Laparoscopic fertility-sparing staging in unexpected early stage ovarian malignancies

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1 Laparoscopic fertility-sparing staging in unexpected early stage ovarian malignancies Ludovico Muzii, M.D., a Innocenza Palaia, M.D., b Milena Sansone, M.D., b Marco Calcagno, M.D., b Francesco Plotti, M.D., b Roberto Angioli, M.D., a and Pierluigi Benedetti Panici, M.D. b a Department of Obstetrics and Gynecology, Campus Biomedico University and b Department of Obstetrics and Gynecology, Sapienza University, Rome, Italy Objective: To assess feasibility and safety of fertility-sparing laparoscopic staging in women affected by unexpected ovarian cancer desiring to preserve their fertility. Design: Prospective study. Setting: University clinic. Patient(s): Twenty-seven patients already operated on elsewhere for a presumably benign ovarian cyst. Intervention(s): Laparoscopic fertility-sparing staging operations. Main Outcome Measure(s): Perioperative and survival data, reproductive outcome. Result(s): Histologic findings after first surgery: 12 low malignant potential neoplasms, 11 invasive epithelial ovarian carcinomas,1 sex-cord stromal, and 3 germ cell neoplasms. Fertility-sparing staging consisted of exploration of the peritoneal cavity, peritoneal washing cytology, multiple peritoneal biopsies, omolateral adnexectomy (except in borderline tumors), omentectomy, omolateral or bilateral pelvic and aortic lymph node sampling (except in borderline tumors, well differentiated, mucinous, and granulosa cell (GC) neoplasms), endometrial biopsy, appendectomy in mucinous type. Overall, seven patients (26%) were upstaged. Six patients received adjuvant platinum-based chemotherapy. Two term pregnancies occurred. After a median follow-up of 20 months all patients are alive; one patient has FIGO stage Ic clear cell carcinoma, which recurred 8 months after surgery. Conclusion(s): Laparoscopic fertility-sparing staging in early ovarian malignancies is feasible and safe in selected and counseled patients and should be performed in experienced gynecological oncology centers trained in endoscopic procedures. (Fertil Steril Ò 2009;91: Ó2009 by American Society for Reproductive Medicine.) Key Words: Early stage ovarian cancer, laparoscopic staging, fertility-sparing surgery Accurate surgical staging is, for all ovarian malignancies, a pivotal step for correct management. According to the International Federation of Gynaecology and Obstetrics (FIGO) guidelines, surgical staging should include peritoneal washing, total hysterectomy, bilateral salpingo-oophorectomy, multiple peritoneal biopsies (Douglas pouch, paracolic gutter, left and right hemidiaphragm, prevesical peritoneum), infracolic omentectomy, appendectomy, pelvic and para-aortic lymph node sampling, and biopsy of all suspicious lesions (1). Several investigators have demonstrated that, in case of ovarian cancer, the completeness of surgical staging represents an independent prognostic factor affecting survival (2, 3). Received January 18, 2008; revised March 21, 2008; accepted March 24, 2008; published online June 13, L.M. has nothing to disclose. I.P. has nothing to disclose. M.S. has nothing to disclose. M.C. has nothing to disclose. F.P. has nothing to disclose. R.A. has nothing to disclose. P.B.P. has nothing to disclose. Reprint requests: Pierluigi Benedetti Panici, M.D., Department of Gynecology, Obstetrics and Perinatology, University of Rome Sapienza, Viale del Policlinico 155, Rome, Italy (FAX: ; pierluigi.benedettipanici@uniroma1.it). Recently, some investigators have demonstrated the feasibility and adequacy of laparoscopic staging in case of early ovarian cancer (4 7), advocating the use of a less invasive surgical procedure to improve postoperative outcomes such as pain, hospital stay, complication rate, and aesthetic results. In the past decades many investigators have shown that a staging procedure reveals that 30% of patients presumed to have FIGO stage Ia ovarian cancer are instead in more advanced stages. Therefore, some issues are still unsolved, and in particular, why and who should undergo staging, and which surgery should be proposed to women desiring to maintain their fertility. Many studies have been published on laparotomy staging in borderline (8 12) and invasive ovarian cancers (13 17). Upstaging rates ranged from 12% 47% in borderline and 16% 30% in invasive ovarian cancers. More recently, with the concept of less invasive surgery, several studies have been produced also on laparoscopic staging (4, 18 26), reporting excellent results of feasibility, with upstaging rates similar to those obtained by laparotomy, but with the advantage of a less aggressive surgical approach. Concerning the possibility of a fertility-sparing surgery, data from the literature have shown that conservative staging can be applied safely in borderline tumors (27). For invasive early ovarian cancer, some reports have demonstrated that well selected patients can safely benefit from conservative treatment as well, if platinum-based adjuvant chemotherapy is administered when indicated (clear cell histotype, grading 2 3, FIGO stage more than Ia) (2, 28 31). In addition, germ cell tumors are highly chemosensitive and occur in young women in whom fertility-sparing surgery should always be pursued. The aim of the present study is to evaluate the feasibility and safety of laparoscopic fertility-sparing staging in selected 2632 Fertility and Sterility â Vol. 91, No. 6, June /09/$36.00 Copyright ª2009 American Society for Reproductive Medicine, Published by Elsevier Inc. doi: /j.fertnstert

2 patients referred to our Institutions for the management of an unexpected ovarian malignancy diagnosed elsewhere after primary surgery for a presumably benign adnexal mass. MATERIALS AND METHODS Institutional Review Board (IRB) approval was requested and obtained. Patients referred to the Departments of Obstetrics and Gynecology of Sapienza University and Campus Biomedico University in Rome, for an unexpected ovarian malignancy, were enrolled in the study. Inclusion criteria for submitting patients to fertility-sparing staging were: age <42 years; patients surgically treated elsewhere for a presumed benign adnexal cyst, either by laparoscopy or laparotomy; histologic diagnosis of borderline tumors, invasive epithelial, sex-cord stromal, or germ cell tumors; staging procedure incorrectly performed or not performed at all; meticulous counseling and motivation for a fertility-sparing staging procedure; desire to conceive; negative imaging reports; availability to follow-up; signed informed consent. Pathology slides of the previous surgery were reviewed by a dedicated gynecopathologist, to confirm the diagnosis. All patients underwent a complete clinical and physical examination, pelvic gynecological examination, CA-125 serum dosage in epithelial malignancies and alpha fetoprotein (AFP) in germ cell tumors, pelvic transabdominal and transvaginal ultrasonography, chest roentgenogram, electrocardiogram, blood cell count, and blood chemistry. In case of germ cell tumors and invasive epithelial carcinoma, a positron emission tomography computerized tomography (CT) scan was performed. No mechanical bowel preparation was given the day before surgery. Antibiotic prophylaxis was carried out with 2 g of cefalotin given IV 30 minutes before incision and antithrombotic prophylaxis was carried out with low molecular weight SC heparin 2 hours before surgery and until complete mobilization. Surgical procedures were performed with general endotracheal anesthesia. All procedures were carried out by senior gynecologists specialized in traditional and endoscopic surgery (P.B.P. and L.M.). Open laparoscopy was carried out to access the abdominal cavity. A 10-mm port for the laparoscope was inserted through the umbilicus. Pneumoperitoneum was carried out and three to five ancillary ports were used to perform the adequate surgical steps. Conservative staging always started with a careful inspection of all the peritoneal surfaces and abdominopelvic organs and peritoneal washing. If the inspection was negative, multiple peritoneal biopsies (6 8 at the level of Douglas pouch, paracolic gutters, hemidiaphragm, prevesical peritoneum) were collected. If the visible nodules were present, complete removal of these supposed neoplastic implants was performed. Infracolic omentectomy was conducted using monopolar scissors and bipolar coagulation. Unilateral adnexectomy of the involved ovary was performed in all cases except in borderline tumors or when adnexectomy had already been performed at the time of the first surgery. In case of borderline tumors only a biopsy of the involved adnexum was conducted. Biopsy of contralateral ovary was performed in all cases. Appendectomy in mucinous histotype, pelvic and aortic nodal sampling was performed in all but not in granulosa cell (GC) histotype, borderline, well-differentiated, and mucinous epithelial ovarian cancer. An endoscopic collection bag was always used to remove the specimens from the abdominal cavity. All patients underwent dilatation and curettage of the uterine cavity. Operative time, intraoperative and postoperative complications, and postoperative stay were recorded. Patients with clear cell histotype, scarcely differentiated epithelial carcinomas, FIGO stage Ic or higher, had adjuvant chemotherapy. In case of epithelial ovarian cancer, the chemotherapeutic schedule was carboplatin (area under the curve [AUC] ¼ 6) plus 175 mg/m 2 of paclitaxel every 3 weeks for six cycles. In case of germ cell ovarian tumors, the chemotherapeutic schedule was bleomycin (18 U/m 2 ) on days 2, 9, 16, plus cisplatinum (20 mg/m 2 ) and etoposide (100 mg/m 2 ) on days 1 5, every 4 weeks for six cycles. Patients were followed up every 3 months for the first 2 years, than every 6 months for the next 3 years. RESULTS From June 2003 to January 2007, 41 patients were referred to La Sapienza University and Campus Biomedico University for counseling and management of an unexpected ovarian malignancy diagnosed elsewhere. Among these, 27 patients desiring to maintain their reproductive capability were enrolled in the study and underwent laparoscopic fertility-sparing staging. Median age was 30 years (range years). All patients had recently undergone surgery for a presumably benign ovarian cyst; 18 patients (67%) underwent operative laparoscopy and 9 (33%), a transversal laparotomy (Table 1). Most of the patients (22/27, 81%) underwent cystectomy, whereas 5 patients (19%) had a unilateral adnexectomy. Information regarding the rupture of the cyst and consequent spillage was available only in 10 cases (10/27, 37%). In seven cases a spillage of the cyst content was described, whereas in three cases the surgeons specified that the cyst was removed without capsule rupture. At this first surgery, peritoneal biopsies were not collected; in five patients a peritoneal cytology was performed. Final pathological reports are shown in Table 2. Briefly, most cases were either low malignant potential tumors (44%) or invasive carcinomas (41%). Peritoneal cytologies were all negative. After preoperative workup and counseling, patients were scheduled to undergo conservative laparoscopic staging. Median time to staging (time between the first surgery and the staging procedure) was 48 days (range days) for patients with a diagnosis of invasive epithelial or germ cell ovarian cancer. Patients with borderline and GC tumors were usually referred later to our centers and the median time to staging was longer in this group (75 days, range days). Perioperative data are summarized in Table 3. In particular, median operative time and postoperative stay was longer for staging procedures including Fertility and Sterility â 2633

3 TABLE 1 First surgery data. Variable Approach Pfannestiel laparotomy 9 (33%) Longitudinal laparotomy Laparoscopy 18 (67%) Type of surgery Unilateral salpingo-oophorectomy 5 (19%) Simple cystectomy (uni- or bilateral) 22 (81%) lymphadenectomy (180 minutes, range minutes; 3 days, range 2 7 days, respectively) compared to patients not submitted to these procedures (60 minutes, range minutes; 1 day, range 1 3 days, respectively). All procedures were completed by laparoscopy, as planned, except for one case in which a conversion to longitudinal laparotomy was needed for a vascular injury during lymphadenectomy. No severe postoperative complications occurred. Overall, 7/27 patients (26%) were upstaged (Table 4). Upstaging were due to four positive peritoneal washings in two cases of borderline tumors and in two invasive epithelial ovarian cancer (upstaged to FIGO stage Ic); one peritoneal pelvic nodule biopsy (upstaged to FIGO stage IIb) and one positive omentum (upstaged to FIGO stage IIIa) in two cases of invasive epithelial ovarian cancer; one paraortic node metastasis in one patient with dysgerminoma (upstaged to FIGO stage IIIc). Overall, six patients received adjuvant chemotherapy five for epithelial ovarian cancer (2 FIGO stage Ic, 1 FIGO stage IIb, 1 FIGO stage IIIa, 1 scarcely differentiated FIGO TABLE 2 Histopathology after first surgery. Histotype No. Low malignant potential 12 (44%) Germ cell 3 (11%) Sex-cord stromal 1 (4%) Invasive 11 (41%) Serous 4 Mucinous 3 Endometrioid 2 Clear cell 2 Grade of differentiation Well 5 Moderate 3 Poor 3 stage Ia) and one dysgerminoma (FIGO stage IIIc retroperitoneal). In this last group, one patient reported abnormal menstrual pattern after treatment (carboplatin plus paclitaxel) and subsequently incurred a premature menopause. The remaining five patients reported a return to regular menstruation after completion of chemotherapy with delays that ranged between 0 and 6 months. Concerning reproductive outcome, two pregnancies (one in borderline tumor patient and one in FIGO stage Ia epithelial invasive ovarian cancer) and two spontaneous abortions (both with invasive ovarian cancer) occurred. Concerning survival data, after a median follow-up of 20 months (range 7 38 months) all patients are alive and free of disease, except for one patient with FIGO stage Ic scarcely differentiated ovarian carcinoma, which recurred 8 months after chemotherapy, and is still undergoing palliative chemotherapy. DISCUSSION The completeness of surgical staging was found to be an independent prognostic factor for patients affected by early stage ovarian cancers. In 1998 Zanetta et al. (2) strongly indicated that tumor grade is the single most important biological prognostic factor in this group of patients. Particularly in poorly differentiated carcinomas, the thoroughness of the staging significantly impacts on survival. More recently a trial was conducted by European Organisation for Research and Treatment of Cancer Adjuvant ChemoTherapy In Ovarian Neoplasm trial (3) collaborators on 448 patients to evaluate the impact of adjuvant chemotherapy and surgical staging in early stage ovarian carcinoma. Patients from 40 centers in nine European countries were randomly assigned to either adjuvant platinum-based chemotherapy (n ¼ 224) or observation (n ¼ 224) after surgery. They observed that the benefit of adjuvant chemotherapy on survival was evident only in patients with nonoptimal staging, suggesting that those patients were affected by occult residual disease. In the optimally staged patients, no benefit of adjuvant chemotherapy was seen. Therefore, the completeness of surgical staging was, in addition to tumor grade and histologic cell type, an independent prognostic factor in patients affected by early stage ovarian carcinoma. The frequency of an unexpected ovarian malignancy after a laparoscopic procedure performed for an adnexal mass presumed to be benign ranges between 0.9% and 13% in different series (32). A correct preoperative study and the availability of the frozen section should be considered mandatory before approaching an ovarian cyst. Intraoperative cyst rupture, which commonly occurs during laparoscopy, upstages the unexpected ovarian cancer from stage Ia to stage Ic, with all the consequences of possible delayed staging, necessity of adjuvant chemotherapy, and worse prognosis. Whether this event unfavorably affects prognosis has been a matter of debate for years. Older series consistently reported that surgical rupture adversely 2634 Muzii et al. Fertility-sparing staging in ovarian cancer Vol. 91, No. 6, June 2009

4 TABLE 3 Operative data. Variable Restaging without PAL (borderline, granulosa cell, mucinous well diff.) N [ 18 Restaging including PAL (invasive epithelial, germ cell) N [ 9 Median operative time (min) (range) 60 (40 95) 180 ( ) Conversion to laparotomy 1 Complication rate Intraoperative 1 Postoperative Median blood loss (ml) (range) 70 (50 200) 200 ( ) Median postop stay (days) (range) 1 (1 3) 3 (2 7) Note: PAL ¼ pelvic and aortic lymphadenectomy. influences survival (33 35), whereas recent series with multivariate analyses reported no influence of surgical rupture on survival (36 38). In a recent series of 1,545 patients (39), however, the investigators report that at multivariate analyses, degree of differentiation, age at diagnosis, as well as tumor rupture before or during surgery are associated with poor prognosis in patients with stage I invasive ovarian carcinoma. Hazard ratios were 2.65 for rupture before surgery and 1.65 for rupture during surgery. This study represents the largest published series addressing the issue of the prognostic significance of cyst rupture in stage I ovarian carcinoma. However, the article does not contraindicate the laparoscopic approach for adnexal masses, as cyst rupture should not be considered specific to laparoscopy and even at laparotomy, very capable surgeons may not be able to avoid cyst rupture because of adhesions or tumor size. Staging operation for patients affected by epithelial and nonepithelial ovarian malignancies not primarily adequately staged has been questioned by several investigators. Most underlined the importance of a precise knowledge of stage TABLE 4 FIGO stage after restaging. Histology Stage after restaging % upstaging Borderline 2 Ic 2/12 (17%) tumors Invasive 2 Ic 5/11 (45%) epithelial 1 IIb 1 IIIa Dysgerminoma 1 IIIc 1/3 (33%) retroperitoneal Total 7/27 (26%) of disease to offer patients an adequate adjuvant treatment and a safe possibility of a conservative operation in those desiring to maintain their fertility. In case of borderline tumors the staging procedure aims to assess precisely the stage of the disease and identify invasive peritoneal implants, which represent an indication for adjuvant chemotherapy and a strongly negative prognostic factor (40). In case of invasive early ovarian cancer, again, correct staging is an independent prognostic factor and, most important, identifies patients who can be spared adjuvant chemotherapy. However, some investigators have questioned that the delay in starting chemotherapy due to a second operation could negatively impact on survival (41), but the data on this issue are discordant (42). Reports from series of patients submitted to laparotomy staging surgery revealed an incidence of upstaging ranging from 16% 30% for supposed stage Ia invasive epithelial ovarian cancers (13 17), and from 12% 47% for patients affected by borderline ovarian tumors (8 12). Recently, many investigators have suggested that laparoscopic surgery is feasible, safe, and adequate for staging purpose in ovarian malignancies when compared with the standard laparotomy approach (4 7, 43). In addition, there is definite evidence that a minimally invasive approach offers advantages over open surgery, namely shorter hospital stay, faster recovery, and improved quality of life. A study published by Chi et al. (25) represents the first attempt to compare the results of laparoscopic staging of an apparent early ovarian cancer with those obtained with comprehensive surgical staging by laparotomy. This preliminary study has demonstrated that in selected patients the performance of comprehensive laparoscopic surgical staging of ovarian cancer appears to be as safe and efficacious as surgical staging performed by laparotomy when conducted by gynecological oncologists with training and experience in advanced laparoscopic procedures (25). A subsequent case-control study from Ghezzi et al. (44) performed on 34 patients reported similar results. In the present study we report that laparoscopy was accurate during the staging procedure, with 26% Fertility and Sterility â 2635

5 of patients upstaged. According to data reported in the literature the upstaging rate of patients with apparent early ovarian cancer (EOC) after complete laparotomy staging range from 7% 30% (17, 45), mainly because of positive peritoneal cytology or tumor deposits in the omentum or lymph nodes. In addition in the present study, patients submitted to laparoscopic staging underwent conservative surgery, without removal of the uterus and contralateral ovary. Concerning fertility-sparing surgery in early ovarian malignancies, data from the literature are difficult to evaluate because consistent published series are scarce. In young patients affected by low malignant potential tumors and germ cell tumors, most investigators are in agreement that the surgical treatment should be conservative, with preservation of the uterus and contralateral ovary, to preserve fertility. Some reports also advise conservative surgery in case of epithelial invasive ovarian cancer. In particular, Zanetta et al. (2) first reported a 95% rate of overall survival after conservative surgery in an ovarian cancer series of 55 patients with stage Ia c. Later on Raspagliesi et al. (28) reported on a series of 10 patients treated conservatively, also in the presence of discouraging prognostic factors (2 patients had FIGO stage Ia grade 3 disease, 2 patients had stage Ic disease, and 6 patients had stage III disease). Among those 10 patients with high-risk ovarian carcinoma, none experienced recurrence. Schilder and colleagues (31) reported that the estimated 5-year and 10-year survivals of patients were 98% and 93%, respectively, which compare favorably to the reported survival rates of patients with stage I ovarian cancer treated by more radical surgery. In the present study, young patients desiring to maintain their fertility underwent conservative operations and adjuvant chemotherapy when indicated. After a median followup of 20 months, all patients are alive, one patient affected by FIGO stage Ic clear cell carcinoma, recurring 8 months after surgery. Two term pregnancies and two spontaneous abortion occurred. These data suggest that conservative surgery is feasible and safe in selected patients in referral centers. The question of whether hysterectomy and contralateral adnexectomy should be undertaken after completion of childbearing remains unsolved. This is an attractive option to some patients, given the potential for a second primary or recurrent ovarian cancer in a patient already proven to be at risk. However, the salvage rate of patients who recurred, and the longterm disease-free survival in those patients who did not undergo completion surgery, suggests that expectant management is a viable option as well, particularly in case of borderline ovarian tumors. 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