Borderline tumours of the ovary, current controversies regarding their

diagnosis and treatment

María Guadalupe Patrono1, Lucas Minig1, Ivan Diaz-Padilla2, Nuria Romero2, Juan Francisco Rodriguez Moreno2 and
Jesus Garcia-Donas2

1
Gynaecology Oncology Programme, Clara Campal Comprehensive Cancer Centre, HM Hospitals, Madrid 28050, Spain
2
Gynaecology Oncology Programme, Medical Oncology, Comprehensive Oncology Centre Clara Campal, HM Hospitals, Madrid 28050, Spain.

Correspondence to: Lucas Minig. Email: lucasminig@yahoo.com

Abstract

Borderline ovarian tumours generally affect women of reproductive age. The positive prognosis is related to the fact that over 80% of cases
are diagnosed at an early stage of the disease. Although radical surgery is the standard of care for this disease, fertility-sparing surgery
can be performed in selected cases. Since it was first described in 1929, the knowledge of the molecular and histologic characteristics has
been significantly improved. In this review, advances in the clinical behaviour, pathologic characteristics, prognostics factors, and different
strategies of treatment are discussed.

Review
Keywords: borderline ovarian tumour, conservative treatment of fertility, gynaecological cancer, ovarian cancer surgery

Published: 17/12/2013 Received: 18/09/2013

ecancer 2013, 7:379 DOI: 10.3332/ecancer.2013.379

Copyright: © the authors; licensee ecancermedicalscience. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction
in any medium, provided the original work is properly cited.

1
 ecancer 2013, 7:379

Introduction

Epithelial tumours of the ovary can be either benign (cystadenomas) or malignant (cystadenocarcinomas). However, there is an interme-
diate state of epithelial tumours of the ovary called ‘borderline tumours’. Neither the oncological behaviour of this intermediate group of
tumours nor the histological changes of the cells of the ovarian epithelium meet the specific criteria of benignity or malignancy. In 1973, the
International Federation of Gynaecology and Obstetrics (FIGO) gave this group of ovarian tumours a ‘low malignant potential’ [1], and since
then, the World Health Organization (WHO) has called them borderline ovarian tumours (BOTs) [2].

They are tumours that usually occur during the third to fourth decade of women’s lives and are diagnosed as being limited to the ovary in
80% of cases. Because of this, their biological–oncological behaviour is very good, with an overall survival rate of ten years for 90% of those
in the initial stages [3] and 60–70% of those in the advanced stages [4, 5].

While the recommended treatment is a hysterectomy with double adnexectomy, this frequently raises the clinical dilemma of diagnosis in
women who have not yet given birth. Here, the conservative treatment of fertility may be a safe possibility in selected cases. The effec-
tiveness of the chemotherapy is limited due to the slow rate of growth of the altered cells, meaning its use is limited and not advised. This
chapter will describe the main histological features and clinical behaviour, and the different therapeutic options at the time of both the
diagnosis and the recurrences of BOTs.

Epidemiology and risk factors

Review
BOTs comprise 15–20% of epithelial tumours [6]. Unlike invasive ovarian cancer, these tumours are diagnosed in the early stages in 80%
of cases [7]. The average age at which such tumours are diagnosed is 40 years, but almost 30% of women with them are diagnosed before
the age of 40 [8, 9].

Ritman et al [10] assessed the risk factors for BOTs in a case control study using the regional registry of tumours in Sweden. They ran-
domly assigned 3899 control patients from the population register of all the residents in the country. The results showed that the women
who had given birth more than once had a lower risk of developing borderline tumours compared with those women who had not given
birth at all [odds ratio (OR): 0.44 (confidence interval (CI): 0.26–0.75) for serous tumours and 0.63 (CI: 0.34–1.19) for the mucinous
tumours]. The authors found, in contrast, that breast-feeding served as a protective factor. This is similar to what has been observed for
ovarian cancer. However, unlike the latter, the use of oral contraceptives was not a protective factor against the development of BOTs
[OR: 1.4 (CI: 0.87–2.26)]. Thus, the authors suggested that this finding could support the concept that BOTs would represent a distinct
disease to that of invasive ovarian cancer [10].

Classification and histological characteristics

BOT of the ovary is characterised histologically by the presence of epithelial cells with nuclear atypia and mitotic activity in 10% or more of
the tumour but without ovarian stromal invasion [8, 11]. The histological subtypes of epithelial BOTs can be serous, mucinous, endometri-
oid, clear, and transition cells (Brenner). The first two variants include 95% of the total [9].

Serous BOTs
Serous tumours represent 65% of all the BOTs [9]; they are unilateral in 70% of cases, and 30% of them can occur with peritoneal implants.
In turn, it is important to note that almost 30% of these implants have microscopic characteristics of stromal invasion [12] The implants with
and without invasion are described in this way, reducing the ten-year survival from 95% to 60%, respectively [13].

The relationship of serous BOT as a precursor of invasive carcinoma has been extensively studied in recent years [14], suggesting two
morphology-pathogenic tracks of epithelial ovarian tumours, based on their molecular differences and on their clinical behavioural–biological
differences [15]. In this way, the serous tumours of type 1 would have a slow growth, generally limited to the ovary at the time of diagnosis, and

2 www.ecancer.org
 ecancer 2013, 7:379

would be developed from well-established precursor lesions from the cystadenoma, serous BOT until the micropapillary carcinoma low-grade
serous. Genetically, they are characterised by mutations in the track of the KRAS, BRAF, PTEN, and A-catenin [15].

Reinforcing this theory, a study published by Shvartsman et al [16] found that serous BOTs often coexist with low-grade serous ovarian
carcinomas. The purpose of the study was to compare the oncological outcomes of patients with low-grade serous carcinoma stage II/IV
(group 1), with patients with relapsing BOT as low-grade serous carcinoma (group 2). The time free of the disease was studied from its
diagnosis in group 1 and from the first relapse in group 2. We identified 112 patients in group 1 and 41 in group 2. There were no statistically
significant differences between the two groups in average age (42.7 versus 45.4 years, p = 0.37), progression-free survival (19.5 months
versus 25, p = 0.92), nor in the overall survival (81.8 versus 82.8 months, p = 0.84) [16].

Ovarian tumours of type II, in contrast, are fast-growing without precursor lesions and with a high degree of aggressiveness [15]. They
manifest themselves as high-grade ovarian carcinomas, with extensive peritoneal dissemination and extra-abdominal disease and include the
high-grade serous carcinomas, malignant mixed mesodermal tumours (carcinosarcomas), and undifferentiated carcinomas [15]. This group
of tumours has a high level of genetic instability and is characterised by the mutation of the P53 gene and the overexpression of the genes of
HLA-G, HER2, and AKT [17]. Most of the malignant epithelial tumours of the ovary belong to this type II.

Borderline ovarian mucinous tumours

Mucinous BOTs represent 32% of all epithelial BOTs [7]. They are divided into two histologic subtypes: the intestinal (90%) and
the Müllerian (endocervical type). In contrast to the serous BOT, the mucinous subtype is associated more rarely with peritoneal
implants [9]. Like the serous tumours, the survival of women with stage I is 100%, while that in advanced stages is only 50% [9].

Review
Following the type I morphology-pathogenic pathway previously described for the serous tumours, the mucinous BOT usually reaches a
large size, tends to be unilateral, and can coexist with areas of mucinous cystadenoma or low-grade invasive carcinoma [14].

Diagnosis

Clinical differentiation between borderline ovarian cysts, benign or malignant, is difficult. The majority of patients show an asymptomatic
adnexal mass, in the annual gynaecological exam as an incidental finding in a gynaecological ultrasound. Of all forms, the most frequent
symptoms are those of any type of adnexal mass and include abdominal pain, changes in intestinal transit, pelvic pain, and dyspareunia
among others. The ability to manifest itself with abdominal distension because of ascites is less likely than in cases of ovarian cancer.

Vine et al [18] evaluated the symptoms and their duration before the diagnosis of invasive cancer or BOT. The authors observed that
patients with BOT were twice as likely to be asymptomatic at diagnosis. At the same time, women with BOT were two times more likely to
be diagnosed during a routine examination. Among the women with symptoms, those with BOT had a greater duration of symptoms than
women with ovarian cancer (six versus four months). These aspects of the clinical presentation of BOT are probably a reflection of the
more indolent nature of these tumours.
The vaginal ultrasound is the first step in the evaluation of patients with an adnexal mass. Exacoustos et al [19] determined that the pres-
ence of papillae within the cyst was the most common finding in the BOT. However, neither the sonographic features nor the papillae are
ultrasound markers of high sensitivity. A Japanese study [20] also showed the usefulness of employing magnetic resonance imaging (MRI)
to distinguish between BOTs and other conditions that are invasive to the ovary.

The tumour marker CA-125 may be high in more than half of the patients with BOT [8]. Engelen et al [21] assessed the level of the CA-125
preoperatively, which was found to be high in 8 of 33 (24%) patients, levels of CEA in 3 of 32 (9%), and levels of CA 19-9 in 11 of 24
(46%) cases. In patients with mucinous BOT, CA 19-9 was most frequently high (8/14, 57%) when compared with the CA-125 (3/20, 15%)
(p = 0.02) or the CEA (2/18, 11%) (p = 0.02). Ayhan et al [22] found that the positivity of the CA-125 in the BOT serous group was statistically
greater than in the group of BOT mucinous, whereas positivity for CA 19-9 and CEA in the mucinous histology was significantly greater than
those of the serous tumours after analysing 60 patients.

3 www.ecancer.org
 ecancer 2013, 7:379

Kolwijck et al [23] found that preoperative serum levels of CA-125 were significantly higher in patients with advanced stages (median
181 IU/ml; reaching values of I413 U/ml) compared with patients with initial stage (median 28 IU/ml; reaching values of 1123 IU/ml). The
median in patients with serous histology was 59 IU/ml compared with the mucinous histology, which was 25 IU/ml.

Other diagnostic methods such as MRI and positron emission tomography-computed tomography (PET-CT) are usually reserved for
selected cases since the sonographic features of the adnexal mass, coupled with the value of the tumour marker CA-125, are usually suf-
ficient to indicate diagnostic or therapeutic surgery. Computed tomography (CT) is useful in the case of an adnexal mass with suspected
BOT or malignancy. The objective is to detect intra-abdominal presence of disease [24].

In any case, the definitive diagnosis of the adnexal mass is made by an intraoperative histological study. In this sense, many studies have
evaluated the accuracy of the histological diagnosis of the adnexal mass [25, 26]. As a result, the diagnosis is not often easy, mainly in
large and mucinous tumours [25, 26]. The intraoperative diagnosis has proven to be reliable in discriminating between a benign and a
malignant mass in a BOT (overdiagnosis less than 10%). However, a subdiagnosis of 25–30 % has been shown in differentiating a BOT
from a malignant tumour [27, 28].

The clinical consequence of this limit is the need to re-operate to surgically stage the cases diagnosed as ovarian cancer in the final histo-
logical analysis that had been BOT in the intraoperative diagnosis.

Treatment

Surgery is the initial treatment for BOTs. Its principle is the same as that in invasive cancer, to remove the whole of the disease that is mac-

Review
roscopically visible. The recommended surgical staging includes having a hysterectomy, bilateral salpingo-oophorectomy, omentectomy,
multiple biopsies, and peritoneal cytology. In the case of mucinous BOTs, an appendectomy should also be performed (Figure 1). The role
of a lymphadenectomy has been extensively discussed in recent years [29–32]. However, according to the results of multiple studies, a
pelvic and aortic lymphadenectomy does not improve the disease-free time or overall survival rate for women with BOT [29–33].

Figure 1: Surgical procedures in patients with borderline tumor with and without the desire to preserve fertility.

4 www.ecancer.org
 ecancer 2013, 7:379

In contrast, the diagnosis may also be made at the time of the removal of a seemingly benign ovarian cyst. In that case, the dilemma is
whether the patient should or should not be re-operated on, with the objective of completing the surgical staging and of making a careful
inspection of the entire abdominal and pelvic cavity, to detect the presence of possible peritoneal implants. According to the data from the
literature, this must be done mainly in the serous subtypes [33]. However, the majority of authors recommend this routinely, regardless of
the histological subtype of the BOT [34, 35].

Staging of borderline tumours of the ovary

The FIGO and the American Joint Committee on Cancer (AJCC) have designated stages to define ovarian tumours of a low malignant
potential. The FIGO system as seen below is the most frequently used (Table 1) [36, 37].

Table 1. FIGO staging of borderline ovarian tumours.

Stage
I Tumour limited to the ovary
Tumour limited to an ovary, absence of malignant cells in ascites,
Ia
intact capsule without tumour extension on the ovarian surface
Ib Tumour limited to both ovaries, absence of malignant cells in ascites,
intact capsule without tumour extension on the ovarian surface

Review
Ica Presence of tumour cells in ascites or peritoneal lavage, presence of
tumour on the ovarian surface of one or both ovaries, broken capsule
II Condition of one or both ovaries with pelvic extension
IIa Extension and/or in utero metastasis and/or fallopian tubes
IIb Extension to other pelvic tissues
IIc a
IIa or IIb with the presence of tumour cells in ascites or peritoneal
lavage, presence of tumour on the ovarian surface of one or both
ovaries, broken capsule
III The tumour compromises one or both ovaries with histologically
confirmed peritoneal implants outside of the pelvis and/or positive
pelvic lymph nodes. Superficial hepatic metastasis corresponds with
stage III. The tumour is limited to the true pelvis but with histologically
confirmed malignant extension in the small intestine or the omentum
IIIa Tumour limited to the pelvis with negative nodes, positive peritoneal
implants, or extension to the small intestine or the mesentery
IIIb Condition of one or both ovaries with histologically confirmed implants,
positive peritoneal metastasis, no more than 2 cm in diameter, and the
nodes are negative
IIIc Peritoneal metastasis beyond the pelvis > 2 cm in diameter and/or
positive regional lymph nodes
IV Condition of one or both ovaries with distant metastases. Positive
pleural effusion. Metastasis of the hepatic parenchyma
a
To assess the impact in the diagnosis of stages Ic or IIc, it would help to know if
the rupture of the capsule was spontaneous or caused by the surgeon and if the
source of the malignant cells detected was in the peritoneal lavage or ascites.

5 www.ecancer.org
 ecancer 2013, 7:379

Prognostic factors

In patients with BOTs in advanced stages (II–IV), prognostic factors include age at the time of diagnosis, FIGO stage, residual disease
following surgery, type of peritoneal implants (with or without invasion), presence of microinvasion in the ovarian tumour, micropapillary
pattern, and the CA-125 value [38].

Approximately 30% of patients with serous BOTs have peritoneal implants at the time of diagnosis. Of these, 30% are invasive implants
[39]. Morice et al [40] evaluated 80 patients with serous BOTs in FIGO stages II–III, 65 of whom had non-invasive implants, and 15 invasive
implants. They found that the only prognostic factor for patients with advanced stage was the presence of invasive peritoneal implants.
Reinforcing this idea, another study found that, although the overall survival rate of seven years for BOTs in advanced stages is 95% [41],
in the presence of invasive implants, it can drop to 33% [42]. The extent of residual disease is another important prognostic factor. In a
series of 168 patients with serous BOTs (FIGO stage II and III), the survival rate of five years was 75%, 76%, and 56% (p < 0.02) in patients
without residual disease, with residual disease 1–20 mm or more than 20 mm, respectively [43]. In addition to the therapeutic potential,
complete elimination of peritoneal implants allows for complete histological analysis of the disease [11].

Adjuvant chemotherapy

Stage I BOTs do not need adjuvant treatment. A retrospective study from the Gynaecologic Oncology Group (GOG) analysed 988 adequately
staged patients with stage I BOTs who did not receive adjuvant treatment and observed a mortality rate of 0.7% at five years [44].

Review
In contrast, the role of adjuvant therapy in women with advanced stage BOTs is debatable. A meta-analysis of from Cochrane on BOTs
concluded that current evidence does not show any benefits in the use of adjuvant therapy, whether it is chemotherapy or radiotherapy,
independently of the stage or tumour histology [45].

Trope et al [46], after a review of four randomised studies, concluded that adjuvant treatment in patients with stage I of the disease, sig-
nificantly increases intestinal, neurological, and haematological toxicity, without therapeutic benefits. Nor did Sutton et al [47] find benefits
in the use of chemotherapy in patients with stage III randomly assigned to receive treatment with cisplatin plus cyclophosphamide with or
without doxorubicin in a prospective study from the GOG. Of the 32 patients selected after initial cytoreduction, 19 had residual disease
less than 1 cm, and 13 remained without residual disease. Twenty (62.5%) received cisplatin plus cyclophosphamide and 12 cisplatin,
cyclophosphamide, and doxorubicin as monotherapy; 75% of the patients received six or more cycles. A second exploration was done in
15 cases; only six were negative. However, with an average follow-up of 31.7 months (range 1–75), 31 patients remained alive without
clinical evidence of disease.

Conservative fertility treatment

Conservative fertility treatment, which consists of removing the entire disease but preserving the uterus and at least a part of an ovary, is
especially important in women with BOT since nearly 30% of women are diagnosed before 40 years old, and many of them have not even
met their expectations for reproduction [8, 9]. The conservative treatment with BOT consists of doing peritoneal cytology, infracolic oment-
ectomy, peritoneal biopsies, and appendectomy in the case of mucinous BOTs (Figure 1).

Conservative surgery has been extensively evaluated in recent years. After analysing more than 2000 published cases, conservative fertil-
ity surgery is associated with a major risk of recurrence of the disease but has no impact on the overall survival rate [48–50].

The radicalism of conservative surgery, either ovarian cystectomy or unilateral oophorectomy, must be based on the extension of the disease
and the presence of factors associated with a bad prognostic advising against conservative treatment [11]. These include the presence of
microinvasion, a micropapillary pattern, and invasive peritoneal implants [51]. In contrast, based on the data from the literature, there do not
seem to be contraindications for the use of drugs for ovarian stimulation in case of getting future pregnancies following the diagnosis and
treatment of the disease [52, 53].

6 www.ecancer.org
 ecancer 2013, 7:379

Another controversial point is whether the patients who have received conservative treatment of fertility must later receive radical surgical
treatment with removal of the uterus and remaining ovary after meeting their reproduction desires, once they reach menopause or waiting
on a possible disease relapse, independently of the age of the patient.

Given that there are no uniform criteria in that regard, possibly the most important factor of which to take note is the stage of the tumour
at the time of diagnosis. So one could contemplate completing the staging at the time of recurrence or after having met the reproduction
desires in patients with early or advanced stages, respectively [40, 51].

Follow-up

Today there is no consensus with respect to the best way to follow-up with patients following the initial treatment for BOT for the early detec-
tion of recurrence. It seems reasonable that the sum of methods such as physical examination, CA-125 determination, and CT is a method
of choice. Vaginal gynaecologic ultrasound is of vital importance in women who receive conservative treatment of fertility. It is important
to know that the free time of disease for women with BOT who show a relapse is significantly major with respect to women with invasive
ovarian carcinoma. Uzan et al [54] observed a time up until the recurrence of up to 31 months (range 4–242 months) in 162 patients with
advanced stage serous BOT. Similarly, recurrences as far apart as 15 years following initial diagnosis have been described [55]. These
data force the prolongation of the time of follow-up with said patients for many years following the diagnosis. In this way, the recommended
follow-up must be every three months for the first two years, every six months from two to five years and must continue every year up to
15 years after the initial diagnosis [55].

Review
Zanetta et al [56] analysed prospectively the follow-up of 164 women with stage I BOT who have undergone conservative surgery of fertility.
The follow-up was done with a physical examination and vaginal ultrasound every three months for two years and every six months after
that. The CA-125 determination was planned every six months in patients with a serous BOT. The authors concluded that the vaginal ultra-
sound is the most effective diagnosis technique in this group of patients. The clinical practice guide of the National Comprehensive Cancer
Network (NCCN) [57] recommends follow-up with gynaecologic ultrasound; but in those patients with invasive implants the follow-up must
be similar to that of ovarian cancer: CT of thorax-abdomen-pelvis and CA-125. Likewise, women who meet maternity expectations and
were previously treated under conservative must receive the aforementioned standard surgical treatment [57].

With respect to hormonal contraception, the Centres for Disease Control and Prevention (CDC) classifies as category 1 (there is no restric-
tion on the use of contraceptive methods) the use of combined contraceptive pills as well as progestins, patches, vaginal ring, copper
intrauterine device and levonorgestrel, birth control methods for patients with ovarian cancer; hence the choice of contraceptive methods
is not considered limited by the diagnosis of a BOT [58].
Something similar happened with the use of hormone replacement therapy (HRT): a Swiss study done by Mascarenhas et al [59] analysed
the five-year survival rate in patients with BOT and invasives that received HRT. They did a prospective cohort study in which they included
799 women diagnosed with invasive cancer (n = 649) and BOT (n = 150) between the ages of 50 and 74 years in 1993–1995. Follow-
ing five years of follow-up, 45% of patients with carcinoma and 93% of patients with BOT were alive. For women with BOT, there was no
association between the use of HRT used before or after diagnosis and the survival rate. Nor was there any association for women with
ovarian cancer.

Treatment of relapses

Surgical treatment with the objective of maximum cytoreduction is the goal of treatment for relapsed BOTs [7, 34, 60]. This concept is
equally valid for women following a conservative fertility pretreatment who want to do it again but with adequate counsel, accepted the
major risk of relapse and with the concrete possibility of a strict follow-up [34, 61].

7 www.ecancer.org
 ecancer 2013, 7:379

Conclusion

BOTs constitute a group of epithelial tumours that can affect women of reproductive age who have excellent prognosis due to the low
aggressiveness and the fact that they are largely diagnosed in initial stages. Conservative surgery of fertility is possible in select cases with
disease limited to the ovary and when there is a strong desire to become a mother. Radical surgery of maximum cytoreduction is the goal
of treatment in women with advanced or recurrent diseases. Residual disease following surgery and the presence of invasive peritoneal
implants are the main prognostic factors. The benefits of adjuvant chemotherapy are limited by the fact that its use is still inadvisable. The
follow-up of patients must be done up to 15 years following the initial diagnosis.

Conflicts of interest

The authors have no conflicts of interest to declare.

References

1. Kottmeier HL, Kolstad P and McGarrity KA (1973) Annual Report on the Results of Treatment in Gynaecologic Cancer vol 17, State-
ments of results obtained in 1969–1972, inclusive (Stockholm, Sweden, Editorial office, Radiumhemmet: FIGO)

Review
2. Serov SF, Scully RE and Sobin LH (1973) International histological classification of tumors, no 9 Histoloigcal Typing of Ovarian
Tumours (Geneva: World Health Organization)

3. Nikrui N (1981) Survey of clinical behavior of patients with borderline tumors of the ovary. Gynecol Oncol 12 107–19 DOI:
10.1016/0090-8258(81)90102-5 PMID: 6268484

4. Bostwick DG, Tazelaar HD and Ballon SC (1983) Ovarian epithelial tumors of borderline malignancy: a clinical and pathologic
study of 109 cases Cancer 58 2052–64 PMID: 3756820

5. Leake JF, Currie JL and Rosenshein NB (1992) Long-term follow-up of serous ovarian tumors of low malignant potential
Gynecol Oncol 47 150–8 DOI: 10.1016/0090-8258(92)90099-5 PMID: 1468692

6. Lenhard MS, Mitterer S and Kümper C (2009) Long-term follow-up after ovarian borderline tumor: relapse and survival in a large
patient cohort Eur J Obstet Gynecol Reprod Biol 145 189–94 DOI: 10.1016/j.ejogrb.2009.04.031 PMID: 19477060

7. Trillsch F, Mahner S and Ruetzel J (2010) Clinical management of borderline ovarian tumors Expert Rev Anticancer Ther 10
1115–24 DOI: 10.1586/era.10.90 PMID: 20645700

8. Jones MB (2006) Borderline ovarian tumors: current concepts for prognostic factors and clinical management Clin Obstet
Gynecol 49(3) 517–25 DOI: 10.1097/00003081-200609000-00011 PMID: 16885658

9. Lalwani N, Shanbhogue AK, Vikram R (2010) Current update on borderline ovarian neoplasms AJR Am J Roentgenol 194(2)
330–6 DOI: 10.2214/AJR.09.3936 PMID: 20093592

10. Riman T, Dickman PW and Nilsson S (2001) Risk factors for epithelial borderline ovarian tumors: results of a Swedish case–
control study Gynecol Oncol 83 575–85 DOI: 10.1006/gyno.2001.6451 PMID: 11733975

11. Morice P, Uzan C and Fauvet R (2012) Borderline ovarian tumour: pathological diagnostic dilemma and risk factors for invasive
or lethal recurrence Lancet Oncol 13(3) e103–15 DOI: 10.1016/S1470-2045(11)70288-1 PMID: 22381933

12. Seidman JD, Horkayne-Szakaly I and Haiba M (2004) The histologic type and stage distribution of ovarian carcinomas of
surface epithelial origin Int J Gynecol Pathol 23 41–44 DOI: 10.1097/01.pgp.0000101080.35393.16

8 www.ecancer.org
 ecancer 2013, 7:379

13. Sherman ME, Mink PJ and Curtis R (2004) Survival among women with borderline ovarian tumors and ovarian carcinoma: a
population-based analysis Cancer 100 1045–52 DOI: 10.1002/cncr.20080 PMID: 14983501

14. Kurman RJ and Shih IeM (2008) Pathogenesis of ovarian cancer: lessons from morphology and molecular biology and their
clinical implications Int J Gynecol Pathol 27(2)151–60 PMID: 18317228 PMCID: 2794425

15. Shih I and Kurman R (2004) Ovarian tumorigenesis: a proposed model based on morphological and molecular genetic
analysis Am J Pathol 164 1511–8 DOI: 10.1016/S0002-9440(10)63708-X PMID: 15111296 PMCID: 1615664

16. Shvartsman HS, Sun CC and Bodurka DC (2007) Comparison of the clinical behavior of newly diagnosed stages II-IV low-grade
serous carcinoma of the ovary with that of serous ovarian tumors of low malignant potential that recur as low-grade serous
carcinoma Gynecol Oncol 105(3) 625–9 DOI: 10.1016/j.ygyno.2007.01.030 PMID: 17320156

17. Landen CN Jr, Birrer MJ and Sood AK (2008) Early events in the pathogenesis of epithelial ovarian cancer J Clin Oncol 26(6)
995–1005 DOI: 10.1200/JCO.2006.07.9970 PMID: 18195328

18. Vine MF, Ness RB and Calingaert B (2001) Types and duration of symptoms prior to diagnosis of invasive or borderline ovarian
tumor Gynecol Oncol 83(3) 466–71 DOI: 10.1006/gyno.2001.6411 PMID: 11733956

19. Exacoustos C, Romanini ME and Rinaldo D (2005) Preoperative sonographic features of borderline ovarian tumors Ultrasound
Obstet Gynecol 25(1) 50–9 DOI: 10.1002/uog.1823

20. Takemori M, Nishimura R and Hasegawa K (2002) Clinical evaluation of MRI in the diagnosis of borderline ovarian tumors Acta
Obstet Gynecol Scand 81(2) 157–61 DOI: 10.1034/j.1600-0412.2002.810212.x PMID: 11942907

Review
21. Engelen MJ, de Bruijn HW and Hollema H (2000) Serum CA 125, carcinoembryonic antigen, and CA 19-9 as tumor markers in
borderline ovarian tumors Gynecol Oncol. 78(1) 16–20 DOI: 10.1006/gyno.2000.5811 PMID: 10873403

22. Ayhan A, Guven S and Guven ES (2007) Is there a correlation between tumor marker panel and tumor size and histopathology in
well staged patients with borderline ovarian tumors? Acta Obstet Gynecol Scand 86(4) 484–90 DOI: 10.1080/00016340701226138
PMID: 17486473

23. Kolwijck E, Thomas CM and Bulten J (2009) Preoperative CA-125 levels in 123 patients with borderline ovarian tumors: a ret-
rospective analysis and review of the literature Int J Gynecol Cancer 19(8) 1335–8 DOI: 10.1111/IGC.0b013e3181a83e04 PMID:
20009886

24. Liu JH and Zanotti KM (2011) Management of the adnexal mass Obstet Gynecol 117(6) 1413–28 DOI: 10.1097/AOG.0b013e318
21c62b6 PMID: 21606754

25. Tangjitgamol S, Jesadapatrakul S and Manusirivithaya S (2004) Accuracy of frozen section in diagnosis of ovarian mass Int J
Gynecol Cancer 14(2) 212–9 DOI: 10.1111/j.1048-891X.2004.014202.x PMID: 15086718

26. Kim JH, Kim TJ and Park YG (2009) Clinical analysis of intra-operative frozen section proven borderline tumors of the ovary
J Gynecol Oncol 20(3) 176–80 DOI: 10.3802/jgo.2009.20.3.176 PMID: 19809552 PMCID: 2757563

27. Tropé CG, Kristensen G and Makar A (2000) Surgery for borderline tumor of the ovary Semin Surg Oncol 19 69–75 PMID:
10883027

28. Tempfer CB, Polterauer S and Bentz EK (2007) Accuracy of intraoperative frozen section analysis in borderline tumors
of the ovary: a retrospective analysis of 96 cases and review of the literature Gynecol Oncol 107 248–252 DOI: 10.1016/j.
ygyno.2007.06.008 PMID: 17631951

29. Winter WE 3rd, Kucera PR and Rodgers W (2002) Surgical staging in patients with ovarian tumors of low malignant potential
Obstet Gynecol 100(4) 671–6 DOI: 10.1016/S0029-7844(02)02171-3 PMID: 12383532

9 www.ecancer.org
 ecancer 2013, 7:379

30. Rao GG, Skinner E and Gehrig PA (2004) Surgical staging of ovarian low malignant potential tumors Obstet Gynecol 104(2)
261–6 DOI: 10.1097/01.AOG.0000133484.92629.88 PMID: 15291997

31. Kaern J, Tropé CG and Abeler VM (1993) A retrospective study of 370 borderline tumors of the ovary treated at the Norwegian
Radium Hospital from 1970 to 1982 Cancer 71(5) 1810–20 PMID: 8383580

32. Camatte S, Morice P and Thoury A (2004) Impact of surgical staging in patients with macroscopic ‘stage I’ ovarian border-
line tumours: analysis of a continuous series of 101 cases Eur J Cancer 40 1842–9 DOI: 10.1016/j.ejca.2004.04.017 PMID:
15288285

33. Snider DD, Stuart GC and Nation JG (1991) Evaluation of surgical staging in stage I low malignant potential ovarian tumors
Gynecol Oncol 40 129–32 DOI: 10.1016/0090-8258(91)90103-C PMID: 2010103

34. Cadron I, Leunen K and Van Gorp T (2007) Management of borderline ovarian neoplasms J Clin Oncol 25 2928–37 PMID:
17617524

35. Trimble EL and Trimble LC (1993) Epithelial ovarian tumors of low malignant potential Cancer of the Ovary, ed M Markman and
W Hoskins (New York: Raven Press) pp 415–29
36. FIGO Committee on Gynecologic Oncology (2009) Current FIGO staging for cancer of the vagina, fallopian tube, ovary, and
gestational trophoblastic neoplasia Int J Gynaecol Obstet 105(1) 3–4 PMID: 19322933

37. American Joint Committee on Cancer (2010) Ovary and primary peritoneal carcinoma AJCC Cancer Staging Manual 7th edn, ed
SB Edge, DR Byrd, CC Compton, et al (New York: Springer) pp 419–28

Review
38. Gherhenson D (2002) Clinical management potential tumours of low malignancy Best Pract Res Clin Obstet Gynaecol 6(4)
513–27 DOI: 10.1053/beog.2002.0308

39. Gershenson DM, Silva EG and Tortolero-Luna G (1998) Serous borderline tumors of the ovary with noninvasive peritoneal
implants Cancer 83(10) 2157–63 PMID: 9827720

40. Morice P, Camatte S and Rey A (2003) Prognostic factors for patients with advanced stage serous borderline tumours of the
ovary Ann Oncol 14(4) 592–8 DOI: 10.1093/annonc/mdg173 PMID: 12649107

41. Seidman JD and Kurman RJ (2000) Ovarian serous borderline tumors: a critical review of the literature with emphasis on prog-
nostic indicators Hum Pathol 31 539–57 DOI: 10.1053/hp.2000.8048 PMID: 10836293

42. Seidman JD and Kurman RJ (1996) Subclassi!cation of serous borderline tumors of the ovary into benign and malignant
types. A clinicopathologic study of 65 advanced stage cases Am J Surg Pathol 20 1331–45 DOI: 10.1097/00000478-199611000-
00004 PMID: 8898837

43. Uzan C, Kane A, Rey A and Gouy S (2010) Outcomes after conservative treatment of advanced-stage serous borderline tumors
of the ovary Ann Oncol 21(1) 55–60 DOI: 10.1093/annonc/mdp267

44. Barnhill DR, Kurman RJ and Brady MF (1995) Preliminary analysis of the behavior of stage I ovarian serous tumors of low
malignant potential: a Gynecologic Oncology Group study J Clin Oncol 13(11) 2752–6 PMID: 7595734

45. Faluyi O, Mackean M and Gourley C (2010) Interventions for the treatment of borderline ovarian tumours Cochrane Database
Syst Rev 9 CD007696 PMID: 20824864

46. Tropé C, Kaern J and Vergote IB (1993) Are borderline tumors of the ovary overtreated both surgically and systemically?
A review of four prospective randomized trials including 253 patients with borderline tumors Gynecol Oncol 51 236–43 DOI:
10.1006/gyno.1993.1279 PMID: 8276300

10 www.ecancer.org
 ecancer 2013, 7:379

47. Sutton GP, Bundy BN and Omura GA (1991) Stage III ovarian tumors of low malignant potential treated with cisplatin combi-
nation therapy (a Gynecologic Oncology Group study) Gynecol Oncol 41 230–33 DOI: 10.1016/0090-8258(91)90314-U PMID:
1869100

48. Kane A, Uzan C and Rey A (2009) Prognostic factors in patients with ovarian serous low malignant potential (borderline)
tumors with peritoneal implants Oncologist 14 591–600 DOI: 10.1634/theoncologist.2008-0263 PMID: 19487334

49. Zanetta G, Rota S and Chiari S (2001) Behavior of borderline tumors with particular interest to persistence, recurrence, and
progression to invasive carcinoma: a prospective study J Clin Oncol 19 2656–64

50. Uzan C, Kane A and Rey A (2010) Outcomes after conservative treatment of advanced-stage serous borderline tumors of the
ovary Ann Oncol 21 55–60 DOI: 10.1093/annonc/mdp267

51. Nam JH (2010) Borderline ovarian tumors and fertility Curr Opin Obstet Gynecol 22(3) 227–34 DOI: 10.1097/GCO.0b013e32833
84928 PMID: 20386444

52. Beiner ME, Gotlieb WH and Davidson B (2001) Infertility treatment after conservative management of borderline ovarian tumors
Cancer 92(2) 320–5 PMID: 11466685
53. Fortin A, Morice P and Thoury A (2001) Impact of infertility drugs after treatment of borderline ovarian tumors: results of a ret-
rospective multicenter study Fertil Steril 87(3) 591–6 DOI: 10.1016/j.fertnstert.2006.07.1503

54. Uzan C, Kane A and Rey A (2011) How to follow up advanced-stage borderline tumours? Mode of diagnosis of recurrence in a
large series stage II-III serous borderline tumours of the ovary Ann Oncol 22(3) 631–5 DOI: 10.1093/annonc/mdq414

Review
55. Tropé CG, Kaern J and Davidson B (2012) Borderline ovarian tumours Best Pract Res Clin Obstet Gynaecol 26(3) 325–36 DOI:
10.1016/j.bpobgyn.2011.12.006 PMID: 22321906

56. Zanetta G, Rota S and Lissoni A (2001) Ultrasound, physical examination, and CA 125 measurement for the detection of recur-
rence after conservative surgery for early borderline ovarian tumors Gynecol Oncol 81(1) 63–6 DOI: 10.1006/gyno.2000.6099
PMID: 11277651

57. NCCN Guidelines Version 1.2013 Epithelial ovarian cancer/fallopian tube cancer/primary peritoneal cancer

58. Centers for Disease Control and Prevention (CDC) (2010) US Medical Eligibility Criteria for contraceptive use MMWR Recomm
Rep 59(RR-4) 1–86

59. Mascarenhas C, Lambe M and Bellocco R (2006) Use of hormone replacement therapy before and after ovarian cancer diagno-
sis and ovarian cancer survival Int J Cancer 119(12) 2907–15 DOI: 10.1002/ijc.22218 PMID: 16998830

60. Silva EG, Gershenson DM and Malpica A (2006) The recurrence and the overall survival rates of ovarian serous borderline neo-
plasms with noninvasive implants is time dependent Am J Surg Pathol 30 1367–71 DOI: 10.1097/01.pas.0000213294.81154.95
PMID: 17063075

61. Cadron I, Amant F and Van Gorp T (2006) The management of borderline tumours of the ovary Curr Opin Oncol 18 488–93 DOI:
10.1097/01.cco.0000239889.98289.ce PMID: 16894298

11 www.ecancer.org