopause. We showed that the pregnancy rate was 88% when calculated with 51 patients who had desired fertility. This finding is similar to the reports of Romagnolo et al11 and Park et al,6 who observed pregnancy rates of 67% and 87%, respectively (Table 3). Although only 4 of the 51 patients who attempted to conceive had received postoperative adjuvant chemotherapy, all had successful term pregnancies. These findings indicate that reproductive outcomes after fertility-sparing surgery are very promising.
Our study had several limitations. First, systemic lymphadenectomy was not considered beforehand in all cases so that our data may be biased in this respect. According to the literature, lymphadenectomy can be omitted, even for advanced disease.16,17 Nevertheless, Camatte et al9 reported that the absence of peritoneal staging in patients with an "apparent stage I" BOT does not modify survival, even if the recurrence rate is increased. However, further studies involving much larger numbers of patients with BOTs should be carried out to confirm this issue. Second, our study was a retrospective design, therefore possibly introducing some degree of bias. Prospective randomized trials are therefore needed to clarity the roles of fertility-sparing surgery for women with BOTs. Third, given that the median time to recurrence for BOTs has been reported to be 5 to 7 years,18 and given the rare recurrence of stage I BOTs, our sample size and follow-up period may weaken our results.
In conclusion, fertility-sparing surgery for BOTs should be considered for women in the reproductive age group who desire preservation of fertility because the reproductive outcomes are encouraging after fertility-sparing surgery, and there is no significant difference between the 2 surgery groups in recurrence rates.
1. Gershenson DM. Clinical management potential tumours of low malignancy. Best Pract Res Clin Obstet Gynaecol
2. Seidman JD, Ronnett BM, Kurman RJ. Pathology of borderline (low malignant potential) ovarian tumours. Best Pract Res Clin Obstet Gynaecol
3. Bell DA, Weinstock MA, Scully RE. Peritoneal implants of ovarian serous borderline tumors. Histologic features and prognosis. Cancer
4. Michael H, Roth LM. Invasive and noninvasive implants in ovarian serous tumors of low malignant potential. Cancer
5. Gershenson DM, Silva EG. Serous ovarian tumors of low malignant potential with peritoneal implants. Cancer
6. Park JY, Kim DY, Kim JH, et al. Surgical management of borderline ovarian tumors: the role of fertility-sparing surgery. Gynecol Oncol
7. Gotlieb WH, Flikker S, Davidson B, et al. Borderline tumors of the ovary: fertility treatment, conservative management, and pregnancy outcome. Cancer
8. Boran N, Cil AP, Tulunay G, et al. Fertility and recurrence results of conservative surgery for borderline ovarian tumors. Gynecol Oncol
9. Camatte S, Morice P, Thoury A, et al. Impact of surgical staging in patients with macroscopic "stage I" ovarian borderline tumours: analysis of a continuous series of 101 cases. Eur J Cancer
10. Morice P, Camatte S, El Hassan J, et al. Clinical outcomes and fertility after conservative treatment of ovarian borderline tumors. Fertil Steril
11. Romagnolo C, Gadducci A, Sartori E, et al. Management of borderline ovarian tumors: results of an Italian multicenter study. Gynecol Oncol
12. Zanetta G, Rota S, Chiari S, et al. Behavior of borderline tumors with particular interest to persistence, recurrence, and progression to invasive carcinoma: a prospective study. J Clin Oncol
13. Wong HF, Low JJ, Chua Y, et al. Ovarian tumors of borderline malignancy: a review of 247 patients from 1991 to 2004. Int J Gynecol Cancer
14. Wu TI, Lee CL, Wu MY, et al. Prognostic factors predicting recurrence in borderline ovarian tumors. Gynecol Oncol
15. Donnez J, Munschke A, Berliere M, et al. Safety of conservative management and fertility outcome in women with borderline tumors of the ovary. Fertil Steril
16. Cadron I, Leunen K, Van Gorp T, et al. Management of borderline ovarian neoplasms. J Clin Oncol
17. Tinelli R, Tinelli A, Tinelli FG, et al. Conservative surgery for borderline ovarian tumors: a review. Gynecol Oncol
18. Crispens MA, Bodurka D, Deavers M, et al. Response and survival in patients with progressive or recurrent serous ovarian tumors of low malignant potential. Obstet Gynecol