Although cancer usually affects aged population, invasive gynecological tumors can occur during reproductive age. Long-term survival rates after gynecological cancer are improving and preservation of fertility has logically become a major issue.
In gynecologic oncologic surgery, there has been gradual development of fertility-saving surgery (FSS) with the aim of preserving the reproductive organs. Survival should not be compromised and thus indications are restricted to patients of a young age with a desire to preserve fertility and presenting with a well-differentiated cervical, ovarian, or endometrial low-grade tumor in its early stages or with low malignant potential.
In this chapter, we discuss indications for FSS in women with gynecological cancer, according to oncological and reproductive outcomes.
Conservative and functional surgery is increasingly used in surgical oncology. Its aim is to preserve organs’ functionality and to reduce radical resection. Development of new surgical procedures in oncologic gynecologic surgery is a perfect example of this evolution. Although radical surgery remains the gold standard in the treatment of ovarian cancer, a conservative approach can be considered in patients with early-stages disease, in order to preserve their fertility function. These procedures were proposed to selected patients, depending on histologic subtypes and prognostic factors. Ovarian cancers are classified in epithelial (including borderline and malignant tumors) and non-epithelial cancer.
The definition of borderline ovarian tumors (BOT) is relative to the histologic characteristics of the ovarian tumor and not to the peritoneal implants. Four characteristics are used to define the BOT: epithelial proliferation with the formation of papillary configuration; a definable demonstration of atypical epithelial activity; mild or moderate atypicality of the nuclei (these three characteristics are essential to differentiate BOT from ovarian cystadenoma); and the absence of stromal invasion (which makes the whole difference with invasive carcinoma) [1, 2]. Peritoneal implants are associated in 10–40% of cases to BOT. They are either non-invasive in 80% of cases (without stromal invasion), or invasive in 20% of cases [3–8]. A non-invasive implant was defined by a glandular or papillary proliferation, but with no stromal invasion. Peritoneal non-invasive implants can be subdivided into epithelial type (with a predominance of epithelial elements) and desmoplastic type (in which the epithelial elements lay in a predominant inflamed, desmoplastic stroma). Invasive implants are defined by a proliferation in the peritoneum with a stromal invasion [3, 4, 6]. If biopsies or resection of peritoneal implants are too superficial, the degree of invasion could not be accurately determined, and such implants should be considered as “non-specified” implants. In order to avoid such an inconvenience, large biopsies or resection of peritoneal implants should be performed during the surgical procedure . Therefore, the pathologic examination is a crucial point (a) to confirm the diagnosis of BOT (and peritoneal implants), (b) to precise prognostic factors, and (c) to specify the optimal treatment. In order to carry out an adequate sampling, at least one section for each centimeter of the greatest dimension of the ovarian tumor and the examination of the totality of peritoneal implants should be performed .
In patients with non-invasive implants, complete surgical reduction of peritoneal lesions is the only treatment that may improve survival. Prognosis of patients with non-invasive implants is good . However, there is an evolution into a more aggressive disease in one-third of cases, when in presence of invasive peritoneal implants [5, 6, 8]. In such cases, adjuvant treatment should be discussed.
A new entity of patients with peritoneal implants associated with borderline tumor designated as “micropapillary serous carcinoma” (MP) was described in 1996, in order to identify a subgroup of patients with poor prognosis. Tumors with MP pattern are more commonly associated with invasive implants. In this study, the presence of MP pattern was an adverse prognostic factor . On the other hand, Eichhorn et al. reported that the evolution of patients with non-invasive implants associated with MP pattern is similar to that of patients with non-invasive implants without MP pattern . In fact, the behavior of serous borderline ovarian tumors with MP seems to be more related to the presence of invasive implants rather than to this particular histological feature .
The standard treatment of BOT consisted of a total abdominal hysterectomy and bilateral salpingo-oophorectomy, peritoneal cytology, omentectomy, and multiple peritoneal biopsies. These procedures allowed to perform an adequate staging and to eventually propose an adjuvant therapy only in patients with invasive peritoneal implants. The prognosis of BOT is excellent. But late recurrences (after 5 or 10 years) could be observed . Conservative surgery is defined as preservation of the uterus and at least part of one ovary, in order to preserve fertility. BOT arise in a young population, where fertility is a major issue. So, the analysis of conservative management data is crucial in such patients. Analysis of the literature about conservative management in BOT is difficult because most of the series are retrospective and the length of follow-up is too short (<5 years) to evaluate the exact rate of recurrence. Furthermore, the rate of patients adequately staged varied in series and depended on treatment centers. This could explain the different value of recurrence rate. In 2013 Darai et al. reviewed conservative surgery results in BOT . The risk of relapse is increased after this type of surgery. The global recurrence risk is estimated at 13% (10–16% 95% confidence interval [CI]). The rate of recurrence is correlated with the type of conservative treatment used (salpingo-oophorectomy or cystectomy) with a higher rate between 10% and 42% in patients undergoing cystectomy . Nevertheless, the real impact of performing a cystectomy only (as opposed to a salpingo-oophorectomy) on recurrence rates is a subject of debate and some authors report similar recurrence rates for both treatments. In the only randomized trial regarding BOT, Palomba et al. [14, 15] reported 32 patients with bilateral BOT, treated laparoscopically and were randomized between bilateral cystectomy versus unilateral salpingo-oophorectomy on the largest lesion and contralateral cystectomy. After a follow-up period of 81 months, there was no difference between these procedures in terms of the cumulative recurrence rates. On one hand, the cumulative pregnancy rate and cumulative probability of a first pregnancy were higher in patients treated with bilateral cystectomy compared with unilateral salpingo-oophorectomy and contralateral cystectomy . On the other hand, patients undergoing bilateral cystectomy had a shorter time to first recurrence and a higher rate of radical treatment of the recurrence . This study implies that in the case of bilateral serous BOT, if technically feasible, bilateral cystectomy should be performed to improve pregnancy rates.
The high rate of relapse implies that the optimal treatment in patients with intraoperative diagnosis of BOT is unilateral adnexectomy, which reduces the risk of relapse. Cystectomy should be performed only in cases of bilateral tumor and/or in patients with only one ovary (previous history of adnexectomy). In case of relapse on the remaining ovary under borderline form, another conservative management (cystectomy) may be proposed to these patients, in order to preserve fertility. In that case, complete evaluation must be performed preoperatively including:
– MRI with evaluation of possible safe functional ovarian tissue.
– Oncofertility consultation to discuss if fertility preservation technique can be proposed before surgery.
Fertility-sparing surgery is associated with a higher recurrence rate compared to radical treatment (bilateral salpingo-oophorectomy), although it does not affect survival rates, because most of these recurrences are of borderline nature and easily cured by a second surgery (possibly conservative). A nomogram has been proposed to predict recurrence in patients with early- and advanced-stage mucinous and serous BOT. Surgical procedure (radical vs. fertility-sparing) was associated with an increased risk of recurrence, as were International Federation of Gynecology and Obstetrics stage, age at diagnosis, histologic subtype, and completeness of surgery . Nevertheless, the main issue is to evaluate the risk of invasive recurrence, which is at lethal risk.
Forty-seven cases of progression to invasive carcinoma have been collected including 21 cases published since 2009. The risk of progression to invasive carcinoma could be estimated to be 2–3%. Of the 47 invasive recurrences, 20 reported in the literature  were observed in patients with serous BOT, 24 with mucinous BOT and the last three cases were of unknown histological subtype. The mean time of progression to carcinoma was 75 months (range 11–310) for serous BOT and 33 months (range 5–82) for mucinous BOT. Recurrence were less frequent for mucinous BOT but when a recurrence occurred, the risk of invasive lesion was higher. In a large series of stage I BOT including 191 conservative treatments, presence of a micropapillary pattern and mucinous subtype were associated with a higher rate of progression to carcinoma after conservative management . These important results suggest that mucinous BOT belong to a “high-risk” group likely to develop an invasive recurrence after fertility-sparing surgery in stage I BOT.
Of the 20 serous BOT recurrences, eight were observed in patients with peritoneal implants. For 18 of them with known follow-up, seven died of disease and eight were alive without evidence of disease . Among the 24 patients with mucinous BOT recurrences, 23 had initial FIGO stage I. Among 21 patients with mucinous BOT and data on the follow-up, 13 died of disease and only three were alive without disease.
In patients with serous BOT treated by cystectomy, 5 of the 11 were alive without disease compared to one of the nine patients with mucinous BOT. Patients with invasive mucinous BOT recurrence had a higher rate of extra-abdominal metastasis as the first recurrence site (pleural, lung or bones metastasis), whereas patients with invasive serous BOT none of the recurrences were extra-abdominal . Due to the higher risk of lethal recurrence with mucinous BOT, it seems logical for mucinous BOT to recommend initial unilateral salpingo-oophorectomy rather than cystectomy, while for serous BOT cystectomy is an acceptable option in the absence of high risk factor.
In the German large series including 950 patients, two thirds with serous BOT and 30.5% with mucinous BOT, among the 74 patients with relapse, 30% had malignant transformation to invasive ovarian cancer. Five-year progression-free survival and overall survival were 12% and 50%, respectively. Overall, invasive cancer following initial BOT was diagnosed in 2.3% of all 950 patients with confirmed diagnosis .
Fertility Results after Conservative Surgery
Fertility results of conservative treatment of early-stage BOT are summarized in Table 18.1 (only series including more than 50 patients with conservative treatment are reported). Pooled estimate for pregnancy rate is 54% (38–70).
|Patients wishing pregnancy (n)||Patients pregnant (n)||Pregnancy rate (%)|
|Camatte et al.(2002)||29||19||60|
|Boran et al. (2005)||25||10||40|
|Fauvet et al. (2005)||62||31||32|
|Romagnolo et al. (2006)||12||7||58|
|Yinon et al. (2007)||NA||25||40|
|Park et al. (2009)||31||27||73|
|Kokawa et al. (2009)|
|Kanat-Pektas et al. (2011)||44||23||52|
|Koskas et al. (2011)||31||12||38|
|Song et al. (2011)||51||45||88|
|Pooled estimate for proportion (%) (with 95% confidence interval)||54 (38–70)|
Different factors could have influenced fertility rates. The first one is the type of conservative treatment. As previously mentioned, Palomba’s trial demonstrated that the use of cystectomy improves fertility results [14, 15]. This treatment should thus be the preferred option particularly in patients at high risk of bilateral tumor (serous BOT).
The second factor is the age of the patient. Fauvet et al.’s  study clearly demonstrated that spontaneous fertility results were worse in patients over 40 years. Kanat-Pektas et al.  reported similar results. In this series, the median age of patients able to conceive was lower than that of patients unable to conceive (36 years vs. 45 years). However, for these two studies insufficient data are available about ovarian reserve evaluation taking into account antral follicle count and anti-Müllerian hormone serum levels which are known to be markers of the ovarian reserve. Trillsch et al. reported in the large German series that despite favorable survival, young patients of child-bearing age with BOT relapsed were at higher risk for disease recurrence .
The third factor concerns the histologic subtype of the tumor. In the series of Kanat-Pektas et al. , fertility results were better in patients with non-serous (mainly mucinous) compared with serous BOT: 87% were able to conceive in the former group versus 13% in the latter. Interestingly, higher pregnancy rates were reported in Asian series where the percentages of mucinous tumor treated conservatively are higher than in other series. This can be explained by the fact that patients with serous BOT are more likely to have bilateral tumor, peritoneal disease, or a previous history of infertility which can affect subsequent fertility .
Two other factors that could have a potential impact on fertility rates are the use of a laparoscopic approach and the use of a two- or three-step surgery (initial, restaging, second look, etc.), but there are no specific convincing data to support a role for these factors. Further studies analyzing these potential factors would be interesting. A model has been proposed to predict live birth rate after fertility-sparing surgery for patients with BOT, including FIGO stage, age at diagnosis, histological subtype, and surgery type .
Nevertheless, in spite of conservative management in BOT, some patients will experience infertility. Can we propose assisted reproductive technology (ART) to these patients, whereas some studies incriminated infertility treatment (essentially clomifene citrate) in the genesis of BOT and ovarian cancer, in vitro fertilization (IVF) procedures have not been significantly associated with a specific increase in BOT or ovarian cancer rates . In vitro data suggest that gonadotropins and/or high dose of estrogens don’t induce a borderline cell cultures proliferation .
IVF was more often used than simple ovarian stimulation. Analyzing all series , the pooled estimate for pregnancy was 80% (95% CI 68–92%). The pooled estimate for recurrence was 23% (95% CI 6–39%). The rate of recurrence in these women is ‘low’ though this is probably due to the fact that women who are selected as eligible for ART have a better prognosis and more often early-stage BOT. However, there is a real need for fertility preservation referral centers associating oncologists and fertility experts who can evaluate conservative management of BOT along with alternative therapeutic options to preserve fertility as well as ART. Figure 18.1 summarized what can be proposed for these patients.
Figure 18.1 Summarizes fertility preservation options regarding previous histological features of borderline tumor
The differential criterion between epithelial ovarian cancer (EOC) and BOT is the invasion of the ovarian stroma. Standard surgical procedure in EOC is radical (hysterectomy with bilateral salpingo-oophorectomy). The results concerning conservative management of EOC are difficult to analyze in the literature because many reported series were either mixed dealing with conservative treatment in EOC and non-epithelial ovarian cancer, or included invasive and borderline ovarian tumors, considering them as epithelial. Some series reported the results of conservative management but mixing epithelial, borderline, and non-epithelial tumors. But in fact few series reported about conservative treatment exclusively in EOC.
In Table 18.2 are summarized results of the literature regarding recurrence risk and survival rates after conservative treatment for patients with epithelial ovarian cancer.
|Author (Year)||Number of patients (n)||Histologic type||Stage IA (n)||Stage IB (n)||Stage IC (n)||Grade 1 (n)||Grade 2 (n)||Grade 3 (n)||Recurrence n (%)||Death N (%)||5-year recurrence free survival %|
|Zanetta (1997)||56||All types||32||2||22||35||14||7||5 (8.9)||3 (5.3)|
|Schilder (2002)||52||All types||42||0||10||38||9||5||2 (3.8)|
|Morice (2005)||34||All types||30||0||3||15||15||4||4 (11.7)|
|Borgfeldt (2007)||11||All types||10||0||1||9||1||1||1 (9)||1 (9)|
|Park (2008)||62||All types||36||2||21||48||5||9||6 (9.7)|
|Anchezar (2009)||16||All types||11||0||5||14||1||1||2 (12.5)||1 (6.2)|
|Schlaerth (2009)||20||All types||11||0||9||15||5||1||3 (15)||3 (15)|
|Kwon (2009)||21||All types||17||0||4||16||3||2||1 (4.7)||0|
|Wright (2009)*||432||All types||370||0||62||157||92||37||NA||94 %|
|Satoh (2010)||211||All types||126||0||85||160||15||36||5 (2.4)|
|Kajiyama (2010)||60||All types||30||1||29||41||7||12||8 (13,3)||7 (11.7)|
|Hu (2011)||94||All types||46||8||28||64||13||1||2 (2.4)||NA|
|Kajiyama (2011 b)||40||Mucinous||27||0||14||NA||NA||NA||NA||NA||97.5%|
|Cheng (2012)||17||All types||10||0||6||15||2||0||1 (5.9)||0|
|Fruscio (2013, 2016)||240||All types||130||2||105||141||70||29||11 (4.6)|
|Kashima (2013)||18||All types||0||0||18||14||0||4||5 (27.7)||4 (22.2)|
|Kajiyama (2010,2014)||94||All types||43||0||51||59||14||4||14||11||84,3|
|Lee (2015)||35||Mucinous||21||0||13||27||5||1||6 (17.1)||91 %|
|Ditto (2015)||70||All types||46||2||15||36||24||9||NA||98 %|
|Bentivegna* (2016)||673||All types||396||46||231||442**||126**||58**|
* Review including data from Colombo 1994 Zanetta 1997 Schilder 2002 Morice 2005 Anchezar 2009 Satoh 2010 Fruscio 2013.
** Stages 1 A and 1C (stage IB excluded).
S : Serous, M : Mucinous, E : Endometriod, CC : Clear cell.
Recurrence rate by histologic type has been indicated for series including more than ten patients with recurrence.
Di Saia first proposed conservative treatment for EOC, in highly selected cases, that is, patients with fertility desire, willing to undergo close gynecologic follow-up and stage IA, well-encapsulated ovarian cancer without peritumoral adhesions, ovarian capsule lymphatic channels and/or mesovarium invasion, and negative peritoneal washings .
In 1994, Colombo et al.  and in 1997 Zanetta et al.  published the first series specifically dedicated to EOC. Their series comprised 56 patients and the authors performed conservative treatment in selected cases of stage IA to IC disease (any grade) with excellent survival (96% 5-year survival rate in Colombo et al.).
An American multicenter study comprising 52 patients was reported in 2002 . In that study, the estimated overall survival of patients with early-stage EOC who underwent conservative treatment was 98% at 5 years and 93% at 10 years. The authors proposed that conservative treatment be performed in stage I EOC of any grade.
In 2005, a French multicenter study reported a series of 34 patients  with strict inclusion criteria (systematic review of slides, complete staging surgery and chemotherapy for patients with stage ≥IC). The results reported were: 1 recurrence out of 13 patients in case of stage I grade 1, 8 out of 20 patients in case of grades 2 and 3 stages IA to IC.
The study by Park et al. in 2008  comprised 62 patients with EOC, 59 of whom had early-stage disease. Patients with stage IC or grade 3 tumors had significantly poorer survival (5-year survival 88%). The authors reported that fertility-sparing surgery could be considered in young patients with stages IA–C, grades 1–2.
A Japanese multicenter study  included a total of 211 patients from 30 institutions who underwent conservative treatment for EOC. Five-year recurrence-free survival rates was 97.8% for stage IA with favorable histology (grade 1, grade 2, not clear cell), 100% for stage IA clear cell, 33.3% for stage IA grade 3, 92.1% for stage IC with favorable histology, 66% for stage IC clear cell, and 66.7% for stage IC grade 3. The authors recommended conservative treatment in stage IA disease either with a favorable histological subtype or clear-cell histology, in stage IC only with a favorable histology, but specified that conservative treatment should be avoided in the case of grade 3 tumors.
A large analysis in the SEER (Surveillance, Epidemiology and End Results) database of FSS with preservation of the ovary in stage IA or IC disease seems to confirm the absence of impact on survival rates . Nevertheless, as stated by the authors, “to detect a 20% difference in survival for patients with stage IC disease, a cohort of 1282 pts with 52 deaths is required.” Therefore, since none of the published series involved such large numbers of patients, it is not possible to conclude definitively about the safety of conservative management in this situation.
The largest series was published by Fruscio et al. in 2013 with an update in 2016 [51, 52]. This Italian retrospective study evaluated 240 patients treated with conservative treatment. Oncological prognosis was the same for patient with radical or conservative treatment. For grade 3, prognosis was worse but didn’t seem to depend on the type of surgery. The authors concluded that conservative treatment can be proposed to all young patients when the tumor is limited to the ovaries. Distant recurrences were considered more frequent in the case of grade 3 tumors and the patients should be closely monitored.
The results reported in those studies (Table 18.2) suggested that such conservative surgery could be safely performed in patients with stage IA grade 1 and probably grade 2 diseases, with a recurrence rate of 6% and 13%, respectively. In 33 patients with stage IA grade 3 disease, 14 recurrences were observed (42%) suggesting that FSS should not be performed in such cases.
In case of recurrence after conservative surgery for EOC, the prognosis remains poor, particularly in the case of recurrent disease outside from the preserved ovary . If the recurrence is limited to the preserved ovary, the prognosis is good .
In patients with “limit” indication for conservative surgery (stage IA grade 3 disease, stage IB or IC grade 2 or 3 disease), removal of both ovaries with uterine preservation (including absence of uterine curettage at the time of staging surgery) could be considered to allow pregnancy using egg donation. Such a proposal has never been explored in EOC but should be evaluated. In the SEER database analysis there is no impact on the survival of uterine preservation in stage IA or IC disease .
For patients with clear cell stage I tumor, regarding recent data [55, 56], conservative treatment should be discussed in dedicated tumor boards. For example, in France a national expert website has been developed (www.ovaire-rare.org), in which all cases of rare ovarian tumor and conservative treatment for EOC can be discussed.
Obviously, conservative treatment is avoided for disease extending beyond the ovaries because of the major risk of recurrences [47, 48]. Nevertheless, some cases have been reported in the literature and were analyzed in the review by Petrillo et al. . The authors identified 21 patients with stage II–III disease undergoing conservative treatment. Recurrent disease occurred in nine patients (42.8%) and 23.8% of them died of disease. Radical surgery remains the standard treatment for advanced EOC.
Few fertility results are available in the literature and they are summarized in Table 18.3.
|Author (Year)||Number of patients (n)||Number of patients wishing a pregnancy, N (%)||Number of pregnant patients, n (%)||Live birth (n)|
|Schilder (2002)||52||24 (46)||17 (71)||26|
|Park (2008)||62||19 (30)||15 (79)||22|
|Schlaerth (2009)||20||15 (75)||6 (40)||9|
|Kwon (2009)||21||5 (24)||5(100)||5|
|Satoh (2010)||211||84 (40)||45 (53)||56|
|Cheng (2012)||17||8 (47)||5 (62)||6|
|Fruscio (2013, 2016)||240||105 (44)||84 (80)||91|
|Kashima (2013)||18||10 (55)||5 (50)||7|
|Total||641||270/641 (42)||182/270 (67.4)||222|