Review

Borderline ovarian tumour: pathological diagnostic dilemma and risk factors for invasive or lethal recurrence
Philippe Morice, Catherine Uzan, Raaele Fauvet, Sebastien Gouy, Pierre Duvillard, Emile Darai

By comparison with ovarian carcinomas, borderline ovarian tumours are characterised clinically by superior overall survival, even in women with peritoneal spread. In this Review, we aimed to clarify the histological and clinical factors potentially dening 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 identied. Other factors are controversial owing to increased risk of invasive recurrence: micropapillary patterns in serous borderline ovarian tumour, intraepithelial carcinoma in mucinous lesions, stromal microinvasion in serous lesions, and use of cystectomy in mucinous borderline ovarian tumours. The pathologist has a pivotal role in assessment of the borderline nature of ovarian tumours and in identication of high-risk criteria, most of which are histological. But, reproducibility of the histological interpretation of some of these potential criteriaeg, classication of peritoneal implants (particularly in desmoplastic subtype), stromal microinvasion, micropapillary patterns, and intraepithelial carcinoma in mucinous borderline ovarian tumoursremains unclear, and should be investigated.

Lancet Oncol 2012; 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 and Gynaecology, CHU Amiens and 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 morice@igr.fr

Introduction
Borderline ovarian tumours dier from ovarian carcinoma by absence of stromal invasion. Classications for these lesions have been modied extensively over past decades. Borderline ovarian tumours were reported initially in 1929 as semi-malignant disease. In 1961 and 1971, the International Federation of Gynecology and Obstetrics (FIGO) proposed the term low malignant potential. In 1973, FIGO and WHO suggested creation of a group of tumours with morphological criteria (in particular, absence of stromal invasion), which dierentiated them from carcinoma. In this same year, WHO adopted the synonym borderline, which is still used in the current (2003) classication.1 WHO thereafter dened extra-ovarian peritoneal disease as implants (and not metastases) because of their indolent nature. In 1988, Bell and colleagues2 proposed classication of peritoneal implants (invasive vs non-invasive lesions) according to their morphological features. The most frequent borderline ovarian tumours are serous lesions, representing two-thirds to three-quarters of these tumours.3 However, in a Danish register-based cohort study, mucinous tumours represented 50% of borderline ovarian tumours and serous tumours comprised 44%.4 The ratio in Asia is dierent, with an equivalent or higher rate of mucinous borderline ovarian tumours.5 The true incidence of borderline ovarian tumours remains unknown. 1520% of serous tumours are judged borderline.6 Data from the SEER (surveillance epidemiology and end results) programme showed an incidence of 25 per 100 000 women-years in the USA.7 Compared with carcinoma, borderline ovarian tumour is characterised clinically by a younger age at diagnosis (10 years earlier) and better overall survival, even with peritoneal spread. 5-year and 10-year survival rates for stage I, II, and III disease are 99% and 97%, 98% and 90%, and 96% and 88%, respectively.8 Despite these favourable data, some patients relapse or succumb to disease.
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Borderline ovarian tumours can be unilateral or bilateral. Similar to carcinoma, they can spread to the peritoneum and, eventually, to lymph nodes. High-risk borderline ovarian tumour has not been dened by consensus, therefore, identication of risk factors for invasive recurrence or disease-related death is pivotal. In this Review we aimed to analyse prognostic factors for invasive recurrence and death from disease for serous and mucinous borderline ovarian tumours. We have not included rare entities such as endometrioid, Brenner, or clear-cell borderline ovarian tumours because of their very low incidence (<5% of borderline ovarian tumours). Furthermore, invasive recurrences are very exceptional among these three rare subtypes (fewer than three cases reported).914

Histological features of serous borderline ovarian tumours

Serous borderline ovarian tumours are generally classied simply as benign borderline lesions with or without extraovarian disease (non-invasive or invasive implants), and authentic carcinoma is dened typically as showing stromal invasion. Serous lesions are bilateral in 1540% of cases,1,6 and 1540% of serous borderline ovarian tumours are associated with extraovarian disease (peritoneal implants or nodal disease).6,15 In 1996, the idea of serous borderline ovarian tumours displaying micropapillary patterns was introduced. These lesions were characterised not only by specic morphological criteria but also by a greater frequency of bilateral tumours, surface involvement, and a higher rate of invasive peritoneal implants compared with serous lesions without micropapillary patterns (gure 1).16,17 Several researchers have since suggested that serous borderline ovarian tumours with micropapillary patterns have poor prognosis. This idea has contributed to these lesions being regarded as low-grade carcinoma.16,1821 Kurman and colleagues22 divided serous tumours into ve categories, consisting of adenoma or benign disease,
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serous borderline ovarian tumours devoid of micropapillary patterns (now designated atypical proliferative serous tumours), non-invasive micropapillary low-grade serous carcinoma, invasive low-grade serous carcinoma (invasive micropapillary serous carcinoma), and highgrade serous carcinoma. The overriding issue was to ascertain whether patients with serous borderline ovarian tumours with micropapillary patterns should be included in a high risk-group and their disease be deemed low-grade carcinoma. Molecular data seem to conrm this viewpoint.18,21 May and co-workers18 compared RNA from epithelial cells of serous borderline ovarian tumours, serous lesions with micropapillary patterns, and invasive low-grade serous carcinoma and noted that the gene-expression prole of serous lesions with micropapillary patterns was similar to that of invasive low-grade serous carcinoma but distinct from that of serous borderline ovarian tumours, with candidate genes implicated in the MAPK pathway. These data reinforce the notion that invasive low-grade serous carcinoma develops in a stepwise fashion from benign cystadenobroma to classic invasive low-grade serous carcinoma via transformations to serous borderline ovarian tumour (or, atypical proliferative serous tumours)22 and serous lesions with micropapillary pattern (gure 2).18 Findings suggest that epithelium from the fallopian tube could become implanted on the ovary, initiating high-grade serous tumours.28 In patients with low-grade serous disease, mutations in KRAS, BRAF, and occasionally HER2 and PIK3CA have been characterised. TP53 mutations are rare in this subgroup and are encountered more frequently in individuals with highgrade disease.28
A B

Peritoneal implants
The outlook for patients with serous borderline ovarian tumours and peritoneal disease is better than for women with ovarian carcinoma and peritoneal spread. Therefore, peritoneal disease from borderline ovarian tumours is referred to as implants and not metastases. Suggestions about pathogenesis of implants include implantation of cells detached from the ovarian surface (which accords with the high frequency of implants in case of exophytic vegetations) and formation of implants independently of ovarian tumours.25 Molecular data lend support to arguments for both theories but, to date, none of them predominates.25 Implants can be non-invasive (nearly 85% of implants) or invasive.29 Non-invasive implants are dened as a seroustype epithelial proliferation that aects peritoneal surfaces and shows no invasion.2,26 Non-invasive implants are desmoplastic or epithelial, and prognosis of these two subtypes is similar. However, recognition of potential invasion of underlying tissue is more complex in the desmoplastic than in the epithelial subtype.2,6 Invasive implants are dened as a serous-type epithelial proliferation aecting peritoneal surfaces and invading adjacent or underlying tissue.2,6 Morphologically, aspects of these invasive implants are similar to those of invasive lowgrade serous carcinoma, but we should remember that the diagnosis of borderline ovarian tumour is based on ovarian histological features. The pathologist must harvest sucient tissue to be able to discriminate non-invasive from invasive implants, by assessment of the junction between implants and adjacent normal tissue.27 However, Bell and colleagues29 report that 25% of implant biopsy specimens have no underlying tissue. Surgeons go to tremendous eort to remove implants as widely as possible to guarantee resection of surrounding tissue. Subsequently, Bell and colleagues29 suggested use of additional morphological criteria other than invasion of surrounding tissue to classify invasive and non-invasive implants (micropapillary architecture and solid epithelial nests surrounded by clefts). The skill of the pathologist is also important.26,27 Even for expert pathologists, some implants remain too ambiguous to be classied and are categorised as indeterminate for invasion.30 To optimise histological analysis and to minimise interobserver variability, serous borderline ovarian tumours with implants could benet from systematic review by a reference pathologist. To assess the eect of peritoneal implants and to limit risk of bias attributable to small series, we analysed reports including at least 50 patients with serous borderline ovarian tumours with peritoneal implants (table 1). Longacre and colleagues34 reported that the sole independent prognostic factor for overall survival was the implant subtype (eight of 14 patients with invasive implants relapsed). Seidman and Kurman36 noted that the mortality rate for patients with non-invasive and invasive implants was 47% and 34%, respectively (p<00001). Although
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Figure 1: Histopathological features of serous borderline ovarian tumours (A) Serous borderline ovarian tumour with micropapillary patterns. (B) Non-invasive peritoneal implant (desmoplastic subtype) from serous borderline ovarian tumour in the omentum. Tumour is well circumscribed with no invasion of fat lobules. (C) Invasive peritoneal implants from serous borderline ovarian tumour in the omentum. (D) Localisation from serous borderline ovarian tumour inside a node from splenic hilus. All slides are stained with haematoxylin and eosin. Magnication 100.

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Evolution of classications 1973: WHO classication23 1980s: implant characterisation2 1996: description of micropapillary pattern16,17 Proposed current classications 2005 to present: Kurman (2005)22 APST Borderline Non-invasive implants Non-invasive implants* Borderline Non-invasive implants* Borderline 2003 to present: AFIP (1996),24 WHO (2003),1 NCI/NIH workshop (2004)2527 Stage I borderline Non-invasive implants Micropapillary pattern Invasive implants Invasive implants* MPSC Invasive implants Micropapillary pattern Invasive implants* Carcinoma LGSC Carcinoma Carcinoma HGSC Carcinoma

Stage I borderline Stage I borderline

Carcinoma Carcinoma

Figure 2: Evolution of and discrepancies in current classications of serous borderline ovarian tumours Sizes 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.

prognosis for serous borderline ovarian tumours with invasive implants is poor, it is better than that for authentic carcinoma.23,25 Nevertheless, it is noteworthy that the number of cases of invasive implants and follow-up diered widely between series, which could constitute potential biases.27 Furthermore, proportions of patients with residual disease and with micropapillary patterns were not always mentioned. Gershenson and colleagues32,33 recorded very similar rates of progressive and recurrent disease (nearly 30%) in patients with non-invasive and invasive implants. These important data should be used to extend follow-up in advanced-stage borderline ovarian tumours. Silva and co-workers37 suggested that rates of recurrence and overall survival in women with serous borderline ovarian tumours and non-invasive implants are time dependent. Of 35 relapsing patients, eight developed recurrent disease within fewer than 5 years of follow-up, 15 recurrences arose between 5 and 10 years, eight between 10 and 15 years, and four after 15 years of follow-up. Patients with invasive implants relapsed more rapidly than did those with non-invasive implants. The true eect on rate of recurrence (and survival) of implant subtypes should be assessed in series with prolonged follow-up of more than 10 years.2,25,37

Micropapillary patterns
Findings of several studies indicate that serous borderline ovarian tumours with micropapillary patterns have poorer prognosis than do lesions without this histological feature.19,34,3840 Nevertheless, the true prognostic value of micropapillary patterns continues to fuel debate.20 Indeed, serous borderline ovarian tumours with micropapillary patterns without implants (stage I) or with non-invasive implants (stage IIIII) have the same prognosis as do serous borderline ovarian tumours without micropapillary patterns (or, atypical proliferative serous tumours).22 Some ndings indicate that architecture of micropapillary
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patterns does not exert a substantial eect on overall survival when peritoneal implants are controlled for.21,34 Decreased survival of patients with micropapillary patterns could perhaps be linked to the increased rate of invasive peritoneal implants and not to presence of micropapillary patterns itself.19,38 As a result, some researchers suggest that serous borderline ovarian tumours with micropapillary patterns without invasive implants should be classied as serous borderline ovarian tumours and not as invasive low-grade serous carcinoma.27,30 Figure 2 shows the evolution of (but also discrepancies in) these classications of serous borderline ovarian tumours, with morphological description of implants and micropapillary patterns. The main issue for patients with serous borderline ovarian tumours with micropapillary patterns is to ascertain whether the micropapillary pattern is a feature of a high-risk group likely to develop an invasive recurrence and have disease-related mortality. In a series with median follow-up of 4 years, Shih and colleagues3 noted that the micropapillary pattern was associated with low disease-free survival of 759% (95% CI 556878), compared with 943% (884973) for patients without a micropapillary pattern. However, patients with and without invasive implants were not distinguished from those with a micropapillary pattern. Diculties arose in this Review when we tried to ascertain whether some recurrences were linked to the micropapillary pattern or to invasive peritoneal implants (table 2). In eight series (n=144)16,17,19,4044 showing correlations between overall rate of recurrence, rate of invasive recurrence, and rate of disease-related death associated with micropapillary patterns, 56 patients had recurrence (39%). 54% (30 of 56) of recurrences were invasive at recurrence and 10% of deaths were related to disease. Moreover, in seven of eight series (n=107)16,17,19,40,41,44 with information on the nature of peritoneal implants, 29 patients initially had invasive implants (table 2). Of these 29 women, 11 had recurrence in the form of carcinoma or invasive recurrence.16,17,19 The behaviour of
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Patients Non-invasive (n) implants (n) Bell (1988)2 Seidman (1996)17 Zanetta (2001)31 Gershenson (1998)32,33 Longacre (2005)34 Kane (2009)15 Shih (2011)35 Total 56 65 50 52 (with 1 micropapillary patterns) 28 73

Invasive implants (n) 6 13 (with 10 micropapillary patterns) 16 39

Indeterminate Duration of follow-up implants (n) .. .. Mean 66 years, median 6 years For micropapillary patterns, median 76 months; for non-invasive implants, median 99 months Median 70 months Median 103 years (non-invasive implants); median 93 years (invasive implants) >5 years

Recurrences in the form of carcinoma (n) Not reported 2 (non-invasive implants); 7 or 8* (invasive implants) 3 14 (non-invasive implants); 9 (invasive implants) 3 (non-invasive implants); 4 (invasive implants); 3 (indeterminate implants) 10 in non-invasive implants 4 in invasive implants 11 (implant subtypes unknown) 23 (83%) [non-invasive]; 24 or 25 (29%) [invasive]

Deaths related to disease (n) 3 (non-invasive implants); 5 (invasive implants) 1 (non-invasive implants); 6 (invasive implants, 4 of which were micropapillary patterns) 0 6 (non-invasive implants); 6 (invasive implants) 2 (non-invasive implants); 5 (invasive implants); 3 (indeterminate implants) 2 (non-invasive implants); 3 (invasive implants) 4 (implant subtypes unknown) 14 (36%; non-invasive); 23 (25%; invasive)

53 112

9 ..

113

85

14

14

168 80 458

60 348

21 19 87

9 1 23

Mean 57 months Median 48 years ..

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

serous borderline ovarian tumours with micropapillary patterns seems to be more related to presence of invasive implants rather than to this particular histological feature.25

Stromal microinvasion
Stromal invasion is more frequently seen in serous than in mucinous borderline ovarian tumours. Analysis of the eect of microinvasion on the rate of invasive recurrences and disease-related death is especially dicult because of potential confounding factors, such as micropapillary patterns and presence of peritoneal implants for serous borderline ovarian tumours. In 12 series of serous borderline ovarian tumours with microinvasion (n=133), 20 patients had recurrence (15%), including 35% (seven of 20) with invasive disease at recurrence (table 3). Rate of disease-related death was 6% (eight of 133; table 3). In accordance with ndings of previous studies, our data indicate that microinvasion is a prognostic factor for serous borderline ovarian tumours.34,42 Further studies are needed to establish whether microinvasion is a prognostic factor independent of peritoneal implants or micropapillary patterns.

Histological features of mucinous borderline ovarian tumours

Mucinous borderline ovarian tumours are a complex group of lesions, the classications for which have been revised several times. Historically, they were mixed with peritoneal pseudomyxoma, but this entity is now known to result from intraperitoneal spread of non-ovarian adenomatous mucinous neoplasm, most typically from the appendix,
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and should therefore be excluded from mucinous borderline ovarian tumours.1,27,54 Mucinous borderline ovarian tumours are divided into two subtypes, intestinal (comprising 8590%) and mullerian (or endocervical) lesions. The intestinal subtype is more frequently unilateral, whereas bilateral intestinal mucinous borderline ovarian tumours should exclude primary gastrointestinal carcinoma.1 Immunostaining for cytokeratins CK7, CK20, and CDX2, and oestrogen and progesterone receptor status, are both useful for distinguishing primary ovarian tumours from metastatic disease. Moreover, intestinal mucinous borderline ovarian tumour is associated with extraovarian spread in only 2% of patients. The endocervical or mullerian subtype is bilateral in as many as 40% of cases. It coexists with ipsilateral ovarian or pelvic endometriosis in 2030% of patients, including a serous component (also called seromucinous borderline ovarian tumour), which could be associated with invasive or non-invasive peritoneal implants such as serous borderline ovarian tumours.1,55 Mucinous borderline ovarian tumours are thought to represent an intermediate stage in the progression to invasive carcinoma.56 This orderly progression accounts for why benign lesions, borderline ovarian tumours, and invasive tumour coexist in the same specimen.56 From a biological viewpoint, mucinous borderline ovarian tumours express a KRAS mutation in more than 60% of cases. The increasing frequency of KRAS mutation has been described in adenoma, borderline ovarian tumours, and carcinoma in 3386% of cases.57,58 In addition to absence of stromal invasion, mucinous borderline ovarian tumours that show either striking overgrowth of atypical epithelial cells, more than three layers of cell stratication,
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Review

cribriform intraglandular proliferations, or nger-like projections of solid cellular masses devoid of connective tissue are judged intraepithelial carcinoma. However, denition of intraepithelial carcinoma diers between studies. For some investigators, tumours with any of these features alone or in combination are dened as intraepithelial carcinoma.55 A few pathologists also regard complex intraglandular growth patternssuch as cribriform areas or stroma-free papillae, even without severe atypiato correspond with a diagnosis of intraepithelial carcinoma.54,59 One of the major issues in mucinous borderline ovarian tumours, particularly in those showing intraepithelial carcinoma, is that numerous sampling and more tissue sections should be obtained to rule out invasive carcinoma.56 Intestinal mucinous borderline ovarian tumour is typically discovered at FIGO stage I, therefore, prognosis is usually excellent. However, ndings have suggested that mucinous borderline ovarian tumours (excluding peritoneal pseudomyxoma) could be associated with a late and lethal invasive recurrence inside or outside the abdomen.52,53 In a study of mucinous lesions by Koskas and colleagues,52 rate of invasive recurrence 10 years after treatment was 13%. Similarly, Khunamornpong and co-workers53 reported a 42% recurrence rate (three of six
Total SBOT with micropapillary patterns SBOT (n) Total (n) Burks (1996)16 Seidman (1996)17 Eichhorn (1999)S1 Goldstein (2000)41 Deavers (2002)19 Prat (2002)39 Slomovitz (2002)40 Ayhan (2005)S2 Longacre (2005)34 Cusid (2007)S3 Silva (2006)37 Hogg (2007)42 Chang (2008)S4 Laurent (2008)43 Ren (2008)S5 De Iaco (2009)S6 Uzan (2011)44 Kane (2010)S7 Shih (2011)3 Total 17 65 84 7 99* 137 57 54 276 208 80 46 85 15 101 102 168* 18 196 10 11 40 7 18 18 14 11 23 29 11 13 18 15 20 7 56 8 36 144

patients died of recurrence). Four of the six patients with recurrence had microinvasion.53 Of the six patients who recurred, four had invasive recurrence and one had no histological features of recurrence (but had peritoneal and liver metastases); the remaining woman had borderline mucinous disease with intraepithelial and microinvasive carcinoma at the time of histological analysis of the rst recurrence, but she died from progression 14 months after initial surgery.53 These data could be accounted for by the continuum of (benign to frankly invasive) lesions in the same specimen and the frequently associated presence of intraepithelial carcinoma, which makes dierentiation from an invasive component dicult. Moreover, researchers have reported that the prognosis of mucinous invasive carcinoma is worse than that of other epithelial cancers, with diminished chemosensitivity to platinumbased and paclitaxel-based regimens and overall poor prognosis, particularly in stage II or III disease.60,61

Intraepithelial carcinoma
Denition of intraepithelial carcinoma for mucinous borderline ovarian tumours is controversial.54 Presence of severe cytological atypia was the only diagnostic criterion on which a consensus was reached for diagnosis of intraepithelial carcinoma. Seidman and Kurman36 reported
Mean follow-up (months) Deaths related to disease (n [implant subtypes]) 2 (invasive) 4 (invasive) 2 (invasive) 2 (invasive) 5 (2 invasive, 3 non-invasive) 0 0 0 5 (3 invasive, 1 non-invasive implants, 1 stage I) .. .. 1 (non-invasive) .. 1 (non-invasive) 0 0 1 (non-invasive) 1 (non-invasive) .. 14 (10%) 76 883 1884 (median) 678 41 63 (median) 40 605 57 (median) 38 (median) 444 (median)
See Online for appendix

Implants Non-invasive Invasive Recurrences % invasive (n) implants (n) implants (n) (n) recurrence (n) 10 11 11 3 18 13 0 .. 10 .. .. .. .. 9 .. .. 56 .. .. 4 1 8 3 15 12 0 .. 4 .. .. .. .. 8 .. .. 46 .. .. 6 10 3 0 3 1 0 .. 5 .. .. .. .. 1 .. .. 9 .. .. 4 7 4 2 14 2 3 .. .. .. 9 2 .. 11 .. .. 13 .. .. 56 (39%) 50% (2) 71% (5) .. 100% (2) 79% (11) .. 33% (1) 0 .. (3) .. .. 100% (2) .. 9% (1) .. 0 46% (6) .. .. 21% (30)

732 95 .. 996 125 84 433

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 2: Prognostic eect of micropapillary patterns in SBOT

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Histological type

Borderline ovarian tumour with microinvasion Number Recurrences (n) % invasive recurrence (n)* Deaths related to disease (n)* 0 0 0 0 0 0 0 0 0 0 0 0 0 0 7 0 0 1|| 0 0 8 (3%)

Mean follow-up (months)

Katzenstein (1978) Bell (1990)S9 Casey (1993)S10 Hanselaar (1993) S11 Tan (1994)S12

S8

SBOT 21 SBOT SBOT SBOT SBOT 54 MBOT 76 SBOT 126 SBOT 65 SBOT 49 MBOT 84 SBOT 73 MBOT 171 MBOT 25 MBOT SBOT 118 MBOT 10 SBOT 18 SBOT 97 MBOT ..

7 21 2 9 2 7 4 7 4 14 9 8 7 4 50 37 10 8 8 31 249

0 1 0 0 1 0 0 0 0 0 1 0 0 0 9 0 5 3 0 4 24 (10%)

0 0 0 0 0 0 0 0 0 0 0 0 0 0 67% (6) 0 0 33%|| 0 0 3% (7)

131 624 175 54 264 99 96 95 71 744 33 85 924 604 62 38 (median) 48 168

Siriaunkgul (1995)45 Kennedy (1996)S13 Nayar (1996)S14 Seidman (1996)17 Hoerl (1998)46 Eichhorn (1999)S1 Riopel (1999)47 Lee (2000)48 Nomura (2000)49 McKenney (2006)50 Kim (2007)51 Laurent (2009)S15 Kane (2009)15 Koskas (2011)52 Total

Khunamornpong (2011)53 171 MBOT

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 3: Prognostic eect of stromal microinvasion on SBOT and MBOT

290 cases of stage I intraepithelial carcinomas with 18 disease-related deaths. Of 13 patients with advancedstage disease, nine deaths were disease-related. Since publication of that report, ndings of ve series (n=559) with mucinous borderline ovarian tumours and clear histological criteria for diagnosis of intraepithelial carcinoma showed presence of intraepithelial carcinoma in 35% of cases (n=197).47,48,52,53,59 Of these patients, 431 (including 153 showing intraepithelial carcinoma) were followed up.47,48,52,53,59 Nine (6%) of the 153 women had recurrence, with three cases of invasive disease at recurrence. All patients with invasive recurrence died of the disease. In 278 patients without intraepithelial carcinoma, 11 (4%) recurred. In the series by Seidman and Kurman,36 the overall rate of death associated with intraepithelial carcinoma was estimated at 6%. This fairly high rate of death, and the well-known continuum of benign, borderline, and invasive components in the same specimen, should encourage pathologists to increase the number of tissue sections examined to rule out any association with invasive carcinoma.

none died in relation to disease.4549,5153 Microinvasion does not seem to be a prognostic factor for mucinous borderline ovarian tumours.

Preoperative assessment of patients with high-risk borderline ovarian tumours

From an epidemiological point of view, borderline ovarian tumours and carcinoma share very close characteristics. Thus, distinguishing a high-risk group of women with borderline ovarian tumours is dicult. Clinical examination could be helpful for detection of a high-risk group, by looking for clinical ascites, suspicious nodes (in the groin, axillary, or cervical nodes), or peritoneal lesions in Douglas pouch, but such ndings could also be discovered in authentic carcinoma. The relevance of serum tumour markers in patients with borderline ovarian tumours is controversial. Van Calster and colleagues62 showed that amounts of CA125 in serum overlapped between patients with borderline ovarian tumours and early-stage ovarian carcinoma. Abnormal concentrations in serum of CA125 were noted in about 40% of patients with stage I borderline ovarian tumours and reached 83% in women with advanced-stage disease.63 With the exception of advanced-stage borderline ovarian tumours, no data are available to support the relevance of serum tumour markers (eg, CA125, CA199, carcinowww.thelancet.com/oncology Vol 13 March 2012

Stromal microinvasion
Table 3 presents data for mucinous borderline ovarian tumours with stromal micronvasion. In eight series (n=116), no patients developed invasive recurrence and
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embryonic antigen) for identication of a high-risk group of borderline ovarian tumours. Pelvic ultrasound is a key procedure for detection and assessment of ovarian tumours. Some scales or scoring systems have been dened to assess objectively the degree of suspicion for malignant disease in these lesions. However, those scales are used to gauge so-called risk of malignancy before a potential surgical procedure but, at present, no ultrasound criterion can identify a high-risk group of borderline ovarian tumours. Findings of radiological studies underline the contribution of perfusion-weighted and diusion-weighted MRI sequences for dierentiation of benign lesions, borderline ovarian tumours, and ovarian cancer.64 In a series of 12 benign, 13 borderline, and 16 invasive ovarian tumours,64 early tumour enhancement on dynamic contrast-enhanced MRI images was helpful to distinguish between these types of tumours. MRI ndings correlated with angiogenic status of the tumour, which was ascertained after histopathological analysis of VEGF receptor expression in paran-embedded specimens.64 Correlation of such radiohistological ndings could perhaps be of future interest to help identify a high-risk group of borderline ovarian tumours. Yet, since pathological analysis of the tumour specimen (ovary and peritoneum) is key for identication of potentially invasive lesions, establishing a high-risk group before surgery seems uncertain.

Clinical management and eect on rate of invasive recurrence and survival

Surgery
Standard surgical treatment for borderline ovarian tumours is based on bilateral salpingo-oophorectomy, with or without hysterectomy. Staging surgery is also used, which includes peritoneal staging procedures with or without nodal staging methods.

histological subtype. Mean time to progression to carcinoma was 75 months (range 11310) for serous borderline ovarian tumours and 33 months (582) for mucinous borderline ovarian tumours. Eight of the 20 recurrences of serous borderline ovarian tumours were recorded in patients with peritoneal implants. 18 women had follow-up data available; six died of the disease and eight were alive without evidence of disease (table 4). Of the 24 recurrences of mucinous borderline ovarian tumours, 23 initially had FIGO stage I disease. Of 21 with follow-up data, 13 died of disease and only three were alive without disease (table 4). In patients with serous borderline ovarian tumours treated by cystectomy, ve of 11 were alive without disease compared with one of nine who had mucinous borderline ovarian tumours (table 4). Women with recurrence of invasive mucinous lesions had a higher rate of extra-abdominal metastasis as the rst site of recurrence (four in pleura, lung, or bone) whereas no extra-abdominal metastases arose in patients with recurrence of invasive serous borderline ovarian tumours. These diering data do not question the validity of conservative treatment. Such recurrences also arise in patients treated by bilateral salpingo-oophorectomy for borderline ovarian tumours. Nevertheless, they suggest that the rate of death is higher in women with recurrent mucinous borderline ovarian tumours than in those with serous lesions with transformation to invasive carcinoma, which then takes place earlier. Furthermore, a recommendation of initial unilateral salpingo-oophorectomy for mucinous borderline ovarian tumours rather than cystectomy seems logical, whereas in the case of serous lesions, no clear recommendations can be made.52,66

Role of laparoscopy
The role of laparoscopy is relevant because of potential risks of ruptured cysts, intraperitoneal cell dissemination, tumour metastasis in trocar incisions, and recurrence. Findings of previous studies have shown the rate of cyst rupture is higher for laparoscopy than for laparotomy, and laparoscopy has a potentially higher risk of recurrence.67 However, risk of cyst rupture was associated most with a high rate of conservative surgery (cystectomy).63 Similarly, rate of recurrence after laparoscopy was related to conservative treatment, but no association was reported between laparoscopic treatment and risk of invasive recurrence. Only eight cases of trocar implantation metastasis have been reported after laparoscopy for borderline ovarian tumours;68 ve arose in patients with peritoneal implants but none died of the disease. This nding underlines the need to recall use of systematic protected extraction for adnexal tumours.68

Conservative treatment and risk of invasive recurrence

Conservative treatment (dened as preservation of the uterus and at least a part of one ovary) is important for young patients with borderline ovarian tumours. This option is appropriate even for serous lesions with noninvasive implants.31,65 Nearly 2000 cases of conservative treatment have been reported in published work. Fertilitysparing surgery is associated with a higher rate of recurrence than is bilateral salpingo-oophorectomy, but it has no eect on survival because most recurrences are borderline lesions that are cured readily by a second surgical procedure (possibly conservative).15,31,65 Nevertheless, the main issue is to assess risk of invasive recurrence. We analysed 47 cases of progression to invasive carcinoma, including 21 published since 2009, underlining the possibility of publication bias (table 4). Risk of progression to invasive carcinoma was estimated as 23%. Of 47 recurrences, 20 were recorded in patients with serous borderline ovarian tumours, 24 had mucinous borderline ovarian tumours, and three were of an unknown
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Peritoneal staging for identication of high-risk patients

Adequate staging, including careful inspection of the peritoneum, is crucial for identication 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
Borderline tumours (n) Details of initial treatment Initial stage Serous tumours Chambers (1988)S16 Morris (2000)S17 Morris (2000)S17 Zanetta (2001)31 Zanetta (2001)31 Donnez (2003)S18 Longacre (2005)34 Longacre (2005)34 Romagnolo (2006)S19 Yokoyama (2006)5 Suh-Burgmann (2006)S20 Ji (2010)S21 Zanetta (2001)31 Prat (2002)39 Attar (2004)S22 Wong (2007)S23 Vigan (2010)S24 Uzan (2010)65 Uzan (2010)65 Uzan (2010)65 Mucinous tumours Ji (1996)S25 Gotlieb (1998)S26 Zanetta (2001)31 Zanetta (2001)31 Lee (2000)48 Suh-Burgmann (2006)S20 Wong (2007)S23 Wu (2009)S27 45 MBOT stage I 23 MBOT stage I 117 MBOT stage I 117 MBOT stage I 136 MBOT stage IIII intestinal 81 MBOT stage IIII 169 MBOT stage IIII 157 MBOT stage IIII IC IA IC IA IC IC IA IC Cystectomy USO Cystectomy Cystectomy USO and staging USO USO Cystectomy MBOT MBOT MBOT MBOT MBOT, IEC, grade 3 nuclei MBOT MBOT MBOT 11 SBOT 26 SBOT 11 SBOT 156 stage I SBOT 156 stage I SBOT 37 SBOT stage IIII 53 SBOT stage I 53 SBOT stage I 75 SBOT stage IIII 23 SBOT 109 SBOT stage IIII Case report 51 SBOT stage IIIII 40 SBOT stage IIII Case report 65 SBOT stage IIII 10 SBOT 41 SBOT stage IIIII 41 SBOT stage IIIII 41 SBOT stage IIIII IA Unknown IA IA IC Cystectomy USO and cystectomy USO and staging Cystectomy USO and CC SBOT SBOT SBOT SBOT SBOT SBOT SBOT SBOT, SMI SBOT SBOT SBOT SBOT, SMI SBOT SBOT, invasive implants Surgical treatment Histological subtypes

assessed by intraoperative histological analysis.69,70 Fauvet and colleagues70 reported a 46% rate of complete staging by laparoscopy during initial surgery, 214% after conversion to open surgery, and 254% by laparotomy. Lin and co-workers69 recorded a 12% rate of complete staging
Location* Details of recurrence(s) Interval (months) Histology Outcomes

Ipsilateral ovary Ipsilateral ovary Contralateral ovary Ovaries, peritoneum, nodes Ovary At least ovary Colon and gallbladder Axillary nodes Contralateral ovary Contralateral ovary Peritoneum Ovary and peritoneum Contralateral ovary and nodes .. Peritoneum Ipsilateral ovary ..

12 147 39 39 .. 12 288 310 36 107 27 17 50 .. 18 .. .. 42 56 11

Serous adenocarcinoma grade 1 Not reported Serous adenocarcinoma grade 2 Serous adenocarcinoma grade 3 Serous adenocarcinoma grade 1 Invasive (probably) Low-grade serous adenocarcinoma Low- grade serous adenocarcinoma Serous adenocarcinoma Serous adenocarcinoma grade 1 Invasive implants

.. DOD DOD NED .. NED AWD NED DOD NED NED DOD

I (probably) USO and CC IA IA IA IA IC IC IIB II IIIC IIC IIIII II III III .. .. USO Cystectomy USO USO and staging Cystectomy USO

Invasive carcinoma grade 1 NED .. Serous adenocarcinoma Invasive implants Invasive implants Invasive Invasive Invasive DOD AWD NED NED .. DOD ..

USO, CC, and staging SBOT, MPP, positive nodes Cystectomy .. Cystectomy and staging Cystectomy and staging USO SBOT SBOT

SBOT, MPP, non-invasive Ovary and peritoneum implants SBOT, MPP, non-invasive Ovary and peritoneum implants SBOT, SMI, invasive implants Peritoneum

.. Contralateral ovary Pelvis and abdomen Ipsilateral ovary Peritoneum Peritoneum Contralateral ovary and peritoneum Colon serosa and trocar site

.. 5 10 55 12 82

Not reported Endometrioid adenocarcinoma

DOD NED

Mucinous adenocarcinoma DOD grade 3 Mucinous adenocarcinoma NED grade 1 Mucinous adenocarcinoma DOD grade 2 Mucinous adenocarcinoma DOD grade 3 Invasive carcinoma Invasive carcinoma DOD DOD

(Continues on next page)

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Borderline tumours (n) Details of initial treatment Initial stage Surgical treatment (Continued from previous page) Wu (2009)S27 Park (2009)S28 Chiesa (2010)S29 Koskas (2011)52 Koskas (2011)52 Koskas (2011)52 Koskas (2011)52 Koskas (2011)52 Koskas (2011)52 Khunamornpong (2011)53 Khunamornpong (2011)53 Khunamornpong (2011)53 Khunamornpong (2011)53 Ha (2011)S30 Ha (2011)S30 157 MBOT stage IIII 139 MBOT stage IIII Case reported in the Discussion 74 MBOT stage I 74 MBOT stage I 74 MBOT stage I 74 MBOT stage I 74 MBOT stage I 74 MBOT stage I 60 MBOT stage I intestinal 60 MBOT stage I intestinal 60 MBOT stage I intestinal 60 MBOT stage I intestinal 7 conservative treatment 7 conservative treatment 106 MBOT 8 stage III 54 stage III 61 stage I by laparoscopy IIB IA IC IA IA IC IA IA IA I IC IC IC .. .. USO and staging USO and cystectomy USO and staging Cystectomy Cystectomy USO and staging Cystectomy Cystectomy USO and staging .. .. .. .. USO and staging USO MBOT MBOT MBOT intestinal MBOT intestinal MBOT intestinal MBOT intestinal MBOT mixed MBOT endocervical MBOT intestinal, IEC MBOT intestinal, IEC, SMI MBOT intestinal, IEC, SMI MBOT intestinal MBOT intestinal MBOT endocervical and IEC MBOT, IEC Histological subtypes

Location*

Details of recurrence(s) Interval (months) Histology

Outcomes

Peritoneum and nodes Lung Peritoneum Contralateral ovary, peritoneum, bones Ipsilateral ovary Peritoneum and nodes At least ovary Peritoneum Pleura Contralateral ovary Contralateral ovary and nodes Contralateral ovary and peritoneum .. .. Contralateral ovary, bone, lung Contralateral ovary Contralateral ovary Contralateral ovary Ipsilateral ovary and omentum

11 82 70 57 27 10 7 17 36 36 .. 25 23

Invasive carcinoma Mucinous invasive carcinoma Adenocarcinoma grade 1 Invasive carcinoma Invasive carcinoma Invasive carcinoma Invasive carcinoma Invasive carcinoma Invasive carcinoma Invasive disease in nodes Invasive carcinoma Invasive carcinoma Invasive carcinoma Carcinoma Not reported, but progression with metastasis Invasive carcinoma Serous adenocarcinoma Invasive carcinoma

DOD AWD AWD DOD AWD DOD DOD NED DOD DOD .. DOD AWD

Song (2011)S31 Unknown subtype Fort (1989)S32 Kehoe (1996)S33 Maneo (2004)S34

IA I or II IA

.. USO Laparoscopy

.. Not reported Not reported Not reported

26 60 12 44

AWD NED DOD

I (probably) USO

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 rst 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 4: Cases of progression to invasive carcinoma after conservative treatment of borderline ovarian tumours

by laparotomy, 7% for general surgeons, and 50% for oncological surgeons. Study data suggest that incomplete staging has no eect on survival and rate of recurrence.69,71 However, Seidman and Kurman36 noted a recurrence rate of 17% in patients with complete staging versus 99% in those with incomplete staging. Similarly, Camatte and colleagues71 reported no recurrence after complete staging compared with a rate of 8% after incomplete staging. Despite these data, surgery to restage a patient is controversial because it has little eect on management for those with borderline ovarian tumours. In fact, the only way to modify management of women with apparent stage I borderline ovarian tumours is if invasive implants are found at microscopic examination and the patient is upstaged (in such cases, adjuvant treatment could be discussed). If non-invasive implants are identied in a
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woman with a macroscopically normal peritoneal cavity, further treatment (surgery or adjuvant treatment) is not necessary. Nevertheless, only a few cases (n=2) of microscopic invasive implants (with an apparently normal peritoneum at surgical staging) have been noted during microscopic examination only.72,73 Thus, systematic surgical staging for identication of patients in whom adjuvant treatment should be delivered (microscopic invasive implants) is limited. However, features that argue in favour of restaging surgery include mucinous borderline ovarian tumours 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 mucinous borderline ovarian tumours includes appendectomy to
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Panel: Potential prognostic factors for invasive recurrence in SBOT and MBOT Prognostic factors SBOT with implants (worse in case of invasive implants) Peritoneal residual disease Debatable prognostic factors Micropapillary patterns (but not as an independent factor)* MBOT with intraepithelial carcinoma MBOT treated with cystectomy SBOT with stromal microinvasion Not prognostic factors Nodal spread Laparoscopic approach Use of adjuvant treatment (conventional chemotherapy: platinum-based regimens and paclitaxel) MBOT with stromal microinvasion Conservative treatment of SBOT; use of (re)staging surgery
SBOT=serous borderline ovarian tumour. MBOT=mucinous borderline ovarian tumour. *Does not seem to be an independent prognostic factor for invasive recurrence but is correlated with a higher rate of invasive implants. Not a proven independent prognostic factor or attributable to a correlation with a higher frequency of peritoneal implants or micropapillary patterns. This approach is not a prognostic factor for invasive recurrence when undertaken by skilled surgeons with careful technical steps (absence of ruptured cysts, use of extraction in endoscopic bag, etc). Conclusion limited by the few patients with such characteristics in the dierent series published. Use of (re)staging surgery is not a prognostic factor except for patients with micropapillary patterns or incomplete macroscopic exploration during initial surgery.

be higher in patients with lymph-node involvement than in those without nodal spread.50,79 Djordjevic and Malpica79 reported rates of invasive implants of 25% (nine of 36) in patients with lymph-node involvement versus 3% (one of 36) in those without involvement. Lymph-node dissection could be discussed for treatment of peritoneal implants associated with gross nodal disease during surgical exploration and in women with invasive implants.

Residual disease
Residual disease is a prognostic factor for borderline ovarian tumours.29,32,34,35 In addition to the potential therapeutic eect, complete removal of peritoneal implants allows for comprehensive histological analysis. In a series of 168 patients with serous borderline ovarian tumours (FIGO stage II and III), 5-year disease-free survival was 75% in patients with no residual disease, 76% in those with residual disease less than or equal to 2 cm, and 56% in those with residual disease greater than 2 cm (p<002).15 3-year disease-free survival of 71% was reported in patients with residual disease compared with 89% in those without.35 No patients with residual disease received adjuvant chemotherapy.35 Therefore, surgery to remove borderline ovarian tumour should include resection of all macroscopic peritoneal implants. Surgical procedures to achieve complete removal of peritoneal disease are similar to techniques used in advanced ovarian cancer. Ideally, total resection of implants should be done and could reduce possible pathological misdiagnosis of invasive implants, which might be missed if implants are not resected.

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

Chemotherapy for high-risk patients

The role of adjuvant chemotherapy in women with advanced-stage serous borderline ovarian tumours is controversial. In early series,80 adjuvant chemotherapy showed benecial eects, but in a review of four prospective randomised trials of women with stage I and II borderline ovarian tumours without residual disease (n=253), Trop and colleagues81 reported that adjuvant treatment (chemotherapy and radiotherapy) had no eect on overall survival, whereas toxic eectsespecially neurotoxicityincreased after cisplatin. Likewise, ndings of a Gynecologic Oncology Group study82 recorded no advantage of adjuvant chemotherapy in 32 patients with FIGO stage III borderline ovarian tumours. In a series of 39 women with borderline ovarian tumours and invasive implants with macroscopic residual disease, Gershenson and co-workers33 reported complete responses to platinumbased chemotherapy of 14%, with shorter progression-free survival. Researchers on a Cochrane meta-analysis of borderline ovarian tumours concluded that evidence did not support use of any specic type of adjuvant treatment.83 In a series of 80 patients with FIGO stage IIIV borderline ovarian tumours, Shih and colleagues35 noted a recurrence rate of nearly 21%, with no dierence in 3-year progressionfree survival between patients who had received adjuvant chemotherapy or not (706% vs 899%, respectively).
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Eect of lymphadenectomy and lymph-node involvement on survival

Lymph-node involvement is recorded in about 25% of patients with advanced-stage borderline ovarian tumours (FIGO stage III or IV).75 Lymph-node involvement is sometimes associated with lymph-node endosalpingiosis. Molecular and histological data suggest that most nodal implants are metastases from synchronous ovarian neoplasms, but a few arise from de novo nodal endosalpingiosis.76 Pathways by which nodal metastases proceed in non-invasive neoplasms are unclear. Fadare and colleagues77 showed no dierence in lymphatic vessel density between node-positive and node-negative tumours, suggesting that these lesions might have a predilection for peritoneal rather than lymphatic spread. Several researchers have reported no eect of lymphnode involvement on survival of patients with borderline ovarian tumours.34,36,77,78 In a series of 123 patients, including 68 with complete surgical staging, Kanat-Pektas and colleagues78 recorded no dierence between diseasefree and overall survival. Data from our institution and from the SEER database accord with these ndings and show that survival correlates with FIGO stage irrespective of nodal status.75 The rate of invasive implants seems to
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Moreover, Lesieur and co-workers75 recorded no eect of adjuvant chemotherapy on disease-free survival in patients with lymph-node involvement. Concern persists for patients with invasive implants. Most teams currently propose chemotherapy as treatment, although the proven eectiveness of this option continues to be debated. If undertaken, the chemotherapy regimen is similar to that used in ovarian cancer (a platinum-based regimen with paclitaxel). Dierent pathways (particularly the MAPK signalling pathway) have been identied in the carcinogenesis of serous borderline ovarian tumours with micropapillary patterns and low-grade carcinoma, suggesting that targeted treatments could be used in these diseases.18,21,84 May and colleagues18 suggested that inhibition of PARP1 could be a target. A trial has started to test a MEK inhibitor in recurrent low-grade serous carcinoma with the poorest response to conventional chemotherapy compared with high-grade carcinoma (ClinicalTrials.gov identier NCT00551070).

Search strategy and selection criteria Data for this Review were identied from searches of Medline, Current Contents, PubMed, and references in relevant articles, with the terms borderline ovarian tumours, lowmalignant 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 dierent 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 rst time or series reporting the largest number of patients or the most complete results (in terms of variables studied).

Follow-up to detect invasive recurrences

Several researchers have described outcomes of patients with borderline ovarian tumours, including advancedstage disease, but very few have focused on useful methods for detection of recurrences.67,85,86 Transvaginal ultrasonography is the most eective procedure for conservative management of early-stage disease. In a series of ve patients with invasive recurrence after conservative treatment for early-stage borderline ovarian tumours,85 all had abnormal ndings on ultrasound and abnormal amounts of CA125. Uzan and colleagues86 conrmed the importance of imaging (abdominopelvic ultrasonography) for detection of recurrence (422%) in women with stage II or III serous borderline ovarian tumours who were treated conservatively. A raised level of CA125 in serum formed part of the initial diagnosis in only 156% of all recurrences, but this marker was the most frequent method for diagnosis of recurrent invasive lesions (six of 13 patients relapsed with carcinoma).86 Thus, a combination of follow-up proceduresie, both imaging and determination of CA125 in serumseems to be an adequate option, particularly in patients with invasive implants. For conservative treatment, abdominopelvic ultrasound is needed. Abdominopelvic CT or MRI could be proposed for women treated for stage II or III disease with abnormal or inconclusive ndings on ultrasound (due to complex previous surgeries or obesity). Nevertheless, very few series have been published on this specic topic, and the combination of blood markers and imaging has not had an eect on overall survival in this context. Potential prognostic factors for invasive recurrence in borderline ovarian tumours are presented in the panel.

Conclusions
The pathologist has a pivotal role in assessment of the borderline nature of ovarian tumours and in identicawww.thelancet.com/oncology Vol 13 March 2012

tion of high-risk criteria for invasive recurrences and possible death from disease. We have identied two factors that are important for recurrence of invasive disease. First is invasive peritoneal implants (in serous borderline ovarian tumours), and second is residual disease after surgery. Other factors are controversial owing to increased risk of invasive recurrence, for example, presence of micropapillary patterns in serous borderline ovarian tumours, presence of intraepithelial carcinoma in mucinous lesions, presence of stromal microinvasion in serous tumours, and use of cystectomy in mucinous borderline ovarian tumours. Variability in rates of recurrence and survival between series depends not only on pathological criteria used to classify entities but also on how published material was gathered. Population-based studies from academic institutions, data obtained over several decades, cohort studies, or collection of specimens by one pathologist all represent potential biases.20 Publication bias cannot be ignored because it can lead to overestimation of risk for poor prognosis. To avoid such biases, all studies should verify the quality of tissue collection and sampling for histological analysis to enable centralised uniform pathological review (particularly important in multicentre series) with sucient patients and prolonged follow-up, which will allow relevant conclusions to be drawn for routine practice.21 At present, the only pragmatic way to better identify patients at high risk of invasive recurrence is pathological review of tumour slides by a skilled pathologist (or a panel of pathologists) for patients in at-risk situationseg, those with borderline ovarian tumours with implants (to clearly distinguish invasive from non-invasive implants), with micropapillary patterns (associated with a higher rate of implants), with intraepithelial carcinoma, stromal microinvasion, or both (could ultimately be diagnosed as invasive carcinoma), and mucinous borderline ovarian tumours (pathological classication of this tumour is arduous). In some countries, centralised pathological reviews (or registries) are being organised to decrease the rare but potentially lethal risk of invasive recurrences.
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