Recommendations of the Fertility Task Force of the European Society of Gynecologic Oncology About the Conservative Management of Ovarian Malignant Tumors

Recommendations of the Fertility Task Force of the European Society of Gynecologic Oncology About the Conservative Management of Ovarian Malignant Tumors

Philippe Morice, Dominik Denschlag, Alex Rodolakis, Nick Reed, Achim Schneider, Vesna Kesic, and Nicoletta Colombo

Abstract: In young patients with borderline ovarian tumor a conservative treatment ap- proach does not seem to have a significant impact on survival, and the outcome regarding fertility is good in general. It can be considered even if noninvasive peritoneal implants are discovered at the time of the initial surgery.

In contrast, in patients with epithelial ovarian cancer, conservative surgery should be considered only in adequately staged patients, with a stage IA grade 1 (and probably 2) serous, mucinous or an endometrioid tumor, including a careful follow-up. Such an ap- proach could also probably be discussed in stage IC grade 1 disease.

In patients with nonepithelial malignant ovarian tumors, conservative surgery is also fea- sible, particularly in patients with malignant germ cell tumors because of their high che- mosensitivity leading to an excellent prognosis in general.

Key Words: Borderline tumor, Conservative treatment, Epithelial tumor, Fertility, Nonepithelial tumor, Ovarian cancer, Recurrence

Received December 21, 2010, and in revised form February 21, 2011.

Accepted for publication March 18, 2011.

(Int J Gynecol Cancer 2011;21: 951Y963)

A

lthough bilateral salpingo-oophorectomy, hysterectomy, lymphadenectomy, and omentectomy continue to be the criterion standard for the treatment of ovarian cancer, con- servative management (defined as the preservation of at least a part of 1 ovary and the uterus) can be considered in patients with early-stage disease, to preserve ovarian function and fertility. These procedures are proposed to selected patients, depending on the histological subtypes and prognostic factors (eg, disease stage, tumor grade, etc). Ovarian cancers are classified as epithelial (including borderline tumors and in- vasive cancers) and nonepithelial cancers. The present rec-

ommendations from the Fertility Task Force of the European Society of Gynecologic Oncology will focus on the current evidence regarding fertility-sparing management according to these 3 histological subtypes. A recommendation upon the management of infertility and the impact of infertility treat- ment after conservative treatment has already been published by the European Society of Gynecologic Oncology Task Force on fertility preservation in gynecologic cancers.¹In the present article, we focus on conservative treatment to pre- serve fertility and hormonal functions. Procedures performed to preserved hormonal functions without preservation of the subsequent fertility (such as ovarian transposition in cervical cancer) will not be covered.

Whatever the tumor subtype is, 5 common requirements should be fulfilled to consider the indications for conservative treatment:

1. The main aim of conservative surgery is to promote subsequent fertility. It should be discouraged in patients older than 40 years (too strong) because fertility results are poor in this age group.²

2. Patients have to be fully informed with potential onco- logical and obstetrical outcomes.

ESGO Task Force for Fertility Preservation in Gynecological Can- cer. Geneva, Switzerland.

Address correspondence and reprint requests to Philippe Morice, Service de Chirurgie Gyne´cologique, Institut Gustave-Roussy, 39 rue Camille-Desmoulins, 94805 Villejuif Cedex, France.

E-mail: morice@igr.fr.

Copyright * 2011 by IGCS and ESGO ISSN: 1048-891X

DOI: 10.1097/IGC.0b013e31821bec6b

3. Patients should agree to comply with a thorough follow- up after the treatment.

4. As the histological subtypes of the tumor (clear cell, small cell) and other histological characteristics (tumor grade in case of epithelial ovarian cancer (EOC), pres- ence of a micropapillary pattern or stromal microinvasion (SMI) in case of a serous borderline tumor, etc) are major determinants in the selection of patients for conserva- tive treatment, a careful histological review of the ovarian tumor (and peritoneal spread if present) should be carried out by a designated gynecologic pathologist.

5. As the tumor stage is also a major determinant in the selection of patients for conservative treatment, a careful description of the abdominopelvic cavity (with an ade- quate description in the operative report) should be pro- vided during initial surgery (and/or restaging surgery if performed).

BORDERLINE OVARIAN TUMORS

The management of serous and mucinous tumors will be discussed separately.

Serous Borderline Ovarian Tumor

The definition of borderline ovarian tumors (BOTs) is based on the histological characteristics of the ovarian tumor itself and not of peritoneal implants if present. Peritoneal implants are associated with BOT in 10% to 40% of the cases.

They are either noninvasive in 80% (without stromal inva- sion), or invasive in 20%.^3Y8A noninvasive implant is defined as a glandular or papillary proliferation, in the absence of stromal invasion. Noninvasive peritoneal implants can be subdivided into 2 different types, the epithelial type (with a predominant epithelial component) and the desmoplastic type (in which the epithelial components are embedded in a pre- dominantly inflamed, desmoplastic stroma). In contrast, in- vasive implants are defined as proliferation in the peritoneum with stromal invasion.^3Y5If a biopsy or resection of peritoneal implants is too superficial, the question whether an implant is invasive cannot be accurately determined, and such implants should be considered as ‘‘unspecified’’ implants. To avoid such an indeterminate result, large biopsies or a complete resection of peritoneal implants should be performed during the surgical procedure.⁸The final pathological examination is crucial to confirm the diagnosis of BOT, and, if present, the type of peritoneal implants to pass on important prognostic information to the treating physician, which then can decide on the optimal treatment. To carry out an adequate analysis, at least 1 section per centimeter of the largest dimension of the ovarian tumor and should be examined.⁹

In patients with noninvasive implants, complete surgi- cal cytoreduction of peritoneal lesions is the only treatment likely to improve survival. The prognosis of those patients is good.⁸ However, when peritoneal implants are invasive, the disease appears to be more aggressive in one third of the cases.^5,6,8 In such cases, adjuvant therapy should be discussed.

A new entity called ‘‘micropapillary serous carcinoma’’

(MP) describing the combination of peritoneal implants with an ovarian borderline tumor was described by Burks et al⁷

in 1996, to identify a subgroup of patients who appeared to have a less favorable prognosis. Those tumors with an MP pattern seem to be more commonly associated with invasive implants, thus conferring an impaired prognosis.⁹In contrast to this, Eichhorn et al¹⁰reported that the natural course of the disease in patients with noninvasive implants associated with an MP pattern was similar to that of patients with noninvasive implants without an MP pattern. Thus, the real prognostic impact of this entity is still considered controversial.

Initial Treatment of the Ovarian Tumor

Borderline ovarian tumors arise often in a young pop- ulation, where fertility is a major issue. An analysis of the literature regarding the conservative management of BOT is difficult, because most of the series are retrospective, and the duration of follow-up is too short (G5 years) to accurately evaluate the exact recurrence rate. Furthermore, the percen- tage of patients who were adequately surgically staged varies among the series, depending on the contributing treatment center. These variable percentages could account for the dif- ferences in recurrence rates. Several recent reviews have been published concerning the results of conservative surgery in such tumors.^11Y13 The risk of relapse is reported to be be- tween 0% and 25%, which is on average higher compared with conventional extirpative surgery.^11Y13 It is also higher after a simple cystectomy compared with a complete salpingo- oophorectomy (between 12% and 58%).^11Y13Nevertheless, the real impact of performing only a cystectomy (in contrast to a salpingo-oophorectomy) on the increased rate of recurrences continues to be debated by some authors.¹⁴ Some of these recurrences were observed long time after treatment of the initial BOT (the latest recurrences occurred 72 months after the initial diagnosis in the series reported by Gotlieb et al¹⁵and 240 months).¹⁶It is therefore highly likely that some of them are, in fact, new primary tumors and not true recurrences of the initial BOT.

Lim-Tan et al¹⁷published 1 of the first series on con- servative surgery in BOT. They reported on 35 patients (33 with stage I disease) treated conservatively.¹⁷To decrease the risk of recurrence after a cystectomy, Lim-Tan et al¹⁷recommended a complete pathological analysis of the margins to rule out any microscopic residual disease. Nevertheless, in a recent series reported by Papadimitriou et al,¹⁸among 18 patients who un- derwent a cystectomy with histologically confirmed free mar- gins, 7 had a relapse.

If an increased risk of recurrence is associated with fertility-sparing surgery, the question remains if this trans- lates into an impaired survival of these patients. Zanetta et al¹⁹ reported on a series of 189 patients who underwent fertility-sparing surgery. Seven cases of recurrence as an in- vasive ovarian carcinoma were observed, 1 of them very shortly (9 months) after the initial treatment of the BOT.¹⁹Six of these patients were alive after the treatment of their re- currence.¹⁹In a recent series reported by Park et al,²⁰among 164 conservatively treated patients with a median follow-up of 70 months, 9 recurrences were observed (with only 1 invasive recurrence in the lung and pericardium detected 82 months after the initial treatment). This latter patient died of her recurrent disease.²⁰

In the literature, nearly 10 of 1800 patients treated conservatively for early-stage disease (whatever the histo- logical subtypes) developed a recurrence in the form of an invasive carcinoma.²¹Invasive recurrent disease is therefore a rare event in patients with early-stage disease. Most recurrent lesions were again of noninvasive nature conferring an excel- lent prognosis. According to those data, it appears that this in- creased recurrence rate following conservative surgery finally does not seem to have an impact on survival.2,15,19,20,22Y26

Conservative surgery can therefore be safely performed in young patients treated for BOT.

Nevertheless, because those data are only summarized retrospectively, there is no scientific proof of level 1 evi- dence that there is no potential risk regarding the oncological safety after conservative management of BOT. Several series compared the outcome in terms of survival after conserva- tive and radical treatment of BOT.2,15,19,20,22Y26 However, such a comparison is very difficult because, in most cases, the patients who were treated by radical surgery were more prone to have a poorer prognosis in general (eg, advanced- stage disease). Furthermore, if any impact on survival exists due to conservative treatment, it appears to be very small, and therefore only a rather large series including a significant number of patients would be able to detect such a small difference.

Even if there is no prospective evidence regarding the benefit of performing a complete salpingo-oophorectomy, the rate of recurrence (between 12% and 58%) in patients who undergo just a simple cystectomy should lead to per- forming a complete salpingo-oophorectomy in case of uni- lateral disease.

A cystectomy should be performed exclusively in patients with only 1 ovary (previous history of an adnex- ectomy) or if a recurrent BOT arises in the remaining ovary.

In patients with bilateral ovarian involvement (which is exceptional in mucinous BOT [MBOT] but is observed in 10%-20% of serous disease), 2 options can be proposed:

(salpingo)oophorectomy on the side harboring the largest tumor and a contralateral cystectomy or alternatively bilateral cystectomies. One randomized trial (the only randomized trial concerning the treatment of BOT) compared both con- servative treatment modalities.²⁷ Thirty-two patients treated laparoscopically were randomized between the 2 treatments.

After a follow-up period of 81 months, there was no differ- ence between these procedures in terms of the cumulative rate of recurrences. Nevertheless, the cumulative pregnancy rate and the cumulative probability of a first pregnancy were higher in patients treated with bilateral cystectomies com- pared with unilateral salpingo-oophorectomy and a contra- lateral cystectomy.²⁷ Such results suggest that bilateral cystectomies should be preferred in case of bilateral disease if technically feasible.

A bilateral salpingo-oophorectomy should be per- formed only in patients with bilateral massive BOT, in which a preservation of a part of 1 ovary is not feasible. The uterus should be preserved in such patients, because pregnancies have been reported in patients who underwent a bilateral salpingo-oophorectomy (with uterine preservation) for BOT, using donated oocytes or a successful transfer of frozen

embryos (after stimulation) obtained before the bilateral salpingo-oophorectomy.^28Y30 Feasibility of cryopreservation of ovarian tissue was reported, but this procedure remains under evaluation in this indication.³¹

Another important issue includes the question whether the histological subtype of the serous BOT (SBOT) (ie, the presence of an MP pattern and/or SMI) should have an in- fluence on the proposal for conservative management. Con- cerning serous tumors with an MP pattern, only 1 series was published on conservative management in this context. This series included 15 cases (8 stage I and 7 stage III disease).³² Eleven recurrences were observed: 6 of them exclusively on the ovary, 3 exclusively on the peritoneum (invasive perito- neal disease in 1), and 2 combined on the ovary and perito- neum. One of those latter 2 patients died due to recurrence (in form of an invasive adenocarcinoma). The other patients were, in fact, disease-free. Five patients achieved 8 sponta- neous pregnancies.³²This recurrence rate might appear to be high but should be interpreted with caution because initially two thirds of the patients had a bilateral ovarian involvement, and almost half of the patients had stage III disease (perito- neal implants). To date, while awaiting further publications on this topic, there is no indication to propose radical treat- ment in patients with an MP pattern if the patient wants to preserve her fertility, but an oophorectomy should perhaps be preferred to a cystectomy if the tumor is unilateral.

Whether the presence of SMI in borderline tumors should guide our proposed treatment is another matter of controversy. Only 1 series (including 10 cases) was published on the conservative management of SBOT with microinvasion (excluding patients with an MP pattern). In this small series, it seems that the presence of SMI should not necessarily influ- ence the patient selection for conservative surgery.³³

Staging Surgery

The standard treatment of BOT consists of the removal of the ovarian tumor combined with a peritoneal staging surgery (including peritoneal cytology, omentectomy, and multiple peritoneal biopsies). These procedures altogether define an adequate surgical staging, which guides our decision upon adjuvant therapy exclusively in patients with invasive perito- neal implants. A surgical lymph node assessment in case of no suspicion is not required. Lymphadenectomy (or selective adenectomy) is required only in cases of patients with perito- neal spread and lymphadenomegaly during the surgical ex- ploration (or on computed tomography scan). It is of note that, in patients with a macroscopically normal peritoneal surface on exploration, the value of random biopsies with respect to sur- vival is unproven in BOT.^34Y36Only in case of an MP pattern this peritoneal staging surgery is required in SBOT.³⁶In case of borderline malignancy not recognized during the first surgery by a frozen section analysis, should a restaging surgery be systematically performed? This procedure could be omitted in patients having an SBOT without MP pattern and a careful inspection of the abdominopelvic cavity (described in the op- erative report) with a macroscopically normal-appearing peri- toneum. Such patients could then be carefully followed up without a new surgical procedure that could impair their sub- sequent fertility.

Some authors also propose in case of unilateral disease a routine biopsy of the contralateral normal-appearing ovary.

However, the yield of this procedure (ie, detection of a small focus of borderline disease in a macroscopically normal- appearing ovary) is very low. Furthermore, several series have reported recurrences in patients who had a normal routine biopsy of the contralateral ovary.^37,38 It is noteworthy that this is not a procedure without adverse effects, as it may induce infertility because of postoperative ovarian adhesions.

Thus, macroscopic inspection appears to be sufficient. A biopsy should be performed only in case of a lesion with suggestive macroscopic findings.

Apart from this, there is no indication to perform a uterine curettage as there is no increased rate of endometrial cancer in those patients. Furthermore, there is no indication for an appendectomy in patients with an SBOT.

Conservative Treatment of Advanced-Stage Serous BOT

Data in the literature concerning conservative man- agement of BOT with peritoneal implants are rare19,26,39Y41

(Table 1). To date, only 2 large series have been published.

These 2 series concluded that conservative management may be proposed to patients with peritoneal implants, in case these implants are entirely removed with a reliable pathological re- view.^19,41Zanetta et al¹⁹reported on 12 patients with nonin- vasive implants treated conservatively: 3 of them developed a recurrent BOT in the contralateral ovary, 1 of those as an in- vasive ovarian carcinoma, but all 3 were salvaged with surgery and chemotherapy. All these patients were free of disease at the latest follow-up. Uzan recently reported on a series of 41 patients treated conservatively for a BOT with peritoneal implants.⁴¹ Twenty-two recurrences occurred (19 of them noninvasive). Nonetheless, 1 patient (with micropapillary pat- tern and noninvasive implants during initial management) had invasive recurrence and died of the disease.⁴¹The risk of death appears to be rare in case of conservative treatment in patients with an SBOT with noninvasive peritoneal implants. How- ever, a complete resection of implants appears to be crucial in this context.

In contrast, according to the sparse literature, in patients with invasive implants the safety of fertility-sparing

surgery appears to be questionable. Zanetta et al¹⁹reported on 7 patients with invasive implants treated conservatively.

Five BOT recurrences were observed in the remaining ovary (1 of them associated with lymph node spread) (we have no information about the use of adjuvant chemotherapy during the initial management in these 5 patients).¹⁹ All patients were alive 21, 25, 30, 35, and 81 months after salvage sur- gery.¹⁹In our experience, 3 patients with invasive implants did receive fertility-sparing surgery, of whom 1 had pro- gressive peritoneal disease.⁴¹ In another series reported by Prat and De Nictolis,³⁹the only patient treated conservatively for BOT with invasive implants (without micropapillary patterns) died of recurrent disease (but we have no details about the use of adjuvant treatment during initial manage- ment and the location of recurrent disease). However, it should be recognized that the poor prognosis is mainly related to the extraovarian tumor and probably not to the preservation of the ovary itself. Considering the aggressiveness and the poorer prognosis of BOT with invasive peritoneal implants, conservative treatment should be used with caution.⁴¹

Follow-Up, Fertility Results After Conservative Surgery, and Management of Recurrent

Ovarian Disease

Pregnancies have been reported in patients with conservatively treated BOT. Lim-Tan et al¹⁷initially reported on 8 patients who conceived. Eight series (involving 910 patients seeking parenthood) specifically reported the ob- stetrical results of conservative treatment.2,15,16,19,20,25,42,43

The rate of spontaneous pregnancies ranged between 30%

and 80%.

To our knowledge, only 2 series reported on the mo- dalities of follow-up in BOT.^44,45Of most value appears to be vaginal ultrasonography to detect local recurrences.⁴⁴ With respect to the use of tumor markers, Zanetta et al⁴⁴failed to demonstrate the value of such measurements in this context.

In contrast, a recent series about the follow-up of patients with advanced-stage BOT suggested that the use of tumor markers could be helpful for detecting recurrent invasive dis- ease earlier.⁴⁵In concordance with invasive disease, follow-up examination contains a clinical examination and abdomino- pelvic and vaginal ultrasonography combined with a tumor

TABLE 1. Literature review of recurrence rates in advanced-stage serous ovarian borderline tumor (in particular with invasive implants) after conservative treatment

No.

No.

Recurrences

No. of Deaths

No. of Invasive Implants

Recurrence in Patients With Invasive Implants

Death in Patients With Invasive Implants

Zanetta et al¹⁹ 25 10 0 7 5 0

Prat and De Nictolis³⁹ 10 3 1 1 1 1

Longacre et al⁴⁰ 21 5 0 V V V

De Iaco et al²⁶ 21* 4 ? ? ? ?

Uzan et al⁴¹ 41 22 1 3 2 0

Total 97 40 (41.2%) 2 (2%) 11 8 1

*Mixed histology (mucinous, serous tumor).

marker determination (CA-125). There is no consensus about the regularity of follow-up, but we suggest evaluating the pa- tient at least every 6 months during the first 3 years and yearly thereafter. Prolonged follow-up (915 years) is required because very late recurrences have been reported.

The interest in completion surgery (removal of re- maining ovary) when family planning has been completed remains controversial. Because the reported recurrence rate is between 0% and 25%, a routine oophorectomy would be unnecessary in 75% to 100% of patients.^11Y13Furthermore, the majority of those recurrent lesions (most of them again in form of a BOT) can be easily cured, using a simple surgical procedure. The systematic removal of the remaining ovary is thus not mandatory provided the patients are followed up regularly. However, some patients prefer to undergo a pro- phylactic oophorectomy after completion of their individual family planning.

Most recurrences occurring on the remaining ovary are again borderline lesions. If such recurrences occur in patients younger than 40 years, a repeated conservative treatment ap- proach (cystectomy) can be discussed.^11Y13Recurrent disease in form of invasive cancer is rare and should be treated radically.^19Y21

Mucinous BOT

Most of patients with a diagnosis of MBOT are ex- clusively treated with surgery. Mucinous BOTs are, in fact, a complex group of tumors with several histological sub- types, with few of them morphologically presenting as a transition between benign mucinous tumors and invasive carcinoma.^46,47

Mucinous BOTs are histologically classified as follows:

& intestinal (the most frequent subtype); these tumors can be very large (sometimes up to 30 cm). In this subtype, bilateral involvement is very rare, and, if a primary tumor of the tumors are bilateral, intestine should be ruled out (colono- scopy and gastroscopy).

& endocervical-like (former ‘‘mu¨llerian’’) is a subtype with mild or moderate nuclear atypia; these tumors can be bi- lateral and can be associated with endometriosis and/or other histological components of borderline malignancy (serous or endometrioid).^48Y50

Whatever the subtype of MBOT, those ovarian tumors can present with microinvasion defined as stromal infiltra- tion of less than 10 mm². In some cases of MBOT, archi- tectural and cytological features of an adenocarcinoma (with marked nuclear atypia) can be observed but without stromal invasion. Such tumors are considered as ‘‘intraepithelial carcinoma.’’

Extraovarian spread is rare in MBOT. Historically, patients with MBOT and mucinous peritoneal disease in form of a peritoneal pseudomyxoma were classified as another subtype of MBOT. The prognosis and the treatment of this entity are totally different from those of other patients exhi- biting MBOT. In patients with peritoneal pseudomyxoma, an MBOT appears to be only as an adjunct because most of them present a dissemination from an appendiceal mu-

cinous tumor.^51,52 Moreover, patients exhibiting peritoneal pseudomyxoma are treated differently (by predictive surgery and heated intraperitoneal chemotherapy), and therefore, those tumors are no longer classified as an MBOT subtype.

As already pointed out, extraovarian disease (likewise to peritoneal implants in SBOT) is very uncommon in MBOT, but could be observed in patients with an endo- cervical subtype. Consequently, as the presence of peritoneal spread in MBOT is very rare, the value of routine peritoneal staging in patients without obvious peritoneal lesions remains unclear.⁵³In the intestinal subtype, an appendectomy should be performed because isolated mucoceles may be observed in the appendix.

According to the literature in comparison to serous dis- ease, MBOT appears to be more prone to recur in form of an invasive adenocarcinoma, especially in patients in whom only a cystectomy was performed rather than a complete salpingo- oophorectomy.⁵⁴This could be explained by the fact that most of these tumors were large, and the histological analysis of such bulky tumors is difficult with a risk of missing an invasive component due to an inadequate evaluation. In case of an in- vasive epithelial carcinoma, conservative treatment could be proposed (performing a salpingo-oophorectomy), but a cys- tectomy only does not appear to be safe in patients undergo- ing conservative management for EOC. Thus, in MBOT, a (salpingo)oophorectomy should be preferred to cystectomy to avoid the risk of a (potentially lethal) recurrence in form of invasive cancer.^21,54

EPITHELIAL OVARIAN CANCER

The differential criterion between EOC and BOT is the invasion of the ovarian stroma. The standard surgical proce- dure for EOC includes simple hysterectomy with bilateral salpingo-oophorectomy. The results published in the litera- ture concerning conservative management of EOC are ham- pered by the fact that many series only summarize pooled data from epithelial and non-EOC, as well as invasive and BOTs. Only a few studies have focused exclusively on con- servative treatment in EOC (Table 2).^55Y65

Specific Requirements

A conservative approach should be considered only in case of early-stage disease after an adequate surgical staging.

This staging should include peritoneal washings, excision of any suspicious peritoneal lesions, multiple random peritoneal biopsies, omentectomy, an endometrial curettage (to exclude synchronous endometrial carcinoma), and a pelvic and para- aortic lymph node dissection.⁶⁶ Nevertheless, the use of nodal staging surgery could be probably omitted in patients with stage I disease and mucinous subtypes or serous grade 1 subtypes, as there is a very low rate of nodal spread in these 2 situations.

In addition, in case of a conservative approach, some authors such as Munnell⁶⁷propose a random biopsy of the remaining ovary, because according to their data a contralateral microscopic involvement was found in 12% of the cases.⁶⁷In addition, Benjamin et al⁶⁸ found microscopic disease in the contralateral ovary in 3 (2.5%) of 118 patients with stage I

EOC. However, all these 3 patients had a grade 3 tumor, and none of the patients with stage I grade 1 or 2 disease had occult metastasis on the contralateral ovary.⁶⁸It is of note that such a biopsy of the contralateral ovary can theoretically lead to in- fertility by causing postoperative adhesions on the remaining ovary. Moreover, many authors did not find any microscopic implants in a macroscopically normal-appearing ovary.^56,58 Consequently, we do not recommend a routine biopsy of the contralateral ovary if a preoperative vaginal ultrasonography and an intraoperative assessment do not reveal any abnormal- ities on the contralateral ovary.

Finally, in case of ovarian cancer in a young patient with a suspicious family history, a hereditary predisposition to ovarian or breast cancer should be ruled out (testing for BRCA mutation gene).

Indications

Initially, DiSaia⁶⁹proposed a conservative treatment in EOC only in selected cases (ie, patients who seek parenthood, are willing to comply with a close gynecological follow-up, and have stage IA diseaseVwell-encapsulated ovarian cancer without peritumoral adhesions and involvement of neither the ovarian surface nor mesovarium infiltration⁶⁹). Moreover, such conservative management would be proposed in most common histological subtypes (serous, mucinous, and en- dometrioid) EOC.

We have very few data to evaluate the safety of such conservative treatment in patients with different (and more

‘‘aggressive’’) histological subtypes of EOC (particularly clear cell, anaplastic, and small cell). The ‘‘bad’’ prognosis of these diseases is perhaps not related to the preservation of the ovary itself but to the ‘‘natural history’’ (and frequency of extraovarian spread) of these tumors. In patients with clear cell disease, recent data reported by Asian series suggested that conservative surgery could be proposed in patients at early stage.^62,70Nevertheless, the natural history of clear cell carcinoma (more frequent in Asia) is perhaps less aggressive in this area than when observed in Europe or North America.

In patients with anaplastic or small cell carcinoma, the bad prognosis of the disease is so high that radical surgery followed by polychemotherapy (and perhaps pelvic radiation therapy at the end of treatment in stage I/II small cell carci- noma) should be proposed.⁷¹Thus, there is clearly no place for conservative management in this context.

With respect to grading, the outcome reported in the literature suggests that conservative surgery could be safely performed in patients with stage IA grade 1 (and probably grade 2) disease (Table 2).^55,64,72In contrast, in 18 patients with stage IA grade 3 disease, 8 recurrences were observed (Table 2). It is not possible to say if this rate of recurrence is related to the preservation of the ovary itself or more simply to the ‘‘natural history’’ of the disease. Nevertheless, waiting potential further reports on this topic, we should consider that conservative management should not be offered to such patients.

A major controversy exists about the question whether a conservative approach can be safely offered to patients with stage IC disease (Table 2). The conflicting data reported in the literature disease might be explained by the heterogeneous TABLE2.LiteraturereviewofresultsofconservativemanagementinEOC(7seriesreportedincluding910cases)* StageIAGrade1StageIAGrade2StageIAGrade3StageICGrade1StageICGrade2StageICGrade3 Italianseries Zanettaetal55 / Colomboetal56

1recurrenceamong 24patients3recurrencesamong 8patients1recurrenceamong 4patientsNorecurrenceamong 10patients1recurrenceamong 6patientsNorecurrenceamong 3patients Americanseries Schilderetal572recurrencesamong 33patients2recurrencesamong 6patientsNorecurrenceamong 3patientsNorecurrenceamong 5patients1recurrenceamong 3patientsNorecurrenceamong 2patients Frenchseries Moriceetal581recurrenceamong 13patients4recurrencesamong 14patients1recurrenceamong 3patients2recurrencesin2patientsNopatient1recurrencein1patient Borgfeldtetal59 Norecurrenceamong8patientsNorecurrencein1patientNopatientNopatientNopatient1recurrencein1patient Parketal601recurrenceamong 29patientsNorecurrencein 3patients4recurrencesin 4patients1recurrencein 15patients1recurrencein 2patients2recurrencesin 4patients Anchezaretal61 1recurrenceamong 10patientsNopatient1recurrencein 1patient†Norecurrencein 3patientsNorecurrencein 1patientNorecurrencein 1patient Satohetal62 5recurrencesamong 95patientsNorecurrencein 13patients2recurrencesin 3patients5recurrencesamong 65patientsNorecurrencein 2patients1recurrencein 3patients Total11(5%)recurrences among207patients9(20%)recurrences among45patients8(45%)recurrences among18patients8(8%)recurrencesamong 100patients4(29%)recurrences among14patients5(33%)recurrences among15patients *Inthistable,therecentseriesbySchlaerthetal63including20cases,byKajiyamaetal64including60cases,andbyKwonetal65including21caseswerenotincludedbecausethereportslackedprecisedetailsconcerning thetumorgradedistributionforstagesIAandICdisease. †PatientconsideredashavingastageIAgrade3tumorafterpathologicalreviewoftheinitialtumoratthetimeoftherecurrence.

International Federation of Gynecology and Obstetrics cri- teria leading to the definition of stage IC disease. According to the 1988 International Federation of Gynecology and Obstetrics classification, patients are defined as having stage IC disease in case of a unilateral or bilateral tumor with (a) tumor spread on the surface of the ovary (excrescences) and/or (b) ascites containing malignant cells or positive cy- tology after peritoneal washing and/or (c) capsular rupture.

Thus, patients with stage IC can represent a variety of dif- ferent disease features with different tumor biology. Fur- thermore, the histological subtype (mucinous, serous, or other) could have been different. In a recent series reported by Kajiyama et al,⁶⁴ including 60 patients (29 stage IC) who underwent conservative treatment, the survival of patients was worse among patients with stage IC disease because of positive cytology or surface involvement in comparison to stage IC due to capsular rupture in which survival was ex- cellent. In this report, only 2 of 30 patients with stage IA developed recurrence (1 grade 1 and 1 grade 2), in contrast to 5 of 29 with stage IC (4 grade 1 and 1 grade 3).⁶⁴ In the subgroup of 9 patients with stage IC disease related to posi- tive cytology, 4 of them had a recurrence (3 had grade 1 dis- ease).⁶⁴If we take into account the recent data published by Park et al⁶⁰and Satoh et al,⁶²conservative management could probably be considered in stage IC grade 1 disease but should not be performed in grade 2 or 3 disease. Recent data suggest that conservative treatment should not be used in stage IC (even grade 1) disease with presence of positive cytology.⁶⁴

In contrast, a recent article reporting an analysis of the SEER (Surveillance, Epidemiology and End Results) data- base suggests that preserving an ovary in stage IA or IC disease does not have a deleterious impact on survival.⁷³ However, according to their sample size calculation, ‘‘to de- tect a 20% difference in survival for patients with stage IC disease, a cohort of 1282 patients with 52 deaths is re- quired.’’⁷³So far, none of the published series included such a large number of patients, and therefore it is not possible to draw a definitive conclusion about the safety of conservative management in stage IC disease.

Last but not least, in a recent article by Schlaerth et al,⁶³ the survival of 20 patients treated conservatively for stage I disease was comparable to the survival of patients (G45 years) treated radically. Nevertheless, such comparison is severely inadequate because even if none of the prognostic factors attained statistical significance because of lack of power, these factors tended to be better in general in the group of patients treated conservatively.⁶³

Another possibility for a restrictive fertility-preserving approach in patients with stage IC and/or grade 3 disease would be the removal of both ovaries but with uterine con- servation, which would keep the option of entering an oocyte donation program. This option has never been explored in EOC but should be evaluated. In the recent SEER database analysis, there was no impact on survival with uterine pres- ervation in stage IA and/or IC disease.⁷³

A conservative management including leaving 1 ovary and the uterus in EOC is clearly contraindicated in case of stage greater than stage I, a synchronous endometrial cancer, grade 3 disease, bilateral involvement of the ovaries (stage IB or IC

with bilateral spread), an identified hereditary syndrome, or a histologically aggressive tumor variant (anaplastic tumor, small cell carcinoma/neuroendocrine tumor).^58,60,61

The prognosis of patients with recurrent EOC after conservative surgery is poor in general, particularly when re- current disease arises outside the preserved ovary.⁷⁴

Follow-Up and Fertility Results After Conservative Surgery

The follow-up entails a clinical examination, analysis of tumor markers, and the use of systematic imaging (abdomi- nopelvic ultrasonography), especially of the remaining ovary.

Only a few reports upon the fertility outcome in those patients are available in the literature. Zanetta et al,⁵⁵for ex- ample, reported on 27 pregnancies in 20 patients. In another series, 17 pregnancies were reported in 24 patients attempting to conceive.⁵⁹ In the French series, only 9 pregnancies were achieved.⁵⁸Park and coworkers reported on 15 pregnancies in 19 patients.⁶⁰In the series reported by Anchezar et al,⁶¹6 of 7 patients attempted to conceive and achieved in total 7 preg- nancies. In the recent series reported by Satoh et al,⁶²fertility results were not investigated.

The completion of the surgery after childbearing (or after the age of 40 years) has to be discussed with the patient, because some reports describe recurrent EOC 10 years after conservative treatment.⁷⁵

NONEPITHELIAL MALIGNANT OVARIAN TUMORS

Nonepithelial malignant tumors are characterized by (1) the occurrence of disease mainly in younger patients and (2) a good prognosis in general (even in case of extraovarian disease) as in most cases the chemosensitivity of these tumors is excellent. Those tumors can be differentiated into 2 main groups: germ cell tumors (GCTs) and sex cord stromal tumors (SCSTs). In cases of mixed histology, the histological subtypes with the worse prognosis should be taken into ac- count to discuss the option of conservative treatment.

Germ Cell Tumors

Most of the articles reporting on the results of con- servative surgery in nonepithelial cancers are focusing on GCTs^76j88(Table 3). The most frequent entities in this group are dysgerminomas, endodermal sinus tumors (ESTs), malig- nant teratoma, and mixed subtypes. Because these tumors most often occur in young women, conservative surgery is consid- ered to be the criterion standard including only a unilateral salpingo-oophorectomy. The role of a complete routine staging (peritoneal and nodal) is unclear. In EST with a macro- scopically normal contralateral ovary, a random biopsy is not indicated. In contrast to this, in dysgerminomas and/or malig- nant teratomas, the risk of occult contralateral disease is reported to be up to 10%. For example, in a recent series by Boran et al,⁸³2 (11%) of 17 patients with a dysgerminoma and a macroscopically normal contralateral ovary had occult in- volvement. Adjuvant chemotherapy is conventionally used in stage IC or greater and is based on BEP regimen (bleomycin, etoposide, and cisplatin).

The follow-up is similar to patients with epithelial cancer, but the use of tumor markers depends on the histo- logical subtype.

The fertility outcome reported after 1995 is shown in Table 3. Menstruation and endocrine ovarian function were maintained in the vast majority of these young patients treated with BEP (Table 3). Because of the high chemosensitivity, conservative management could also be considered in patients with bilateral involvement (especially in case of bi- lateral teratomas) or even in patients with peritoneal disease treated with adjuvant chemotherapy (particularly in dysger- minomas or malignant teratomas) (Table 3).

Given the high rate of cure among these patients, there is no need to complete the surgery after childbearing. In teratomas, there may be occasions for surgery to excise dif- ferentiated remnants.

Sex Cord Stromal Tumors

The most frequent subtypes of these tumors are granu- losa cell, Sertoli-Leydig, and thecal cell tumors. Only very few articles report on the conservative management of such tumors (mostly case reports). In a series reported by Zhang et al,⁸⁹ among the 376 women treated for SCST, 71 young patients underwent only a salpingo-oophorectomy for stage I disease.

The survival of patients treated conservatively was not sig- nificantly different from those who were treated radically.⁸⁹

Two important characteristics observed in granulosa cell tumors have an impact on the performance of a conser- vative approach: a bilateral tumor occurrence is uncommon (between 2% and 8% of the cases⁹⁰), and these tumors are frequently associated with endometrial disorders (hyperplasia or cancer) due to their hormonal activity. Consequently, a random biopsy of the contralateral ovary is not required (if macroscopically normal appearing), but a uterine curettage should be performed systematically. Peritoneal staging is usually performed in this tumor, in contrast to nodal staging procedures for which no supporting evidence exists.⁹⁰ The overall prognosis of granulosa cell tumors is generally good in early-stage disease (stage IA); thus, conservative man- agement could be considered in young patients wishing to retain their fertility. However, in advanced-stage disease, conservative management should not be proposed to the patient because the impact on the prognosis is less clear.

In case of Sertoli-Leydig tumors, conservative man- agement should be discussed only in stage IA disease without a retiform, poorly differentiated, or sarcomatoid appearance in the histological analysis. In patients with advanced-stage disease, there are not enough data to evaluate the safety of conservative treatment.

The question whether the surgery should be completed after childbearing in patients with in SCST is also unclear, so far.⁹¹

CONCLUSIONS

In young patients with BOT, a conservative treatment approach does not seem to have a significant impact on sur- vival, and the outcome regarding fertility is good in general. It can be considered even if noninvasive peritoneal implants are discovered at the time of the initial surgery.

TABLE3.LiteraturereviewoffertilityresultsfollowingconservativemanagementinGCTs(seriespublishedafter1995) SeriesPeccatori etal76Mitchell etal*77Tewari etal78Low etal79Zanetta etal80Tangir etal81Zanagnolo etal82Boran† etal83Ayhan etal*84

Breweretal†85 ; Gershenson etal86Kang etal*87

delaMotte Rouge etal*88 No.patients1296972741691065523291372052 No.conservative10850467413864392315711541 Menstruation maintained?24/26?43/45128/13032/40‡2619/23‡10§621539/40 No.pregnancies?11?19/2055in32patients38in29patients116in5patients337in24patients219in12patients No.conservative II/III/IV37?1||194611(9pregnancies)118(4pregnancies)???4pregnancies *ArticlesexclusivelyreportingonESTornondysgerminomatoustumors. †Articlereportingonlyondysgerminomatoustumors. ‡Menstruationconsideredsimilartothatobservedbeforechemotherapy. §Fivepatientsexcludedfromassessmentofmenstruationbecauseofalethalrecurrence. ||Pregnantpatient.

In contrast, in patients with EOC, conservative surgery should be considered only in adequately staged patients, with a stage IA grade 1 (and probably 2) serous, mucinous, or an endometrioid tumor, including a careful follow-up. Such an approach could also probably be discussed in stage IC grade 1 disease (except of patients with stage IC disease due to positive cytology where radical treatment should be preferred).

In patients with nonepithelial malignant ovarian tumors, conservative surgery is also feasible, particularly in patients with malignant GCTs because of their high chemo- sensitivity, leading to an excellent prognosis in general.

ACKNOWLEDGMENT

The authors thank Lorna Saint Ange for editing.

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