Feasibility, safety, and efficacy of conservative laparoscopic treatment of borderline ovarian tumors

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1 Feasibility, safety, and efficacy of conservative laparoscopic treatment of borderline ovarian tumors Raffaele Tinelli, M.D., a Mario Malzoni, M.D., a Francesco Cosentino, M.D., a Ciro Perone, M.D., a Andrea Tinelli, M.D., a Antonio Malvasi, M.D., a and Ettore Cicinelli, M.D. b a Advanced Gynecological Endoscopy Center, Malzoni Medical Center, Avellino; and b Department of Obstetrics and Gynecology, University Medical School of Bari, Bari, Italy Objective: To outline the most recent information regarding conservative laparoscopic surgery for young women with borderline ovarian tumors. Design: Review article. Setting: Advanced Gynecological Endoscopy Center, Malzoni Medical Center, Avellino, Italy. Patient(s): Young women with low-stage borderline ovarian tumors who wish to preserve their fertility. Intervention(s): Conservative laparoscopic surgery with unilateral salpingo-oophorectomy or cystectomy. Main Outcome Measure(s): Recurrence rate and outcomes. Result(s): Laparoscopic cystectomy may have more chance of preserving a woman s fertility compared with adnexectomy because of the removal of less ovarian tissue. Its greatest danger is the risk of inadvertently leaving behind some malignant cells. Therefore, this procedure should be reserved for patients with previous unilateral salpingo-oophorectomy or when bilateral lesions are present to preserve at least some ovarian tissue. Conclusion(s): When borderline ovarian tumors are identified at surgery by intraoperative histology, the recommended conservative treatment should be laparoscopic salpingo-oophorectomy. Recurrence can be noted after this type of treatment, but the cases of recurrent disease can be detected with close follow-up and treated accordingly. For these reasons, careful selection of candidates for this kind of treatment is, of course, necessary and close follow-up is required. If these restrictions are rigorously applied, then fertility-sparing surgery may be considered a safe option for this pathology, but all laparoscopic procedures should be reserved for oncologic surgeons trained in extensive laparoscopic procedures. (Fertil Steril Ò 2009;92: Ó2009 by American Society for Reproductive Medicine.) Key Words: Borderline ovarian tumor, cystectomy, laparoscopy, recurrence, salpingo-oophorectomy A borderline tumor of the ovary is an epithelial tumor with a low rate of growth and a low potential to invade or metastasize (1, 2). They account for 10% 15% of all ovarian tumors (3, 4). In particular, this type of ovarian tumor is characterized by a degree of cellular proliferation (stratification of the epithelial lining of the papillae, and nuclear atypia and mitotic activity) in the absence of stromal invasion (5). The 1987 International Federation of Gynecology and Obstetrics classification was used for staging (6). Stage was recorded by using the macroscopic description during the surgical procedure and by reviewing pathology records. Stage I is defined as a tumor limited to one or both ovaries; stages II and III are defined by the presence of an ovarian borderline tumor in addition to pelvic (stage II) or abdominopelvic (stage III) peritoneal implants. Peritoneal implants were classified as noninvasive or invasive according to the absence or presence of stromal invasion of the peritoneum (7, 8). Received March 25, 2008; revised June 11, 2008; accepted July 9, 2008; published online September 15, RT. has nothing to disclose. M.M. has nothing to disclose. F.C. has nothing to disclose. C.P. has nothing to disclose. E.C. has nothing to disclose. D.I. has nothing to disclose. M.R. has nothing to disclose. Reprint requests: Raffaele Tinelli, M.D., Advanced Gynecological Endoscopy Center, Malzoni Medical Center, Avellino, Italy (FAX: ; raffaeletinelli@tiscali.it). Borderline epithelial ovarian tumors are generally discovered at an earlier stage than malignant tumors. They frequently affect young women in which conservative and minimally invasive surgery is required to preserve childbearing potential (9). Laparoscopy can be used to perform all the surgical procedures needed in patients with early borderline ovarian tumors (BOT), including excision (adnexectomy and hysterectomy) and staging (peritoneal biopsies, omentectomy, appendectomy in patients with mucinous tumors, and removal of pelvic and paraaortic lymph nodes, although this last procedure has generated controversy in recent years). Laparoscopic management seems feasible in early BOT (10 12). Laparoscopic treatment of adnexal masses has proved to be a safe and effective diagnostic and therapeutic tool in the hands of experienced laparoscopists (13). THERAPY All procedures are performed under general endotracheal anesthesia. The patient are usually placed in the dorsolithotomy position, with the legs in universal Allen stirrups. In addition, intraoperative lower extremity sequential compression devices for venous thrombosis prophylaxis are used. The entire procedure is performed through laparoscopy and all patients are given antibiotic prophylaxis (cefoxitin 736 Fertility and Sterility â Vol. 92, No. 2, August /09/$36.00 Copyright ª2009 American Society for Reproductive Medicine, Published by Elsevier Inc. doi: /j.fertnstert

2 2 g IV). The vaginal cavity is cleansed with povidone-iodine solution and a Foley catheter is placed in the bladder. After a carbon dioxide pneumoperitoneum by Veress needle is induced at the level of umbilicus, a 10-mm trocar that incorporates the zero-degree laparoscope is inserted through an umbilical vertical incision and the entrance into the abdominal cavity is made under direct visualization, The laparoscope is connected to a video monitor. Once the trocar has been safely introduced into the abdominal cavity, the intra-abdominal pressure is maintained at 15 mm Hg. Three suprapubic ancillary trocars are used: one 5-mm trocar is inserted in the midline 3 cm under the umbilicus, and one in each iliac fossa (5 mm on the left side and 10 mm on the right size) laterally to the inferior epigastric vessels. Before the operative procedure, all the pelvic structures are inspected and the abdomen explored through the laparoscope in a clockwise fashion. Guidelines for surgical treatment of BOT, in women who do not wish any other pregnancy, include peritoneal washing, hysterectomy with bilateral salpingo-oophorectomy, omentectomy, and multiple peritoneal biopsies (14 17). As has already been discussed, patients with BOT tend to be younger than women with invasive ovarian cancer. For many of these patients, fertility is an important issue. Previous studies have suggested the safety of conservative surgery with unilateral salpingo-oophorectomy or cystectomy for patients with stage I BOT. They are characterized by an excellent long-term survival (14, 18 20). The laparoscopic approach follows a standardized procedure. First, an observational time of adnexal masses in search of macroscopic findings suggestive of malignancy is performed. These features are: presence of extraovarian implants, presence of exophytic growth, anarchic vascularization on the surface of the ovary, and ascites (21). The laparoscopic surgery includes a cytologic evaluation of pelvic and abdominal washings and treatment of adnexal mass by cystectomy or unilateral salpingo-oophorectomy in accordance with recommendations for laparoscopic treatment of benign adnexal mass (21). Tissue is removed from the abdominal cavity using a plastic bag to reduce the possibility of parietal implantation of neoplastic cells. An intraoperative histologic examination on a frozen section preparation is carried out in all patients. Multiple pelvic and abdominal peritoneal and contralateral ovarian biopsies, cytologic evaluation of pelvic and abdominal washings, infracolonic omentectomy, and an accurate abdominal inspection to obtain the intraoperative staging of the disease are performed. Systematic appendectomy is also a criterion for complete staging of mucinous borderline tumors. If there are no obvious abdominal or pelvic peritoneal lesions, random peritoneal biopsies are performed. Laparoscopic salpingo-oophorectomy should be considered as the first choice of conservative treatment in most patients, because it seems to be associated with lower recurrence rates compared with laparoscopic cystectomy. The greatest risks of this procedure are cysts rupture, intra-abdominal spillage, and contamination of the abdominal wall. These risks can be reduced to an acceptable level by the use of a plastic bag, reducing the possibility of parietal implantation of neoplastic cells (13). The laparoscopic approach to borderline tumors, as any suspicious adnexal mass, should follow strict criteria to reduce the risk of spreading and relapse. Spillage should be minimized and in case of intraoperative rupture during laparoscopy or laparotomy, the treatment is the same: a copious washing of the pelvis and abdomen; manipulation of the tumor should be kept to the minimum; any biopsy specimen should be extracted with an endobag protecting the abdominal wall. Laparoscopic cystectomy may have more chance of preserving a woman s fertility compared with adnexectomy because of the removal of less ovarian tissue. Its greatest danger is the risk of inadvertently leaving behind some malignant cells. Therefore, this procedure should be reserved for patients with previous unilateral salpingo-oophorectomy or when bilateral lesions are present to preserve at least some ovarian tissue (13). If bilateral adnexal masses are present in a young patient wanting to preserve fertility, intraoperative decision making is more difficult. Before any resection, the ovarian masses should be carefully inspected and assessed for adjacent normal ovarian tissue. In general, the more suspicious ovary should be removed using the most conservative means on the contralateral side (ovarian cystectomy, if possible) and the specimens sent for frozen section analysis. If a borderline tumor is diagnosed, then either ovarian cystectomy or oophorectomy should be performed on the contralateral side (7, 8, 22, 23). The accuracy of frozen section diagnosis of ovarian tumors is important, especially in young women who may be managed conservatively with preservation of fertility. A recent series by Ilvan et al. (24) confirmed that frozen section diagnosis is a reliable method for the surgical management of BOT with a sensitivity of 87 % and a specificity of 98 %. However, diagnostic problems can occur in mucinous borderline tumors during frozen section examination (24). Although several investigators would recommend routine biopsy of a normal-appearing contralateral ovary, some investigators believe that careful macroscopic inspection of the normal ovary should be sufficient because unnecessary biopsy or wedge resection may result in peritoneal adhesions or ovarian failure (25). Darai et al. (26) reported a series of 25 patients with BOTs first treated by the laparoscopic approach. Among the 25 patients first treated by laparoscopic approach, 15 had conservative treatment and 10 had radical treatment. Three recurrences occurred after cystectomy. Twenty-three patients were alive without evidence of disease, one died of Fertility and Sterility â 737

3 intercurrent disease. Their data suggested that laparoscopic approach to BOTs is possible in early stage disease, but associated with a high risk of recurrence after cystectomy. Maneo et al. (27) evaluated the risk of the laparoscopic approach to patients with BOTs compared with the laparotomic management. Sixty-two patients had fertility-sparing surgery: 30 operated by laparoscopy, 32 by laparotomy. Rupture of the cyst was more frequent in the laparoscopic group. After a follow-up of 61 months for the laparoscopic group, they observed 11 patients (37%) with persistent disease after primary laparoscopy (Table 1). After primary laparotomy, no patients showed early persistence of tumor, and ovarian relapses were diagnosed in seven women (22%). They concluded that laparoscopic treatment of BOTs should be reserved to masses not more than 5 cm. When conservative therapy is desired, the entire affected ovary should be removed. If the neoplasia is bilateral, cystectomy could be allowed in women who wish to preserve fertility, although they are at high risk of relapse. Morice et al. (28) observed in their study the high proportion of patients (42.5%) with peritoneal implants (stage II or III disease). Of patients who were treated conservatively 27 % had a stage II or III disease. In patients with peritoneal implants, location (stage II or III) was less important than their characteristics (invasive or noninvasive) in terms of prognosis (7, 8). In a study by Gersherson et al. (7), 39 patients had invasive peritoneal implants, of which 30% developed into progressive or recurrent disease. At this potential rate TABLE 1 Recurrences after conservative surgery for borderline ovarian tumors: review of literature. Authors of study Patients Treatment Recurrences Darai et al. 25 Laparoscopy 3 Maneo et al. 30 Laparoscopy Laparotomy 7 Deffieux et al. 9 Laparoscopy 4 Romagnolo 113 Laparoscopy 13 et al. 61 Laparotomy Seracchioli 19 Laparoscopy 1 et al. Donnez et al. 3 Laparotomy 3 13 Laparoscopy Fauvet et al. 149 Laparoscopy Laparotomy 19 Boran et al. 56 Laparotomy 4 6 Laparoscopy Camatte 31 Laparoscopy 6 et al. Tinelli et al. 43 Laparoscopy 3 Total Tinelli. Treatment of borderline ovarian tumors. Fertil Steril of progression, performing conservative procedures in patients with invasive implants seems to put them at risk. In the series by Morice et al. (28), as reported by Tazelaar et al. (19), all patients with recurrence who initially received conservative treatment were alive and free of disease. No patients treated conservatively experienced recurrence in the form of invasive ovarian cancer and none of the 10 patients with noninvasive peritoneal implants who were treated conservatively experienced invasive recurrence. All recurrences were diagnosed during routine follow-up procedures (clinical examination or pelvic ultrasonography) and were treated with surgery. The only three patients who had a poor outcome had initial radical surgery, and therefore cannot be considered to have had failure of conservative treatment. Thus, even if conservative surgery increases the risk for ovarian recurrence of BOT tumor, recurrent disease is amenable to surgical treatment and patient survival is not affected by this conservative approach. Conservative treatment should therefore be considered safe only for treatment of younger patients with BOTs who will comply with routine follow-up (28). According to the literature, the most important prognostic factors of patients with advanced stage borderline tumor are: [1] the histologic characteristic of the implants (noninvasive or invasive) and [2] the presence of residual disease at the end of the surgical procedure (7, 8, 28). The rate of recurrent invasive disease is significantly increased in patient with invasive peritoneal implants, compared with patients with noninvasive implants (28). Therefore, prognosis of patients with noninvasive implants is good (if a complete resection of peritoneal disease is performed) (29, 30). On the other hand, prognosis of patients with invasive implants is poor. According to these results, several investigators are more reticent to propose a conservative treatment in patients with invasive implants. To perform an accurate diagnosis of the peritoneal implants, the initial surgical procedure of borderline tumor should include a resection of all macroscopic peritoneal implants. Therefore the total removal of macroscopic implants in BOT has a diagnostic and therapeutic value. Boran et al. (31) observed that recurrence after cystectomy and adnexectomy was 15% and 2.4%, respectively. They suggested that the recommended conservative treatment should be unilateral oophorectomy, because the rate of recurrence after cystectomy was high. In a French multicenter study of 358 women with BOT, 149 women underwent laparoscopy. Conservative treatment and cyst rupture were more frequent in the laparoscopy group than in the laparoconversion and laparotomy groups. No difference in the recurrence rate was noted between the groups, but a higher recurrence rate was observed after conservative treatment. Laparoscopic management of BOTs is associated with a higher rate of cyst rupture and incomplete staging. Recurrence was more frequent after conservative treatment (32). Deffieux et al. (33) reported the clinical outcomes of laparoscopic treatment of BOTs with peritoneal implants for stage II or stage III BOT. Nine patients underwent 738 Tinelli et al. Treatment of borderline ovarian tumors Vol. 92, No. 2, August 2009

4 a laparoscopic treatment of stage II/III serous borderline tumor. A conservative management was performed in seven patients. There was a recurrence in four patients. Three spontaneous pregnancies were observed. All patients were alive without evidence of disease with a median follow-up of 35 months after the laparoscopic treatment. Their series suggested that laparoscopic treatment of patients with BOT associated with noninvasive implants is feasible and seems to be safe. Romagnolo et al. (34) reported 113 patients affected by low malignant ovarian tumor who were operated by laparoscopic surgery. Fifty-three patients (46.9%) underwent fertility-sparing surgery to preserve their childbearing potential. In 22/113 (19.5%) cases, they observed tumor rupture or spilling during surgery, and this incidence was greater in the group of patients treated by laparoscopy compared with laparotomy. In 13 (11.5%) patients they observed a relapse, although there was a difference in relapse rate according to the type of the surgical approach: 7% for radical and 17% for conservative therapy. Type of surgical approach, laparoscopic versus laparotomic, did not seem to influence the progression-free survival. When cystectomy was performed, the progression-free survival was significantly lower when compared with nonconservative surgery or unilateral salpingo-oophorectomy. Eight pregnancies were observed. The investigators concluded that conservative laparoscopic surgery may be the treatment of choice, but this surgery should be reserved for oncologic surgeons trained in extensive laparoscopic procedures to obtain a correct surgical staging and better results in terms of both relapse-free survival and pregnancies (34). Seracchioli et al. (13) suggested that a limited laparoscopic approach to the surgical management of BOT may be safe. They treated 19 reproductive-age women by laparoscopic cystectomy or unilateral salpingo-oophorectomy. A limited staging was performed that included a careful exploration of the peritoneal cavity, washings, targeted peritoneal biopsies, and biopsy of the controlateral ovary. At a mean follow-up of months, only one patient had a recurrence. She recurred in the same ovary after a cystectomy for her initial tumor, and was treated with repeat cystectomy. There were six spontaneous pregnancies, and all went to term (13). Donnez et al. (35) reported a recurrence after adnexectomy with contralateral cystectomy. They reported 12 pregnancies in 7 of 11 women who underwent fertility-sparing management and who wished to become pregnant. For women who are treated conservatively, follow-up is important. Zanetta et al. (36) evaluated physical examination, pelvic ultrasonography, and CA125 levels to determine the best modality for following patients after conservative treatment for BOT. Patients were evaluated every 3 months for the first 2 years and then every 6 months thereafter. Of 164 women treated with fertility-sparing surgery, 28 (17%) recurred. The investigators concluded that using all three modalities, pelvic examination, pelvic ultrasound, and CA125 measurements, would seem to be the most prudent approach. Camatte et al. (30) reported 34 patients who underwent laparoscopic treatment for BOT. Conservative treatment was performed in 31 (91%) patients. After a median follow-up time of 45 months, six (17%) patients recurred (5 of whom in the remaining ovary after conservative surgery and in the peritoneum in 1 patient). Two port-site metastases were observed. Nine spontaneous pregnancies were observed in 6 patients from a group of 15 patients desiring pregnancy. In our recent study of women with BOT, among 43 women who underwent conservative surgery, 21 (49%) became pregnant during the follow-up period. Among the three patients (7%) who developed recurrences after conservative surgery, two occurred after cystectomy and one after oophorectomy, but all the recurrences did not occur in the cases of intraoperative rupture of cyst. The histologic type of recurrences was similar to the primary tumor (37). According to a recent study in 317 women with diagnosis of borderline tumor of the ovary (38), which showed an incidence of retroperitoneal metastasis of 3,7% and lymph node recurrence of 0.4% after a median follow-up exceeding 6 years, lymph node sampling as part of the staging procedures is not routinely performed (38). The influence of lymph node removal on outcomes seems small. In the absence of lymph node removal, less than 1% of patients experienced lymph node recurrences (30, 39). At present, complete staging has not been shown to improve survival. In a study by Winter et al. (40), the overall 5-year survival and recurrence rates were similar with or without lymphadenectomy. Thus, in patients with apparently early-stage BOT, the outcomes seem more heavily dependent on histology than on the extent of surgery. Serous micropapillary tumors and microinvasive tumors have been associated with poorer outcomes (41). The presence of peritoneal implants may be the most significant prognostic factor (42). Removal of the remaining ovary should be performed once childbearing is no longer a consideration, to reduce the risk of recurrent contralateral lesions (28, 35). The remaining ovarian cortex may be cryopreserved with recommendations previously described. Although the recommendation that all women who are conservatively managed should have the contralateral ovary removed after childbearing is not, at present, standard care, but it seems reasonable to us, as to other investigators (28, 29), to propose this, knowing that there are fewer recurrences with bilateral oophorectomy. Zanetta et al. (29) also noted a significantly higher rate of recurrence in the spared ovary after conservative surgery when compared with radical surgery. In their large series, the recurrence rate was 15.2% and 2.5%, respectively, after conservative and radical surgery for stage I disease, and 40% and 12.9% for stage II. They also concluded that in Fertility and Sterility â 739

5 young women wishing to preserve fertility, a conservative approach is reasonable, followed, in some cases, by definitive surgery after successful pregnancies. CONCLUSION In our opinion, conservative laparoscopic treatment of BOT is an appropriate and reasonable therapeutic option for young women with low-stage disease who wish to preserve their childbearing potential because the fertility results are encouraging. Recurrence can be noted after this type of treatment, but the cases of recurrent disease can be detected with close follow-up and treated accordingly. For these reasons, careful selection of candidates for this kind of treatment is, of course, necessary and close follow-up is required. Whenever possible, the treatment options for each possible operative finding should be discussed thoroughly with the patient and her family, including the advantages and disadvantages of each treatment approach. The main objective of conservative treatment for women with BOT is to spare fertility without negatively affecting overall and disease-free survival. Our results are in keeping with previous studies in which recurrence rates were higher after cystectomy than after unilateral salpingo-oophorectomy (17, 30, 31, 34, 35, 37, 43, 44). This suggests that laparoscopic cystectomy should be considered only for women with one ovary or with bilateral tumors who wish to preserve their childbearing potential. When BOTs are identified at surgery by intraoperative histology, the recommended conservative treatment should be laparoscopic salpingo-oophorectomy. If these restrictions are rigorously applied, then fertilitysparing surgery may be considered a safe option for this pathology, but all laparoscopic procedures should be reserved for oncologic surgeons trained in extensive laparoscopic procedures. REFERENCES 1. Trope C, Kaern J. Prognosis and management of borderline tumours of the ovary. 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