yufi nakal

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1/13www.thelancet.com/oncology Vol 13 March 2012 e103

Review

Lancet Oncol2012; 13: e10315

Department of Gynaecological

Surgery (Prof P Morice MD,

C Uzan MD, S Gouy MD),

Department of Pathology

(P Duvillard MD), and INSERM

U 10-30 (Prof P Morice, C Uzan),

Institut Gustave Roussy,

Villejuif, France;Universit

Paris-Sud, Le Kremlin Bictre,

France (Prof P Morice);

Department of Obstetrics andGynaecology, CHU Amiensand

INSERM ERI-12, Universit de

Picardie Jules Vernes, Amiens,

France (R Fauvet MD); and

Department of Obstetrics and

Gynaecology, Hpital Tenon,

INSERM UMRS 938, and

Universit Pierre et Marie Curie,

Paris, France(Prof E Darai MD)

Correspondence to:

Prof P Morice, Department of

Gynaecological Surgery, Institut

Gustave Roussy, 114 rue Edouard

Vaillant, 94805 Villejuif Cedex,

France

[email protected]

Borderline ovarian tumour: pathological diagnostic dilemma

and risk factors for invasive or lethal recurrencePhilippe Morice, Catherine Uzan, Raffaele Fauvet, Sebastien Gouy, Pierre Duvillard, Emile Darai

By comparison with ovarian carcinomas, borderline ovarian tumours are characterised clinically by superior overallsurvival, even in women with peritoneal spread. In this Review, we aimed to clarify the histological and clinical factorspotentially defining a high-risk group in whom disease is likely to evolve to invasive disease. Invasive peritoneal implants(in serous borderline ovarian tumours) and residual disease after surgery were the two factors clearly identified. Otherfactors are controversial owing to increased risk of invasive recurrence: micropapillary patterns in serous borderlineovarian tumour, intraepithelial carcinoma in mucinous lesions, stromal microinvasion in serous lesions, and use ofcystectomy in mucinous borderline ovarian tumours. The pathologist has a pivotal role in assessment of the borderlinenature of ovarian tumours and in identification of high-risk criteria, most of which are histological. But, reproducibilityof the histological interpretation of some of these potential criteriaeg, classification of peritoneal implants (particularly

in desmoplastic subtype), stromal microinvasion, micropapillary patterns, and intraepithelial carcinoma in mucinousborderline ovarian tumoursremains unclear, and should be investigated.

IntroductionBorderline ovarian tumours differ from ovarian carcinomaby absence of stromal invasion. Classifications for theselesions have been modified extensively over past decades.Borderline ovarian tumours were reported initially in1929 as semi-malignant disease. In 1961 and 1971, theInternational Federation of Gynecology and Obstetrics(FIGO) proposed the term low malignant potential. In1973, FIGO and WHO suggested creation of a group oftumours with morphological criteria (in particular, absence

of stromal invasion), which differentiated them fromcarcinoma. In this same year, WHO adopted the synonymborderline, which is still used in the current (2003)classification.1 WHO thereafter defined extra-ovarianperitoneal disease as implants (and not metastases)because of their indolent nature. In 1988, Bell andcolleagues2proposed classification of peritoneal implants(invasive vs non-invasive lesions) according to theirmorphological features.

The most frequent borderline ovarian tumours areserous lesions, representing two-thirds to three-quarters ofthese tumours.3However, in a Danish register-based cohortstudy, mucinous tumours represented 50% of borderlineovarian tumours and serous tumours comprised 44%.4

The ratio in Asia is different, with an equivalent or higherrate of mucinous borderline ovarian tumours.5

The true incidence of borderline ovarian tumoursremains unknown. 1520% of serous tumours are judgedborderline.6 Data from the SEER (surveillanceepidemiology and end results) programme showed anincidence of 25 per 100 000 women-years in the USA.7Compared with carcinoma, borderline ovarian tumour ischaracterised clinically by a younger age at diagnosis(10 years earlier) and better overall survival, even withperitoneal spread. 5-year and 10-year survival rates forstage I, II, and III disease are 99% and 97%, 98% and90%, and 96% and 88%, respectively.8 Despite thesefavourable data, some patients relapse or succumb todisease.

Borderline ovarian tumours can be unilateral or bilateral.Similar to carcinoma, they can spread to the peritoneumand, eventually, to lymph nodes. High-risk borderlineovarian tumour has not been defined by consensus,therefore, identification of risk factors for invasiverecurrence or disease-related death is pivotal.

In this Review we aimed to analyse prognostic factors forinvasive recurrence and death from disease for serous andmucinous borderline ovarian tumours. We have notincluded rare entities such as endometrioid, Brenner, orclear-cell borderline ovarian tumours because of their verylow incidence (


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serous borderline ovarian tumours devoid of micro-

papillary patterns (now designated atypical proliferativeserous tumours), non-invasive micropapillary low-gradeserous carcinoma, invasive low-grade serous carcinoma(invasive micropapillary serous carcinoma), and high-grade serous carcinoma. The overriding issue was toascertain whether patients with serous borderlineovarian tumours with micropapillary patterns should beincluded in a high risk-group and their disease bedeemed low-grade carcinoma. Molecular data seem toconfirm this viewpoint.18,21 May and co-workers18compared RNA from epithelial cells of serous borderlineovarian tumours, serous lesions with micropapillarypatterns, and invasive low-grade serous carcinoma andnoted that the gene-expression profile of serous lesions

with micropapillary patterns was similar to that ofinvasive low-grade serous carcinoma but distinct fromthat of serous borderline ovarian tumours, with candidategenes implicated in the MAPK pathway. These datareinforce the notion that invasive low-grade serouscarcinoma develops in a stepwise fashion from benigncystadenofibroma to classic invasive low-grade serouscarcinoma via transformations to serous borderlineovarian tumour (or, atypical proliferative seroustumours)22 and serous lesions with micropapillarypattern (figure 2).18

Findings suggest that epithelium from the fallopiantube could become implanted on the ovary, initiatinghigh-grade serous tumours.28In patients with low-gradeserous disease, mutations in KRAS, BRAF, andoccasionally HER2 and PIK3CAhave been characterised.TP53 mutations are rare in this subgroup and areencountered more frequently in individuals with high-grade disease.28

Peritoneal implants

The outlook for patients with serous borderline ovariantumours and peritoneal disease is better than for womenwith ovarian carcinoma and peritoneal spread. Therefore,peritoneal disease from borderline ovarian tumours isreferred to as implants and not metastases. Suggestionsabout pathogenesis of implants include implantation ofcells detached from the ovarian surface (which accordswith the high frequency of implants in case of exophyticvegetations) and formation of implants independently ofovarian tumours.25 Molecular data lend support toarguments for both theories but, to date, none of thempredominates.25

Implants can be non-invasive (nearly 85% of implants)or invasive.29Non-invasive implants are defined as a serous-

type epithelial proliferation that affects peritoneal surfacesand shows no invasion.2,26 Non-invasive implants aredesmoplastic or epithelial, and prognosis of these twosubtypes is similar. However, recognition of potentialinvasion of underlying tissue is more complex in thedesmoplastic than in the epithelial subtype.2,6 Invasiveimplants are defined as a serous-type epithelial pro-liferation affecting peritoneal surfaces and invadingadjacent or underlying tissue.2,6Morphologically, aspects ofthese invasive implants are similar to those of invasive low-grade serous carcinoma, but we should remember that thediagnosis of borderline ovarian tumour is based on ovarianhistological features.

The pathologist must harvest suffi cient tissue to be ableto discriminate non-invasive from invasive implants, byassessment of the junction between implants and adjacentnormal tissue.27However, Bell and colleagues29report that25% of implant biopsy specimens have no underlyingtissue. Surgeons go to tremendous effort to removeimplants as widely as possible to guarantee resection ofsurrounding tissue. Subsequently, Bell and colleagues29suggested use of additional morphological criteria otherthan invasion of surrounding tissue to classify invasiveand non-invasive implants (micropapillary architectureand solid epithelial nests surrounded by clefts).

The skill of the pathologist is also important.26,27Even forexpert pathologists, some implants remain too ambiguous

to be classified and are categorised as indeterminate forinvasion.30 To optimise histological analysis and tominimise interobserver variability, serous borderlineovarian tumours with implants could benefit fromsystematic review by a reference pathologist.

To assess the effect of peritoneal implants and to limitrisk of bias attributable to small series, we analysed reportsincluding at least 50 patients with serous borderlineovarian tumours with peritoneal implants (table 1).Longacre and colleagues34 reported that the soleindependent prognostic factor for overall survival was theimplant subtype (eight of 14 patients with invasive implantsrelapsed). Seidman and Kurman36noted that the mortalityrate for patients with non-invasive and invasive implantswas 47% and 34%, respectively (p


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prognosis for serous borderline ovarian tumours withinvasive implants is poor, it is better than that for authenticcarcinoma.23,25 Nevertheless, it is noteworthy that thenumber of cases of invasive implants and follow-updiffered widely between series, which could constitutepotential biases.27 Furthermore, proportions of patientswith residual disease and with micropapillary patternswere not always mentioned. Gershenson and colleagues32,33recorded very similar rates of progressive and recurrentdisease (nearly 30%) in patients with non-invasive andinvasive implants.

These important data should be used to extend follow-upin advanced-stage borderline ovarian tumours. Silva andco-workers37suggested that rates of recurrence and overallsurvival in women with serous borderline ovarian tumoursand non-invasive implants are time dependent. Of35 relapsing patients, eight developed recurrent diseasewithin fewer than 5 years of follow-up, 15 recurrencesarose between 5 and 10 years, eight between 10 and15 years, and four after 15 years of follow-up. Patients withinvasive implants relapsed more rapidly than did thosewith non-invasive implants. The true effect on rate ofrecurrence (and survival) of implant subtypes should be

assessed in series with prolonged follow-up of more than10 years.2,25,37

Micropapillary patternsFindings of several studies indicate that serous borderlineovarian tumours with micropapillary patterns have poorerprognosis than do lesions without this histologicalfeature.19,34,3840 Nevertheless, the true prognostic value ofmicropapillary patterns continues to fuel debate.20Indeed,serous borderline ovarian tumours with micropapillarypatterns without implants (stage I) or with non-invasiveimplants (stage IIIII) have the same prognosis as doserous borderline ovarian tumours without micropapillarypatterns (or, atypical proliferative serous tumours).22Somefindings indicate that architecture of micropapillary

patterns does not exert a substantial effect on overallsurvival when peritoneal implants are controlled for.21,34Decreased survival of patients with micropapillary patternscould perhaps be linked to the increased rate of invasiveperitoneal implants and not to presence of micropapillarypatterns itself.19,38 As a result, some researchers suggestthat serous borderline ovarian tumours with micropapillarypatterns without invasive implants should be classified asserous borderline ovarian tumours and not as invasivelow-grade serous carcinoma.27,30 Figure 2 shows theevolution of (but also discrepancies in) these classificationsof serous borderline ovarian tumours, with morphologicaldescription of implants and micropapillary patterns.

The main issue for patients with serous borderlineovarian tumours with micropapillary patterns is toascertain whether the micropapillary pattern is a feature ofa high-risk group likely to develop an invasive recurrenceand have disease-related mortality. In a series with medianfollow-up of 4 years, Shih and colleagues3 noted thatthe micropapillary pattern was associated with lowdisease-free survival of 759% (95% CI 556878),compared with 943% (884973) for patients without amicropapillary pattern. However, patients with and without

invasive implants were not distinguished from those witha micropapillary pattern. Diffi culties arose in this Reviewwhen we tried to ascertain whether some recurrences werelinked to the micropapillary pattern or to invasive peritonealimplants (table 2). In eight series (n=144)16,17,19,4044showingcorrelations between overall rate of recurrence, rate ofinvasive recurrence, and rate of disease-related deathassociated with micropapillary patterns, 56 patients hadrecurrence (39%). 54% (30 of 56) of recurrences wereinvasive at recurrence and 10% of deaths were related todisease. Moreover, in seven of eight series (n=107)16,17,19,40,41,44with information on the nature of peritoneal implants,29 patients initially had invasive implants (table 2). Ofthese 29 women, 11 had recurrence in the form ofcarcinoma or invasive recurrence.16,17,19 The behaviour of

Figure :Evolution of and discrepancies in current classifications of serous borderline ovarian tumoursSizes of divisions do not correlate with frequency of each subtype. AFIP=Air Forces Institute of Pathology. NCI=National Cancer Institute. NIH=National Institutes of Health. MPSC=micropapillary

serous carcinoma. APST=atypical proliferative serous tumour. LGSC=low-grade serous carcinoma. HGSC=high-grade serous carcinoma. *Without micropapillary pattern.

Carcinoma1973: WHO classification23

1980s: implant characterisation2

1996: description of micropapillarypattern16,17

2005 to present: Kurman (2005)22

2003 to present: AFIP (1996),24

WHO (2003),1

NCI/NIH workshop (2004)2527

Evolution of classifications

Proposed current classifications

Borderline

Carcinoma

Carcinoma

Carcinoma

Carcinoma

Stage I borderlineNon-invasive

implantsInvasiveimplants


implants*Invasive

implants*Micropapillary

pattern

Non-invasiveimplants*

Invasiveimplants*

APST HGSCLGSCMPSC

Borderline

CarcinomaBorderline


implantsInvasiveimplants

Micropapillarypattern


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serous borderline ovarian tumours with micropapillarypatterns seems to be more related to presence of invasiveimplants rather than to this particular histologicalfeature.25

Stromal microinvasionStromal invasion is more frequently seen in serous than inmucinous borderline ovarian tumours. Analysis of theeffect of microinvasion on the rate of invasive recurrencesand disease-related death is especially diffi cult because ofpotential confounding factors, such as micropapillarypatterns and presence of peritoneal implants for serousborderline ovarian tumours.

In 12 series of serous borderline ovarian tumours withmicroinvasion (n=133), 20 patients had recurrence (15%),including 35% (seven of 20) with invasive disease atrecurrence (table 3). Rate of disease-related death was 6%(eight of 133; table 3).

In accordance with findings of previous studies, our dataindicate that microinvasion is a prognostic factor for serousborderline ovarian tumours.34,42Further studies are neededto establish whether microinvasion is a prognostic factorindependent of peritoneal implants or micropapillarypatterns.

Histological features of mucinous borderlineovarian tumoursMucinous borderline ovarian tumours are a complex groupof lesions, the classifications for which have been revisedseveral times. Historically, they were mixed with peritonealpseudomyxoma, but this entity is now known to resultfrom intraperitoneal spread of non-ovarian adenomatousmucinous neoplasm, most typically from the appendix,

and should therefore be excluded from mucinousborderline ovarian tumours.1,27,54

Mucinous borderline ovarian tumours are divided intotwo subtypes, intestinal (comprising 8590%) andmullerian (or endocervical) lesions. The intestinal subtypeis more frequently unilateral, whereas bilateral intestinalmucinous borderline ovarian tumours should excludeprimary gastrointestinal carcinoma.1Immunostaining forcytokeratins CK7, CK20, and CDX2, and oestrogen andprogesterone receptor status, are both useful fordistinguishing primary ovarian tumours from metastaticdisease.Moreover, intestinal mucinous borderline ovariantumour is associated with extraovarian spread in only 2%of patients. The endocervical or mullerian subtype isbilateral in as many as 40% of cases. It coexists withipsilateral ovarian or pelvic endometriosis in 2030% ofpatients, including a serous component (also calledseromucinous borderline ovarian tumour), which could be

associated with invasive or non-invasive peritonealimplants such as serous borderline ovarian tumours.1,55Mucinous borderline ovarian tumours are thought torepresent an intermediate stage in the progression toinvasive carcinoma.56 This orderly progression accountsfor why benign lesions, borderline ovarian tumours, andinvasive tumour coexist in the same specimen.56 From abiological viewpoint, mucinous borderline ovariantumours express a KRASmutation in more than 60% ofcases. The increasing frequency of KRAS mutation hasbeen described in adenoma, borderline ovarian tumours,and carcinoma in 3386% of cases.57,58 In addition toabsence of stromal invasion, mucinous borderline ovariantumours that show either striking overgrowth of atypicalepithelial cells, more than three layers of cell stratification,

Patients

(n)

Non-invasive

implants (n)

Invasive

implants (n)

Indeterminate

implants (n)

Duration of follow-up Recurrences in the form of

carcinoma (n)

Deaths related to disease (n)

Bell (1988)2 56 50 6 .. Mean 66 years, median 6 years Not reported 3 (non-invasive implants);

5 (invasive implants)

Seidman

(1996)1765 52 (with

1 micropapillary

patterns)

13 (with

10 micropapillary

patterns)

.. For micropapillary patterns, median

76 months; for non-invasive

implants, median 99 months

2 (non-invasive implants);

7 or 8* (invasive implants)


6 (invasive implants, 4 of which

were micropapillary patterns)

Zanetta (2001)31 53 28 16 9 Median 70 months 3 0

Gershenson

(1998)32,33112 73 39 .. Median 103 years (non-invasive

implants); median 93 years

(invasive implants)





Longacre

(2005)34113 85 14 14 >5 years 3 (non-invasive implants);

4 (invasive implants);

3 (indeterminate implants)


5 (invasive implants);

3 (indeterminate implants)

Kane (2009)15 168 21 9 Mean 57 months 10 in non-invasive implants

4 in invasive implants



Shih (2011)35

80 60 19 1 Median 48 years 11 (implant subtypes unknown) 4 (implant subtypes unknown)Total 458 348 87 23 .. 23 (83%) [non-invasive];

24 or 25 (29%) [invasive]

14 (36%; non-invasive);

23 (25%; invasive)

In case of repeat publications by the same team on a similar topic, the series with the largest number of patients was reported. *One patient with vaginal recurrence died of the disease but the histological

subtype of recurrence was unknown. Series including serous and mucinous borderline tumours. Recurrences from serous disease. Including recurrences after conservative treatment. Includes data from

series reporting initial implant subtypes in patients who relapsed or died.15,17,3234

Table :Series including 50 or more patients with stage II and III serous borderline ovarian tumours


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cribriform intraglandular proliferations, or finger-like

projections of solid cellular masses devoid of connectivetissue are judged intraepithelial carcinoma. However,definition of intraepithelial carcinoma differs betweenstudies. For some investigators, tumours with any of thesefeatures alone or in combination are defined asintraepithelial carcinoma.55A few pathologists also regardcomplex intraglandular growth patternssuch ascribriform areas or stroma-free papillae, even withoutsevere atypiato correspond with a diagnosis ofintraepithelial carcinoma.54,59 One of the major issues inmucinous borderline ovarian tumours, particularly inthose showing intraepithelial carcinoma, is that numeroussampling and more tissue sections should be obtained torule out invasive carcinoma.56

Intestinal mucinous borderline ovarian tumour istypically discovered at FIGO stage I, therefore, prognosis isusually excellent. However, findings have suggested thatmucinous borderline ovarian tumours (excludingperitoneal pseudomyxoma) could be associated with a lateand lethal invasive recurrence inside or outside theabdomen.52,53In a study of mucinous lesions by Koskas andcolleagues,52 rate of invasive recurrence 10 years aftertreatment was 13%. Similarly, Khunamornpong andco-workers53reported a 42% recurrence rate (three of six

patients died of recurrence).Four of the six patients with

recurrence had microinvasion.

53

Of the six patients whorecurred, four had invasive recurrence and one had nohistological features of recurrence (but had peritoneal andliver metastases); the remaining woman had borderlinemucinous disease with intraepithelial and microinvasivecarcinoma at the time of histological analysis of the firstrecurrence, but she died from progression 14 months afterinitial surgery.53These data could be accounted for by thecontinuum of (benign to frankly invasive) lesions in thesame specimen and the frequently associated presence ofintraepithelial carcinoma, which makes differentiationfrom an invasive component diffi cult. Moreover,researchers have reported that the prognosis of mucinousinvasive carcinoma is worse than that of other epithelial

cancers, with diminished chemosensitivity to platinum-based and paclitaxel-based regimens and overall poorprognosis, particularly in stage II or III disease.60,61

Intraepithelial carcinomaDefinition of intraepithelial carcinoma for mucinousborderline ovarian tumours is controversial.54Presence ofsevere cytological atypia was the only diagnostic criterionon which a consensus was reached for diagnosis ofintraepithelial carcinoma. Seidman and Kurman36reported

Total

SBOT

(n)

SBOT with micropapillary patterns Mean follow-up

(months)

Total

(n)

Implants

(n)

Non-invasive

implants (n)

Invasive

implants (n)

Recurrences

(n)

% invasive

recurrence (n)

Deaths related to disease

(n [implant subtypes])

Burks (1996)16 17 10 10 4 6 4 50% (2) 2 (invasive) 732

Seidman (1996)17 65 11 11 1 10 7 71% (5) 4 (invasive) 95

Eichhorn(1999)S1 84 40 11 8 3 4 .. 2 (invasive) ..

Goldstein (2000)41 7 7 3 3 0 2 100% (2) 2 (invasive) 996

Deavers (2002)19 99* 18 18 15 3 14 79% (11) 5 (2 invasive, 3 non-invasive) 125

Prat (2002)39 137 18 13 12 1 2 .. 0 84

Slomovitz (2002)40 57 14 0 0 0 3 33% (1) 0 433

Ayhan(2005)S2 54 11 .. .. .. .. 0 0

Longacre (2005)34 276 23 10 4 5 .. .. (3) 5 (3 invasive, 1 non-invasive

implants, 1 stage I)

76

Cusid (2007)S3 208 29 .. .. .. .. .. .. 883

Silva (2006)37 80 11 .. .. .. 9 .. .. 1884 (median)

Hogg (2007)42 46 13 .. .. .. 2 100% (2) 1 (non-invasive) 678

Chang (2008)S4 85 18 .. .. .. .. .. .. 41

Laurent(2008)43 15 15 9 8 1 11 9% (1) 1 (non-invasive) 63 (median)

Ren (2008)S5 101 20 .. .. .. .. .. 0 40

De Iaco (2009)S6 102 7 .. .. .. .. 0 0 605

Uzan (2011)44 168* 56 56 46 9 13 46% (6) 1 (non-invasive) 57 (median)

Kane (2010)S7 18 8 .. .. .. .. .. 1 (non-invasive) 38 (median)

Shih (2011)3 196 36 .. .. .. .. .. .. 444 (median)

Total 144 56 (39%) 21% (30) 14 (10%)

Supplementary references (S) are listed in the appendix. SBOT=serous borderline ovarian tumour. *With implants. Only series providing correlations with overall rate of

recurrence, rate of invasive recurrence, and disease-related death associated with micropapillary pattern were included in this calculation.S5,16,17,19,4044

Table :Prognostic effect of micropapillary patterns in SBOT

See Online for appendix


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290 cases of stage I intraepithelial carcinomas with18 disease-related deaths. Of 13 patients with advanced-stage disease, nine deaths were disease-related. Sincepublication of that report, findings of five series (n=559)with mucinous borderline ovarian tumours and clearhistological criteria for diagnosis of intraepithelialcarcinoma showed presence of intraepithelial carcinomain 35% of cases (n=197).47,48,52,53,59 Of these patients,431 (including 153 showing intraepithelial carcinoma) werefollowed up.47,48,52,53,59 Nine (6%) of the 153 women hadrecurrence, with three cases of invasive disease at

recurrence. All patients with invasive recurrence died ofthe disease. In 278 patients without intraepithelialcarcinoma, 11 (4%) recurred. In the series by Seidman andKurman,36 the overall rate of death associated withintraepithelial carcinoma was estimated at 6%. This fairlyhigh rate of death, and the well-known continuum ofbenign, borderline, and invasive components in the samespecimen, should encourage pathologists to increase thenumber of tissue sections examined to rule out anyassociation with invasive carcinoma.

Stromal microinvasionTable 3 presents data for mucinous borderline ovariantumours with stromal micronvasion. In eight series(n=116), no patients developed invasive recurrence and

none died in relation to disease.4549,5153Microinvasion doesnot seem to be a prognostic factor for mucinous borderlineovarian tumours.

Preoperative assessment of patients withhigh-risk borderline ovarian tumoursFrom an epidemiological point of view, borderline ovariantumours and carcinoma share very close characteristics.Thus, distinguishing a high-risk group of women withborderline ovarian tumours is diffi cult. Clinical exam-ination could be helpful for detection of a high-risk group,

by looking for clinical ascites, suspicious nodes (in thegroin, axillary, or cervical nodes), or peritoneal lesions inDouglas pouch, but such findings could also be discoveredin authentic carcinoma.

The relevance of serum tumour markers in patients withborderline ovarian tumours is controversial. Van Calsterand colleagues62showed that amounts of CA125 in serumoverlapped between patients with borderline ovariantumours and early-stage ovarian carcinoma. Abnormalconcentrations in serum of CA125 were noted in about40% of patients with stage I borderline ovarian tumoursand reached 83% in women with advanced-stage disease.63With the exception of advanced-stage borderline ovariantumours, no data are available to support the relevance ofserum tumour markers (eg, CA125, CA199, carcino-

Histological

type

Borderline ovarian tumour with microinvasion Mean follow-up

(months)

Number Recurrences (n) % invasive recurrence (n)* Deaths related to disease (n)*

Katzenstein (1978) S8 SBOT 7 0 0 0 131

Bell (1990)S9 21 SBOT 21 1 0 0 624

Casey (1993)S10 SBOT 2 0 0 0 175

Hanselaar (1993) S11 SBOT 9 0 0 0 54

Tan (1994)S12 SBOT 2 1 0 0 264

Siriaunkgul (1995)45 54 MBOT 7 0 0 0

Kennedy (1996)S13 76 SBOT 4 0 0 0 99

Nayar (1996)S14 126 SBOT 7 0 0 0 96

Seidman (1996)17 65 SBOT 4 0 0 0 95

Hoerl (1998)46 49 MBOT 14 0 0 0 71

Eichhorn (1999)S1 84 SBOT 9 1 0 0 744

Riopel (1999)47 73 MBOT 8 0 0 0 33

Lee (2000)48 171 MBOT 7 0 0 0

Nomura (2000)49 25 MBOT 4 0 0 0 85

McKenney (2006)50 SBOT 50 9 67% (6) 7 924

Kim (2007)51 118 MBOT 37 0 0 0 604

Laurent (2009)S15 10 SBOT 10 5 0 0 62

Kane (2009)15 18 SBOT 8 3 33%|| 1|| 38 (median)

Koskas (2011)52 97 MBOT 8 0 0 0 48

Khunamornpong (2011)53 171 MBOT 31 4 0 0 168

Total .. 249 24 (10%) 3% (7) 8 (3%)

Supplementary references (S) are listed in the appendix. SBOT=serous borderline ovarian tumour. MBOT=mucinous borderline ovarian tumour. *Implant subtypes during

initial management. With lymph-node involvement.2 indeterminate, 1 invasive, 1 invasive and micropapillary pattern, 2 microinvasion only .2 indeterminate, 1 invasive,

1 invasive and micropapillary pattern, 1 micropapillary pattern, 2 microinvasion only. With implants. ||1 micropapillary pattern and non-invasive.

Table :Prognostic effect of stromal microinvasion on SBOT and MBOT


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embryonic antigen) for identification of a high-risk group

of borderline ovarian tumours.Pelvic ultrasound is a key procedure for detection andassessment of ovarian tumours. Some scales or scoringsystems have been defined to assess objectively the degreeof suspicion for malignant disease in these lesions.However, those scales are used to gauge so-called risk ofmalignancy before a potential surgical procedure but, atpresent, no ultrasound criterion can identify a high-riskgroup of borderline ovarian tumours.

Findings of radiological studies underline the contri-bution of perfusion-weighted and diffusion-weighted MRIsequences for differentiation of benign lesions, borderlineovarian tumours, and ovarian cancer.64 In a series of12 benign, 13 borderline, and 16 invasive ovarian tumours,64

early tumour enhancement on dynamic contrast-enhancedMRI images was helpful to distinguish between thesetypes of tumours. MRI findings correlated with angiogenicstatus of the tumour, which was ascertained afterhistopathological analysis of VEGF receptor expression inparaffi n-embedded specimens.64 Correlation of suchradiohistological findings could perhaps be of futureinterest to help identify a high-risk group of borderlineovarian tumours. Yet, since pathological analysis of thetumour specimen (ovary and peritoneum) is key foridentification of potentially invasive lesions, establishing ahigh-risk group before surgery seems uncertain.

Clinical management and effect on rate ofinvasive recurrence and survivalSurgeryStandard surgical treatment for borderline ovariantumours is based on bilateral salpingo-oophorectomy, withor without hysterectomy. Staging surgery is also used,which includes peritoneal staging procedures with orwithout nodal staging methods.

Conservative treatment and risk of invasive recurrenceConservative treatment (defined as preservation of theuterus and at least a part of one ovary) is important foryoung patients with borderline ovarian tumours. Thisoption is appropriate even for serous lesions with non-

invasive implants.31,65 Nearly 2000 cases of conservativetreatment have been reported in published work. Fertility-sparing surgery is associated with a higher rate of recurrencethan is bilateral salpingo-oophorectomy, but it has no effecton survival because most recurrences are borderline lesionsthat are cured readily by a second surgical procedure(possibly conservative).15,31,65Nevertheless, the main issue isto assess risk of invasive recurrence.

We analysed 47 cases of progression to invasivecarcinoma, including 21 published since 2009, underliningthe possibility of publication bias (table 4). Risk ofprogression to invasive carcinoma was estimated as 23%.Of 47 recurrences, 20 were recorded in patients with serousborderline ovarian tumours, 24 had mucinous borderlineovarian tumours, and three were of an unknown

histological subtype. Mean time to progression to

carcinoma was 75 months (range 11310) for serousborderline ovarian tumours and 33 months (582) formucinous borderline ovarian tumours. Eight of the20 recurrences of serous borderline ovarian tumours wererecorded in patients with peritoneal implants. 18 womenhad follow-up data available; six died of the disease andeight were alive without evidence of disease (table 4). Ofthe 24 recurrences of mucinous borderline ovariantumours, 23 initially had FIGO stage I disease. Of 21 withfollow-up data, 13 died of disease and only three were alivewithout disease (table 4).

In patients with serous borderline ovarian tumourstreated by cystectomy, five of 11 were alive without diseasecompared with one of nine who had mucinous borderline

ovarian tumours (table 4). Women with recurrence ofinvasive mucinous lesions had a higher rate ofextra-abdominal metastasis as the first site of recurrence(four in pleura, lung, or bone) whereas no extra-abdominalmetastases arose in patients with recurrence of invasiveserous borderline ovarian tumours.

These differing data do not question the validity ofconservative treatment. Such recurrences also arise inpatients treated by bilateral salpingo-oophorectomy forborderline ovarian tumours. Nevertheless, they suggestthat the rate of death is higher in women with recurrentmucinous borderline ovarian tumours than in those withserous lesions with transformation to invasive carcinoma,which then takes place earlier. Furthermore, a recomm-endation of initial unilateral salpingo-oophorectomy formucinous borderline ovarian tumours rather thancystectomy seems logical, whereas in the case of serouslesions, no clear recommendations can be made.52,66

Role of laparoscopyThe role of laparoscopy is relevant because of potentialrisks of ruptured cysts, intraperitoneal cell dissemination,tumour metastasis in trocar incisions, and recurrence.Findings of previous studies have shown the rate of cystrupture is higher for laparoscopy than for laparotomy, andlaparoscopy has a potentially higher risk of recurrence.67However, risk of cyst rupture was associated most with a

high rate of conservative surgery (cystectomy).63Similarly,rate of recurrence after laparoscopy was related toconservative treatment, but no association was reportedbetween laparoscopic treatment and risk of invasiverecurrence.

Only eight cases of trocar implantation metastasis havebeen reported after laparoscopy for borderline ovariantumours;68 five arose in patients with peritoneal implantsbut none died of the disease. This finding underlines theneed to recall use of systematic protected extraction foradnexal tumours.68

Peritoneal staging for identification of high-risk patientsAdequate staging, including careful inspection of theperitoneum, is crucial for identification of high-risk


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patients who are likely to develop invasive recurrence and

die of disease. Findings of studies indicate a low rate (38%)of complete staging (at least peritoneal cytological analysis,omentectomy, and peritoneal biopsy) during initial surgery,even when the borderline nature of the lesion could be

assessed by intraoperative histological analysis.69,70 Fauvet

and colleagues

70

reported a 46% rate of complete stagingby laparoscopy during initial surgery, 214% afterconversion to open surgery, and 254% by laparotomy. Linand co-workers69recorded a 12% rate of complete staging

Borderline tumours (n) Details of initial treatment Location* Details of recurrence(s) Outcomes

Initial

stage

Surgical treatment Histological subtypes Interval

(months)

Histology

Serous tumours

Chambers (1988)S16 11 SBOT IA Cystectomy SBOT Ipsilateral ovary 12 Serous adenocarcinoma

grade 1

..

Morris (2000)S17 26 SBOT Unknown USO and cystectomy SBOT Ipsilateral ovary 147 Not reported DOD

Morris (2000)S17 11 SBOT IA USO and staging SBOT Contralateral ovary 39 Serous adenocarcinoma

grade 2

DOD

Zanetta (2001)31 156 stage I SBOT IA Cystectomy SBOT Ovaries, peritoneum,

nodes

39 Serous adenocarcinoma

grade 3

NED

Zanetta (2001)31 156 stage I SBOT IC USO and CC SBOT Ovary .. Serous adenocarcinoma

grade 1

..

Donnez (2003)S18 37 SBOT stage IIII I (probably) USO and CC SBOT At least ovary 12 Invasive (probably) NED

Longacre (2005)34 53 SBOT stage I IA .. SBOT Colon and gallbladder 288 Low-grade serous

adenocarcinoma

AWD

Longacre (2005)34 53 SBOT stage I IA .. SBOT, SMI Axillary nodes 310 Low- grade serous

adenocarcinoma

NED

Romagnolo (2006)S19 75 SBOT stage IIII IA USO SBOT Contralateral ovary 36 - DOD

Yokoyama (2006)5 23 SBOT IA Cystectomy SBOT Contralateral ovary 107 Serous adenocarcinoma NED

Suh-Burgmann

(2006)S20109 SBOT stage IIII IC USO SBOT Peritoneum 27 Serous adenocarcinoma

grade 1

NED

Ji (2010)S21 Case report IC USO and staging SBOT, SMI Ovary and peritoneum 17 Invasive implants DOD

Zanetta (2001)31

51 SBOT stage IIIII IIB Cystectomy SBOT Contralateral ovaryand nodes

50 Invasive carcinoma grade 1 NED

Prat (2002)39 40 SBOT stage IIII II USO SBOT, invasive implants .. .. .. DOD

Attar (2004)S22 Case report IIIC USO, CC, and staging SBOT, MPP, positive

nodes

Peritoneum 18 Serous adenocarcinoma AWD

Wong (2007)S23 65 SBOT stage IIII IIC Cystectomy SBOT Ipsilateral ovary .. Invasive implants NED

Vigan (2010)S24 10 SBOT IIIII .. SBOT .. .. Invasive implants NED

Uzan (2010)65 41 SBOT stage IIIII II Cystectomy and

staging

SBOT, MPP, non-invasive

implants

Ovary and peritoneum 42 Invasive ..

Uzan (2010)65 41 SBOT stage IIIII III Cystectomy and

staging

SBOT, MPP, non-invasive

implants

Ovary and peritoneum 56 Invasive DOD

Uzan (2010)65 41 SBOT stage IIIII III USO SBOT, SMI, invasive

implants

Peritoneum 11 Invasive ..

Mucinous tumours

Ji (1996)S25 45 MBOT stage I IC Cystectomy MBOT .. .. Not reported DOD

Gotlieb (1998)S26 23 MBOT stage I IA USO MBOT Contralateral ovary 5 Endometrioid

adenocarcinoma

NED

Zanetta (2001)31 117 MBOT stage I IC Cystectomy MBOT Pelvis and abdomen 10 Mucinous adenocarcinoma

grade 3

DOD

Zanetta (2001)31 117 MBOT stage I IA Cystectomy MBOT Ipsilateral ovary 55 Mucinous adenocarcinoma

grade 1

NED

Lee (2000)48 136 MBOT stage IIII

intestinal

IC USO and staging MBOT, IEC, grade 3

nuclei

Peritoneum 12 Mucinous adenocarcinoma

grade 2

DOD

Suh-Burgmann

(2006)S2081 MBOT stage IIII IC USO MBOT Peritoneum Mucinous adenocarcinoma

grade 3

DOD

Wong (2007)S23 169 MBOT stage IIII IA USO MBOT Contralateral ovary

and peritoneum

Invasive carcinoma DOD

Wu (2009)S27 157 MBOT stage IIII IC Cystectomy MBOT Colon serosa and

trocar site

82 Invasive carcinoma DOD

(Continues on next page)


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Review

by laparotomy, 7% for general surgeons, and 50% for

oncological surgeons. Study data suggest that incompletestaging has no effect on survival and rate of recurrence.69,71

However, Seidman and Kurman36noted a recurrence rateof 17% in patients with complete staging versus 99% inthose with incomplete staging. Similarly, Camatte andcolleagues71reported no recurrence after complete stagingcompared with a rate of 8% after incomplete staging.

Despite these data, surgery to restage a patient iscontroversial because it has little effect on managementfor those with borderline ovarian tumours. In fact, the onlyway to modify management of women with apparentstage I borderline ovarian tumours is if invasive implantsare found at microscopic examination and the patient isupstaged (in such cases, adjuvant treatment could bediscussed). If non-invasive implants are identified in a

woman with a macroscopically normal peritoneal cavity,

further treatment (surgery or adjuvant treatment) is notnecessary. Nevertheless, only a few cases (n=2) ofmicroscopic invasive implants (with an apparently normalperitoneum at surgical staging) have been noted duringmicroscopic examination only.72,73Thus, systematic surgicalstaging for identification of patients in whom adjuvanttreatment should be delivered (microscopic invasiveimplants) is limited. However, features that argue in favourof restaging surgery include mucinous borderline ovariantumours treated by cystectomy, micropapillary pattern,microinvasion, incomplete excision of peritoneal implants,and the indeterminate nature of peritoneal implants,attributable to absence of adjacent and underlying tissue.

Conventional complete surgical staging for mucinousborderline ovarian tumours includes appendectomy to

Borderline tumours (n) Details of initial treatment Location* Details of recurrence(s) Outcomes

Initial stage Surgical treatment Histological subtypes Interval

(months)

Histology

(Continued from previous page)

Wu (2009)S27 157 MBOT stage IIII IIB USO and staging MBOT Peritoneum and nodes 11 Invasive carcinoma

Park (2009)S28 139 MBOT stage IIII IA USO and cystectomy MBOT Lung 82 Mucinous invasive

carcinoma

DOD

Chiesa (2010)S29 Case reported in the

Discussion

IC USO and staging MBOT intestinal Peritoneum 70 Adenocarcinoma grade 1

Koskas (2011)52 74 MBOT stage I IA Cystectomy MBOT intestinal Contralateral ovary,

peritoneum, bones

57 Invasive carcinoma AWD

Koskas (2011)52 74 MBOT stage I IA Cystectomy MBOT intestinal Ipsilateral ovary 27 Invasive carcinoma AWD

Koskas (2011)52 74 MBOT stage I IC USO and staging MBOT intestinal Peritoneum and nodes 10 Invasive carcinoma DOD

Koskas (2011)52 74 MBOT stage I IA Cystectomy MBOT mixed At least ovary 7 Invasive carcinoma AWD

Koskas (2011)52 74 MBOT stage I IA Cystectomy MBOT endocervical Peritoneum Invasive carcinoma DOD

Koskas (2011)52 74 MBOT stage I IA USO and staging MBOT intestinal, IEC Pleura Invasive carcinoma DOD

Khunamornpong

(2011)5360 MBOT stage I

intestinal

I .. MBOT intestinal, IEC,

SMI

Contralateral ovary 17 Invasive disease in nodes NED

Khunamornpong


intestinal

IC .. MBOT intestinal, IEC,

SMI

Contralateral ovary

and nodes


Khunamornpong


intestinal

IC .. MBOT intestinal Contralateral ovary

and peritoneum


Khunamornpong


intestinal

IC .. MBOT intestinal .. .. Invasive carcinoma ..

Ha (2011)S30 7 conservative

treatment

.. USO and staging MBOT endocervical and

IEC

.. 25 Carcinoma DOD

Ha (2011)S30 7 conservative

treatment

.. USO MBOT, IEC Contralateral ovary,

bone, lung

23 Not reported, but

progression with

metastasis

AWD

Song (2011)S31 106 MBOT IA .. .. Contralateral ovary 26 Invasive carcinoma AWD

Unknown subtype

Fort (1989)S32 8 stage III I or II USO Not reported Contralateral ovary 60 Serous adenocarcinoma NED

Kehoe (1996)S33 54 stage III I (probably) USO Not reported Contralateral ovary 12 Invasive carcinoma DOD

Maneo (2004)S34 61 stage I by

laparoscopy

IA Laparoscopy Not reported Ipsilateral ovary and

omentum

44 Invasive carcinoma grade 2 ..

In case of repeat publications by the same team on a similar topic, the series with the last updated outcomes or largest number of patients was reported. Supplementary references (S) are listed in the appendix.

AWD=alive with disease. CC=contralateral cystecomy. DOD=died of disease. IEC=intraepithelilal carcinoma. MBOT=mucinous borderline ovarian tumour. MPP=micropapillary pattern. NED=no evidence of

disease. SBOT=serous borderline ovarian tumour. SMI=stromal microinvasion. USO=unilateral salpingo-oophorectomy. *Of first invasive recurrence. Details on the invasive recurrence (some patients had a

previous history of borderline recurrence before invasive recurrence). Number treated conservatively and radically.

Table :Cases of progression to invasive carcinoma after c onservative treatment of borderline ovarian tumours


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Review

exclude synchronous or primitive appendiceal tumour(mucocele). However, in a study focusing on the histologicalinterest of appendectomy, no disease was reported in theappendix in 57 patients with early-stage ovarian tumourswho underwent surgical staging for mucinous tumours(15 were borderline).74

Effect of lymphadenectomy and lymph-nodeinvolvement on survivalLymph-node involvement is recorded in about 25% ofpatients with advanced-stage borderline ovarian tumours(FIGO stage III or IV).75 Lymph-node involvement issometimes associated with lymph-node endosalpingiosis.

Molecular and histological data suggest that most nodalimplants are metastases from synchronous ovarianneoplasms, but a few arise from de novo nodal

endosalpingiosis.76 Pathways by which nodal metastasesproceed in non-invasive neoplasms are unclear. Fadare andcolleagues77 showed no difference in lymphatic vesseldensity between node-positive and node-negative tumours,suggesting that these lesions might have a predilection forperitoneal rather than lymphatic spread.

Several researchers have reported no effect of lymph-node involvement on survival of patients with borderlineovarian tumours.34,36,77,78 In a series of 123 patients,including 68 with complete surgical staging, Kanat-Pektasand colleagues78recorded no difference between disease-free and overall survival. Data from our institution andfrom the SEER database accord with these findings andshow that survival correlates with FIGO stage irrespectiveof nodal status.75The rate of invasive implants seems to

be higher in patients with lymph-node involvement than

in those without nodal spread.

50,79

Djordjevic and Malpica

79

reported rates of invasive implants of 25% (nine of 36) inpatients with lymph-node involvement versus 3% (one of36) in those without involvement. Lymph-node dissectioncould be discussed for treatment of peritoneal implantsassociated with gross nodal disease during surgicalexploration and in women with invasive implants.

Residual diseaseResidual disease is a prognostic factor for borderlineovarian tumours.29,32,34,35 In addition to the potentialtherapeutic effect, complete removal of peritoneal implantsallows for comprehensive histological analysis. In a seriesof 168 patients with serous borderline ovarian tumours

(FIGO stage II and III), 5-year disease-free survival was75% in patients with no residual disease, 76% in those withresidual disease less than or equal to 2 cm, and 56% inthose with residual disease greater than 2 cm (p


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Review

Moreover, Lesieur and co-workers75recorded no effect of

adjuvant chemotherapy on disease-free survival in patientswith lymph-node involvement.Concern persists for patients with invasive implants.

Most teams currently propose chemotherapy as treatment,although the proven effectiveness of this option continuesto be debated. If undertaken, the chemotherapy regimen issimilar to that used in ovarian cancer (a platinum-basedregimen with paclitaxel).

Different pathways (particularly the MAPK signallingpathway) have been identified in the carcinogenesis ofserous borderline ovarian tumours with micropapillarypatterns and low-grade carcinoma, suggesting that targetedtreatments could be used in these diseases.18,21,84May andcolleagues18suggested that inhibition of PARP1 could be a

target. A trial has started to test a MEK inhibitor in recurrentlow-grade serous carcinoma with the poorest response toconventional chemotherapy compared with high-gradecarcinoma (ClinicalTrials.gov identifier NCT00551070).

Follow-up to detect invasive recurrencesSeveral researchers have described outcomes of patientswith borderline ovarian tumours, including advanced-stage disease, but very few have focused on usefulmethods for detection of recurrences.67,85,86 Transvaginalultrasonography is the most effective procedure forconservative management of early-stage disease. In aseries of five patients with invasive recurrence afterconservative treatment for early-stage borderline ovariantumours,85all had abnormal findings on ultrasound andabnormal amounts of CA125. Uzan and colleagues86confirmed the importance of imaging (abdominopelvicultrasonography) for detection of recurrence (422%) inwomen with stage II or III serous borderline ovariantumours who were treated conservatively. A raised levelof CA125 in serum formed part of the initial diagnosis inonly 156% of all recurrences, but this marker was themost frequent method for diagnosis of recurrent invasivelesions (six of 13 patients relapsed with carcinoma).86Thus, a combination of follow-up proceduresie, bothimaging and determination of CA125 in serumseemsto be an adequate option, particularly in patients

with invasive implants. For conservative treatment,abdominopelvic ultrasound is needed. AbdominopelvicCT or MRI could be proposed for women treated forstage II or III disease with abnormal or inconclusivefindings on ultrasound (due to complex previoussurgeries or obesity). Nevertheless, very few series havebeen published on this specific topic, and the combinationof blood markers and imaging has not had an effect onoverall survival in this context. Potential prognosticfactors for invasive recurrence in borderline ovariantumours are presented in the panel.

ConclusionsThe pathologist has a pivotal role in assessment of theborderline nature of ovarian tumours and in identifica-

tion of high-risk criteria for invasive recurrences andpossible death from disease. We have identified twofactors that are important for recurrence of invasivedisease. First is invasive peritoneal implants (in serousborderline ovarian tumours), and second is residualdisease after surgery. Other factors are controversialowing to increased risk of invasive recurrence, forexample, presence of micropapillary patterns in serousborderline ovarian tumours, presence of intraepithelialcarcinoma in mucinous lesions, presence of stromalmicroinvasion in serous tumours, and use of cystectomyin mucinous borderline ovarian tumours.

Variability in rates of recurrence and survival betweenseries depends not only on pathological criteria used toclassify entities but also on how published materialwas gathered. Population-based studies from academicinstitutions, data obtained over several decades, cohortstudies, or collection of specimens by one pathologist allrepresent potential biases.20 Publication bias cannot beignored because it can lead to overestimation of risk forpoor prognosis. To avoid such biases, all studies shouldverify the quality of tissue collection and sampling forhistological analysis to enable centralised uniformpathological review (particularly important in multicentreseries) with suffi cient patients and prolonged follow-up,which will allow relevant conclusions to be drawn for

routine practice.21At present, the only pragmatic way to better identify

patients at high risk of invasive recurrence is pathologicalreview of tumour slides by a skilled pathologist (or a panelof pathologists) for patients in at-risk situationseg, thosewith borderline ovarian tumours with implants (to clearlydistinguish invasive from non-invasive implants), withmicropapillary patterns (associated with a higher rate ofimplants), with intraepithelial carcinoma, stromalmicroinvasion, or both (could ultimately be diagnosed asinvasive carcinoma), and mucinous borderline ovariantumours (pathological classification of this tumour isarduous). In some countries, centralised pathologicalreviews (or registries) are being organised to decrease therare but potentially lethal risk of invasive recurrences.

Search strategy and selection criteria

Data for this Review were identified from searches of Medline, Current Contents, PubMed,

and references in relevant articles, with the terms borderline ovarian tumours, low-

malignant potential ovarian tumours, recurrence, implants, micropapillary, stromal

microinvasion, intraepithelial carcinoma, mucinous ovarian tumours, and serous

ovarian tumours. We did not include abstracts and reports from meetings. We searched

for articles published in English or French (with abstracts in English) between 1985 and

May, 2011. Because many studies have been published on borderline ovarian tumours, the

papers we selected were based on the description of invasive recurrences (with respect to

different factors analysed for clinical management) and on their relevance for our

discussion of histopathology and pathological prognostic factors. Thus, we included series

reporting particular histopathological patterns for the first time or series reporting the

largest number of patients or the most complete results (in terms of variables studied).


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Contributors

PM and ED had the idea for the Review. All authors contributed to theliterature search, analysis of data, and writing of the Review.

Conflicts of interest

We declare that we have no conflicts of interest.

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