REPRODUCTIVE SURGERY Clinical outcome of cystectomy compared with unilateral salpingo-oophorectomy as fertility-sparing treatment of borderline ovarian tumors Yoav Yinon, M.D., Mario E. Beiner, M.D., Walter H. Gotlieb, M.D., Ph.D., Yaacov Korach, M.D., Tamar Perri, M.D., and Gilad Ben-Baruch, M.D. Division of Gynecological Oncology, Department of Obstetrics and Gynecology, The Chaim Sheba Medical Center, Tel- Hashomer, Tel-Aviv University, Israel Objective: To compare recurrence rates and fertility outcomes of patients with borderline ovarian tumors (BOTs) who underwent unilateral salpingo-oophorectomy with those of patients who underwent cystectomy only. Design: Retrospective study. Setting: Gynecologic oncology department of a tertiary center. Patient(s): Sixty-two patients with BOTs who underwent fertility-preserving surgery. Intervention(s): Unilateral salpingo-oophorectomy (USO, n 40) or cystectomy only (n 22). Main Outcome Measure(s): Tumor recurrence rate, incidence of pregnancy. Result(s): All 62 patients were alive with no clinical evidence of disease after a mean follow-up of 88 months. There was no statistically significant difference in mean tumor recurrence rates between patients who had undergone cystectomy only and those who had undergone USO (22.7% and 27.5%, respectively). In the cystectomy-treated group, the disease-free interval was shortened (23.6 compared with 41 mo), but the difference was not significant. However, the mean follow-up period for the cystectomy group was significantly shorter than for the USO group. Of the 62 patients, 25 (40.3%) attained 38 pregnancies, resulting in 35 deliveries. Conclusion(s): Our results support previous findings that conservative surgery is an acceptable option for women with BOTs who wish to preserve fertility. Cystectomy, like oophorectomy, appears to be an adequate treatment, provided that the patient is willing to undergo careful and prolonged follow-up. (Fertil Steril 2007;88:479 84. 2007 by American Society for Reproductive Medicine.) Key Words: Borderline ovarian tumors, conservative treatment, fertility-preserving surgery Borderline tumors of the ovary, also known as low malignant potential tumors, account for 10% 15% of all ovarian tumors. Studies have consistently demonstrated the favorable prognosis of these tumors, with an overall 10-year survival rate of 83% 91% (1, 2). Although these tumors are usually benign, they can present as a metastatic disease and can recur as long as 10 years after the primary diagnosis. Recurrence in the form of invasive carcinoma is rare (3). Borderline ovarian tumors (BOTs) often occur in reproductiveage women. Because of their generally benign behavior, their management has become more conservative, allowing women to maintain fertility (4 6). Fertility-preserving treatments include procedures in which the uterus and at least some functional ovarian tissue remain, enabling pregnancy Received May 13, 2006; revised and accepted November 21, 2006. Reprint requests: Yoav Yinon, M.D., or Gilad Ben-Baruch, M.D., Department of Obstetrics and Gynecology, The Chaim Sheba Medical Center, 52621 Tel-Hashomer, Israel (FAX: 972-3-530-2154; E-mail: yinony@barak-online.net or benbaruc@post.tau.ac.il) achievement even though the loss of a considerable part of the oocyte reserve may reduce fertility (4, 7). Previous studies have indicated the safety of conservative surgery with unilateral salpingo-oophorectomy (USO) or cystectomy for patients with stage I BOTs (8, 9). However, only limited data are available with regard to the clinical outcome and fertility after cystectomy only. The aim of this study was to compare the outcome of patients treated by cystectomy only with that of patients treated by USO. MATERIALS AND METHODS This retrospective study was based on the collected data, including inpatient and outpatient records, surgical notes, and pathology reports, of all consecutive patients with BOTs who were treated in our center between 1979 and 2004 (n 158). Our study group comprised 62 patients who had undergone fertility-preserving surgery, defined as any procedure in which the uterus and at least some ovarian tissue were left intact. Some of these patients were included in our reports published elsewhere (6, 10). 0015-0282/07/$32.00 Fertility and Sterility Vol. 88, No. 2, August 2007 doi:10.1016/j.fertnstert.2006.11.128 Copyright 2007 American Society for Reproductive Medicine, Published by Elsevier Inc. 479
Two pathologists had reviewed all of the original histology slides and confirmed the diagnosis of BOT, defined as an ovarian tumor with stratification of the epithelial lining, formation of microscopic papillary projections, presence of nuclear atypia, and absence of frank stromal invasion (11, 12). Stage of disease had been defined according to the 1988 International Federation of Gynecology and Obstetrics criteria, based on surgical notes and pathology reports. Followup had included physical examination, pelvic sonography, and CA-125 blood test every 3 months for 3 years after the operation and twice yearly thereafter. If a suspicious ovarian mass was found, the patient had undergone another operation. The mean tumor recurrence rate and mean incidence of pregnancy in women who had undergone only cystectomy were compared with those in women who had undergone USO. Student s t-test and the 2 test were used for statistical analysis of the results. P values of.05 were considered significant. The study was approved by the ethics committee of the Chaim Sheba Medical Center. RESULTS Of the 62 patients with BOTs who had undergone conservative surgery, 33 had cystectomy and 29 had USO. The mean age at diagnosis for the total group was 28 years (range 13 44). Tumors were serous in 38 cases (61.3%) and mucinous in 24 (38.7%). Two patients had a serous BOT with micropapillary pattern. There was no significant difference in the median size of the tumor between the patients who initially underwent cystectomy and patients who initially underwent USO (10 cm vs. 9 cm respectively, P.77). In 14 of the 29 patients in the USO group, the procedure had included surgical staging. In 2 of these patients, this was performed within 3 months after the primary surgery FIGURE 1 Primary surgical procedure in women undergoing fertility-sparing surgery for borderline ovarian tumor. TABLE 1 Characteristics of women undergoing cystectomy or unilateral salpingooophorectomy for borderline ovarian tumor. Parameter USO (%) (n 40) Cystectomy only (%) (n 22) P value Mean age (y) 28.5 27.1.44 Histology Serous, n (%) 21 (52.5) 17 (77).056 Mucinous, 19 (47.5) 5 (23).056 n (%) Surgical staging, 25 (63) 1 (5) n (%) Apparent stage I, n (%) 36 (90) 21 (95).46 Note: All P values are statistically nonsignificant. (Fig. 1). Twelve of the patients in the cystectomy-only group had undergone reoperation within 3 months; of these, 9 had undergone USO and surgical staging, 2 had USO only, and 1 had surgical staging that did not include ovarian biopsy (Fig. 1). None of the reoperated patients demonstrated evidence of persistent disease. We defined the extent of surgical treatment on the basis of both the primary surgical procedure and reoperation within 3 months after the primary surgery. Accordingly, the patients were divided into two groups. As shown in Table 1, there were 22 women in the cystectomy-only group and 40 in the USO group. There were no differences between the two groups in age at diagnosis or in the numbers of women whose tumors were serous in nature. Twenty-one patients (95.4%) in the cystectomy group had apparent stage I disease, compared with 36 patients (90%) in the USO group (P.46). The only surgically staged patient in the cystectomy group was found to have stage IIIa disease. Of the 25 patients in the USO group who were staged, one was diagnosed with stage IIc disease and three with stage III disease (one with stage IIIb and two with stage IIIc). Within a mean period of 36 months (range 7 81 mo), 16 (25.8%) of the 62 women developed a local recurrence (Table 2). The cystectomy-only group did not differ significantly from the USO group with regard to the incidence of recurrence, nor in the mean interval between diagnosis and recurrence. The mean follow-up period for the cystectomy group was significantly shorter than for the USO group (Table 2). Comparison of the patients with serous tumors (17 women in the cystectomy-only group and 21 in the USO group; Table 3) revealed no significant difference in their mean recurrence rates. As shown, the mean interval between di- 480 Yinon et al. Conservative treatment of borderline tumors Vol. 88, No. 2, August 2007
TABLE 2 Clinical outcome of women undergoing cystectomy or unilateral salpingo-oophorectomy for borderline ovarian tumor. Parameter USO (%) (n 40) Cystectomy (%) (n 22) P value Reoperation (%) 15 (37.5) 6 (27) Recurrence (%) 11 (27.5) 5 (22.7).8 (NS) Mean interval to recurrence (range), mo 41 (9 81) 23.6 (7 41).2 (NS) No. of women pregnant (%) 19 (47.5) 6 (22.7) No. of pregnancies 31 b 7 a No. of deliveries 28 7 Mean follow up (range), mo 101 (6 30) 65 (6 180).05 Note: NS not significant. a Two after IVF treatment. b Three after IVF treatment. agnosis and recurrence in these patients was shorter, though not significantly, in the cystectomy-only group than in the patients with USO. In the cystectomy-only group, six patients had undergone reoperation because of suspected local recurrence, and in five of them the diagnosis of recurrent borderline tumor was confirmed. All of the recurrences in this treatment group were in patients with serous ovarian tumors (four ipsilateral and one contralateral). Three of these patients underwent salpingo-oophorectomy of the involved ovary, and two underwent a second cystectomy. One patient in this group, after undergoing cystectomy for recurrent tumor in the contralateral ovary, had a second recurrence in the contralateral ovary 3 years after the first recurrence. In view of her desire to preserve fertility, she underwent another cystectomy; 2 months later, however, in view of evidence of borderline tumor in the capsule of the ovary on final pathologic report, she opted to have the remaining ovary removed. Notably, all recurrences in this group were of borderline malignancy. In the USO group, 15 patients had undergone reoperation because of suspected local recurrence, and in 11 of them the diagnosis was confirmed. Nine of the 11 recurrences were in patients with serous tumors. Six of the 11 patients wished to preserve fertility and underwent cystectomy, 2 patients underwent salpingo-oophorectomy, and 3 patients underwent salpingo-oophorectomy and hysterectomy. Pathologic findings were borderline in 10 patients, and in one patient histopathological examination revealed endometrioid ovarian carcinoma. This patient initially underwent LSO staging because of left mucinous BOT. Nine months later, she was reoperated on because of a contralateral ovarian mass and underwent RSO. At this time, the histopathological diagnosis was endometrioid ovarian carcinoma. She was treated with chemotherapy and underwent total abdominal TABLE 3 Clinical outcome of women undergoing cystectomy or USO for serous borderline ovarian tumor. Parameter USO (%) (n 21) Cystectomy (%) (n 17) P values Reoperation (%) 11 (52) 6 (35) Recurrence (%) 9 (43) 5 (29).4 Mean interval to recurrence, mo 46 23.6.12 No. of women pregnant 8 5 No. of pregnancies 11 7 No. of deliveries 8 7 Mean follow-up (mo) 96 80.45 Note: All P values are statistically not significant. Fertility and Sterility 481
hysterectomy (TAH) a few months later because of endometrial carcinoma. She is alive and free of disease 14 years after her initial diagnosis. All patients with recurrences were alive and free of disease at a mean follow-up of 69 months from diagnosis of recurrence. After treatment of the borderline tumor, 38 pregnancies were achieved in 25 women, resulting in 35 deliveries (Table 2). The mean time between operation and pregnancy was 42 months (range, 9 144 mo). In the cystectomy-only group, six women had seven pregnancies (two of them achieved after IVF treatment), resulting in seven deliveries. In the USO group, 19 women had 31 pregnancies (three achieved after IVF treatment), resulting in 28 deliveries. One of these patients had been diagnosed with right-sided BOT during IVF treatments for unexplained infertility. Cystectomy together with complete staging had disclosed stage IIIa serous BOT. After recurrence 6 months later, she had undergone another cystectomy. She subsequently conceived by IVF, delivering her first child 18 months after the primary surgery and another child after IVF treatment 2 years later. Four months after her second delivery, the left ovary developed a second recurrence, and she underwent USO. Currently ( 2 y after the last recurrence), she shows no evidence of disease. DISCUSSION Patients with BOTs tend to be younger than women with invasive ovarian cancer (3, 8), and many of them wish to preserve their fertility. The usual standard management has traditionally been total hysterectomy with bilateral adnexectomy, but conservative treatment of borderline tumors is receiving increasing consideration as an acceptable option. Ovarian cystectomy may provide a better chance of preserving fertility than adnexectomy because in the former procedure, less ovarian tissue is removed. The risk is that some malignant cells inadvertently may be left behind. Although the question of fertility-sparing surgery has been addressed in many studies, only limited published data are available on the safety and outcome of treatment by cystectomy only. We compared the tumor recurrence rates and incidence of pregnancy in 22 women who had undergone only cystectomy with those in 40 women who had undergone USO. There was no significant difference between the two groups in mean recurrence rates (22.7% and 27.5%, respectively; Table 2), and this finding did not change when analyzed according to the histological type of the tumor (serous tumors only; Table 3). The time lapse between diagnosis and recurrence was shorter, though not significantly, in the cystectomy-only group than in the USO group (23.6 and 41 mo, respectively). Accumulating evidence indicates that unilateral oophorectomy provides a safe therapeutic alternative to BOTs in women wishing to preserve fertility (8, 9, 13). In a study of 339 women treated for BOTs, Zanetta et al. (14) reported that despite a higher mean recurrence rate for women undergoing fertility-preserving surgery (35/189 cases, 18.5%) than for women undergoing hysterectomy and bilateral salpingo-oophorectomy (7/150 cases, 4.7%), all but one woman (in whom conservative surgery was followed by progression to carcinoma), were salvaged. Camatte et al. (15) reported recurrence in only 2/17 women with stage II or stage III BOT treated with fertility-preserving surgery, with no deaths at a median follow-up of 60 months. In a recent study by Fauvet et al. (16), in which 162 of 360 women with BOTs underwent conservative surgery, the mean recurrence rate was significantly higher in the conservatively treated group than in the group who underwent radical surgery (16.6% compared with 4.5%). However, in no case did the carcinoma recur during the study period, and none of the conservatively treated women died of the disease. A lower mean recurrence rate after conservative surgery (6.5%) was recently reported, but it was still higher than that obtained after radical surgery (17). All of the above studies thus demonstrated that although conservative surgery is associated with a higher incidence of recurrence, in most cases surgical salvage is possible and therefore recurrence does not affect survival (4, 14 17). The findings of the present study indicate that cystectomy, like oophorectomy, appears to be a satisfactory therapy in women who are willing to undergo careful and prolonged follow-up examination. We are aware of the fact that the lack of difference in recurrence rates between our two groups may be attributable, at least in part, to the small sample size and the shorter follow-up period of the cystectomy group compared with those of the USO group (a discrepancy that arises from the relatively recent introduction of cystectomy as an acceptable treatment for BOT). Another limitation of this study is the imbalance between the cystectomy-only and the USO groups with regard to histology. However, when we restricted our analysis to patients with serous tumors only, similar results were obtained. Lim-Tan et al. (9) reported on a series of ovarian cystectomies for serous borderline tumors. Follow-up evaluations of their 35 patients demonstrated that despite four cases of tumor recurrence, all of the women were alive and evidently free of disease 3 to 18 years after the initial surgery. However, within weeks to months after the initial procedure, many of these patients had undergone extension of their surgical treatment and therefore did not fit our definition of cystectomy-only treatment (Table 4). In a prospective Gynaecologic Oncology Group study (8), seven patients underwent ovarian cystectomy with subsequent surgical reexploration to complete the staging procedure. No residual tumors were detectable in any of the cystectomized ovaries. Zanetta et al. (14) reported nine recurrences in 50 women (18%) with stage I borderline tumors treated by cystectomy only (Table 4). In contrast to our findings are those of Morice et al. (5) in their study of 44 patients who were treated conservatively, 482 Yinon et al. Conservative treatment of borderline tumors Vol. 88, No. 2, August 2007
TABLE 4 Summary of published reports on women with borderline tumors treated by cystectomy. Reference No. of patients Mean follow-up (mo) Clinical outcome Interval to recurrence (mo) Recurrence rate (%) Lim-Tan et al. (9) 35 a 90 NED NS 11.4 Morice et al. (5) 11 109 NED NS 36.3 Zanetta et al. (14) 50 70 NED 39 18 Present study 22 65 NED 23.6 22.7 Note: NS not stated; NED no evidence of disease at last follow-up. a Twenty-one patients underwent re-operation, thus only 14 patients fit our definition of cystectomy-only treatment. 11 with cystectomy and 33 with USO. Recurrence rates were 36.3% and 15.1%, respectively. The investigators concluded that the ideal conservative treatment is USO and that cystectomy should be reserved for patients who have previously undergone adnexectomy but who subsequently require treatment for a recurrent borderline tumor and wish to preserve fertility. Our findings suggested, however, that the procedures are equally safe. The apparent difference in the findings may be attributable to the smaller study group of Morice et al. (5) (Table 4). A diagnosis of BOT is often made after laparoscopic cystectomy for an apparently benign ovarian cyst. Our data suggested that in young women with an incidental diagnosis of serous- or endocervical-type BOT, reoperation can safely be avoided and careful follow-up instituted instead. Of our 62 patients, 33 had undergone cystectomy as their initial operation, and in 11 of them, the surgical treatment was expanded to salpingo-oophorectomy within 3 months. Retrospectively, in view of the results, this second surgery was probably not advisable. Our data also confirm that cystectomy offers a safe treatment for patients with recurrent borderline tumor and a history of adnexectomy who wish to preserve fertility. Even if cystectomy increases the risk of recurrence, the recurrent disease is amenable to surgical treatment, and patient survival is not affected by this approach (5). In our study, 25 women had achieved 38 pregnancies after treatment, resulting in 35 deliveries. Five of these pregnancies were achieved as a result of IVF. Reported spontaneous fertility rates after conservative treatment for BOT vary between 32% and 65% (16, 18). Seracchioli et al. (19) described 10 patients who attempted pregnancy of 19 women who had undergone conservative surgery for BOTs. Six of them conceived spontaneously and delivered at term. The disease did not affect the gestation or the follow-up period after the pregnancy. Fauvet et al. described 65 women who attempted to conceive after conservative treatment for BOT (16). Of the 30 pregnancies attained, 27 were spontaneous and 3 followed ovarian stimulation or IVF. With regard to the rate of tumor recurrence or mean time to recurrence, women who conceived did not differ from women who did not conceive (16). We described elsewhere 43 patients who were treated conservatively for BOTs (10). Thereafter, 19 patients delivered 25 healthy children. Seven of these patients were treated with IVF. Of these 7 women, 4 experienced recurrence of BOT, 2 before and 2 after IVF treatments. Our data therefore support the feasibility of fertility treatments and pregnancy for women treated for BOT, because even if disease recurs, it is almost always treatable. An additional question is whether reoperation should be performed to remove the remaining ovary when fertility is no longer desired. To date, no standard practice has been accepted. It appears, however, that because recurrent diseases (borderline type in most cases) can easily be cured by removal, it would probably be safe to consider that systematic removal of the spared ovary is not mandatory (20). Our current policy does not include systematic removal of the spared ovary, provided that the patient is willing to undergo a prolonged follow-up. In conclusion, our results confirm that conservative surgery is an acceptable option for women with BOTs who wish to preserve fertility. Cystectomy, like oophorectomy, appears to be an adequate treatment, provided that the patient is willing to undergo careful and prolonged follow-up. REFERENCES 1. Nikrui N. Survey of clinical behavior of patients with borderline epithelial tumors of the ovary. Gynecol Oncol 1981;12:107 19. 2. Gershenson DM, Silva EG. Serous ovarian tumors of low malignant potential with peritoneal implants. Cancer 1990;65:578 85. 3. Crispens MA. Borderline ovarian tumours: a review of the recent literature. Curr Opin Obstet Gynecol 2003;15:39 43. 4. Donnez J, Munschke A, Berliere M, Pirard C, Jadoul P, Smets M, et al. Safety of conservative management and fertility outcome in women with borderline tumors of the ovary. Fertil Steril 2003;79:1216 21. 5. Morice P, Camatte S, El Hassan J, Pautier P, Duvillard P, Castaigne D. Clinical outcomes and fertility after conservative treatment of ovarian borderline tumors. Fertil Steril 2001;75:92 6. Fertility and Sterility 483
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