Best Practice & Research Clinical Obstetrics and Gynaecology 26 (2012) 325336

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Best Practice & Research Clinical

Obstetrics and Gynaecology
journal homepage: www.elsevier.com/locate/bpobgyn

Borderline ovarian tumours

Claes Gran Trop, MD, PhD, Professor a, b, *, Janne Kaern, MD, PhD, Senior
Consultant a, Ben Davidson, MD, PhD, Ass. Professor b, c
a

Department of Gynaecological Oncology, Oslo University Hospital, The Norwegian Radium Hospital, P.O. Box 4953 Nydalen,
N-0424 Oslo, Norway
b
Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
c
Division of Pathology, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway

Keywords:
borderline ovarian tumours
clinical outcome
epidemiology
management
surgery
fertility
prognostic factors

Borderline ovarian tumours account for 1020% of all epithelial

ovarian cancer. Historically, standard primary surgery has included
borderline ovarian tumours, omentectomy, peritoneal washing
and multiple biopsies. As one-third of borderline ovarian tumours
are diagnosed in women under the age of 40 years, fertilitysparing treatment has been more frequently used in the past 10
years. Fertility drugs are well tolerated in women with infertility
after fertility-sparing surgery. Careful selection of candidates is
necessary. Laparoscopic techniques can be used, but should be
reserved for oncologic surgeons. This conservative treatment
increases the rate of recurrence, albeit with no effect on survival.
The pregnancy rate is nearly 50%, and most are achieved spontaneously. These women should be closely followed up. The question
is whether this is acceptable from a gynaecologic oncologic point
of view. For this reason, we will discuss recently published studies
and gynaecologic oncologic concerns about the mode of fertilitysparing surgery and its consequences.
2012 Elsevier Ltd. All rights reserved.

Introduction
Borderline ovarian tumours (BOT) were rst described as a separate group in 1929 by Taylor,1
characterised by histopathologic features and biologic behaviour intermediate between clearly
benign and frankly malignant ovarian tumours.

* Corresponding author. Department of Gynaecological Oncology, Oslo University Hospital, The Norwegian Radium Hospital,
P.O. Box 4953 Nydalen, N-0424 Oslo, Norway. Tel: 47 22 93 56 84; Fax: 47 22 93 42 48.
E-mail address: c.g.trope@medisin.uio.no (C.G. Trop).
1521-6934/$ see front matter 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bpobgyn.2011.12.006

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In 1973, this group of tumours was accepted by the International Federation of Gynecology and
Obstetrics (FIGO) as carcinoma of low malignant potential,2 and from 1973 by the World Health
Organization as BOT,3 the term we use today. MostBOT are comparable to benign cysts, but 1015% may
develop a clinical aggressive behaviour, as invasive carcinoma, and have the potential to spread beyond
the ovary and have the ability to recur as carcinomas, resulting in poor patient prognosis.
The histologic diagnosis of BOT is based on criteria described by Hart and Norris4 and detailed by Scully5:
epithelial cellular proliferation (stratication of the epithelial lining of the papillae, multi-layering of the
epithelium, mitotic activity and nuclear atypia) without stromal invasion. The absence of obvious stromal
invasion is the principal diagnostic criteria for BOT. The degree of microinvasion accepted, however,
depends on the individual pathologist with problematic inter- and intra-observer reproducibility.
Incidence
Borderline ovarian tumours represent between 10 and 20% of all epithelial ovarian malignancies.6
At the Norwegian Radium Hospital and other large institutions, the reported prevalence is lower, at
12%,7,8 probably reecting that women with BOT are treated at local hospitals. Few population-based
studies on BOT are available. Between 1970 and 1993, a total of 2343 women were diagnosed with BOT
in Norway.9 The age-adjusted incidence rate has increased since 1970 to 4.8 per 100,000 persons per
year between 1995 and 2004. Nearly the same trend has been reported in Sweden.10
In a recent review of 6362 women with BOT by Trillsch et al.,11 78.9% of women had stage I disease
and few had abdominal spread, whereas stage IV disease represented an exception. These gures are in
agreement with a large retrospective Norwegian study of 370 women with BOT treated at the
Norwegian Radium Hospital between 1970 and 1982.8 In the latter study, 311 women (84%) were
diagnosed with stage I disease, 20 women (6%) with stage II, and 39 women (10%) at stage III. None had
stage IV disease. Median age at diagnosis was 40 years (27% were younger than 40 years of age)
compared with about 60 years for women with invasive carcinoma,12,13 and the incidence rate
increased with age up to 4549 years, after which the rate stabilised. Between 1970 and 1993 in
Norway, 93% of women were diagnosed with localised tumours. The proportion of tumours with
distant metastases increased from 2.7% between 1970 and 1973 to 6.6% between 1989 and 1993.9
Epidemiology
Besides age, women with BOT do not seem to differ statistically from women with ovarian carcinoma in epidemiologic characteristics. Primary infertility and nulliparity increase the risk of BOT,
whereas oral contraceptives, pregnancies and breast feeding are protective factors.14
Pathogenesis
Recently, a new theory has been developed describing a subset of serous ovarian cystadenomas that
evolve through serous BOT to low-grade epithelial ovarian cancer1518 (Fig. 1). This low-grade
pathway involves mutations in the B-raf and K-ras signalling pathway. The pathway involves serous
BOT as a precursor mimicking the adenocarcinoma sequence in colorectal cancer, in which carcinoma
evolves through a continuum of histological precursor lesions.1921 Only 2% of all serous BOT progress
to carcinoma via the low-grade pathway.17
This is in contrary to the high-grade pathway that involves frequent TP53 mutations and very
seldom B-raf and K-ras mutations. Most serous ovarian carcinomas belong to the typical high-grade
pathway, with no known precursor. TP53 mutations are most often absent in typical serous BOT and
micropapillary serous BOT compared with 88% prevalence in invasive serous carcinomas.2224
The sequence of malignant transformation from benign mucinous tumours to carcinoma represents
transitional stages of mucinous carcinogenesis. Three types of ras oncogenes exist (K, N and H) and
mucinous BOT have a higher frequency of K-ras mutation than that of mucinous cystadenoma, but a lower
rate than that of mucinous carcinoma. Foci suggesting in-situ malignant changes are often identied in
mucinous BOT associated with invasion, and the transition may be identied microscopically in some
cases.24,25 It is for the moment unclear whether BRCA1 and BRCA2 mutations increase the risk of BOT.12

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Fig. 1. Low-grade pathway: frequent B-raf and K-ras mutations (6168%); low cellular proliferation; gradual 53 mutations (70%); high
cellular proliferation, high chromosomal instability; frequent HLA-G expression; 5-year survival about 30%. APST, atypical proliferative
serous tumours; MPSC, micropapillary serous carcinoma; SBT, serous borderline ovarian tumour. Published with permission.17

Histology
Nearly all BOT are of the mucinous or serous type; the remaining 45% are of endometrioid, clear
cell, mixed, and transitional cell or Brenner type. Serous BOT and mucinous BOT make up 4353% and
42.552% of all BOT, respectively.8,9,11,26
Serous borderline tumours
Serous borderline tumours are bilateral in about one-third of cases.8,11 Extra-ovarian spread as peritoneal implants is frequent (35%). Most implants are non-invasive, but invasive implants are found in 20
25% of cases.27 Bilaterality and non-invasive implants do not predict worse outcome compared with the
presence of invasive implants.11,2730 Invasive implants may progress to invasive carcinoma, whereas
most peritoneal implants will remain stable or regress after removal of the main ovarian tumour.29,31
Women with serous BOT without invasive implants have 10-year survival of 95% compared with 60
70% for women with invasive implants.12 Women with invasive implants develop progressive disease in
about 30% of cases, whereas only about 2% of women without invasive implants will progress.24,32
Controversy exists about whether tumours with invasive implants are more likely to have micropapillary features within the primary BOT at diagnosis.28,29
Mucinous borderline tumours
Mucinous borderline tumours are histologically classied as intestinal (85% of mucinous BOT) or
endocervical (15% of mucinous BOT) (former Mllerian).11,30 The ovarian tumours of the intestinal
subtype can be large, and are nearly always unilateral. In case of bilaterality, the woman should be
further examined for a primary intestinal tumour. The endocervical subtype might be bilateral and
associated with endometriosis and mixed-BOT. Both subtypes can present with intra-epithelial
carcinoma, micro-invasion with less than 10 mm2,8 Extraovarian spread is infrequent (1015%) and
nearly always as pseudomyxoma peritonei. The condition may occur in any type of intra-abdominal
mucinous neoplasm but occurs most often in association with mucinous BOT.33 Most of these represent dissemination from a mucinous appendix tumour. An appendectomy should be carried out at
primary surgery for intestinal M-BOT. All M-BOT might recur as invasive adenocarcinoma, especially

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when only ovarian cystectomy rather than salpingo-oophorectomy has been carried out. This might be
explained by missing an invasive component owing to inadequate histopathologic evaluation of these
large tumours. Therefore, unilateral salpingo-oophorectomy is recommended in mucinous BOT.11,14
Prognostic factors
As BOT in general has an excellent survival, it might be difcult to identify variables that improve
survival. As many women with BOT are of reproductive age at diagnosis, more conservative treatment
preserving the childbearing ability is desirable. International Federation of Gynecology and Obstetrics stage
is the strongest prognostic factor for recurrence and survival for BOT, as well as for invasive ovarian cancers.
Micropapillary histology was reported as an additional risk factor for serous BOT, but this issue is controversial, as poor prognosis is only seen if this histology is associated with invasive implants.28,3436 Tumours
with evidence of stromal invasion of less than 10 mm2 behave clinically as BOT and are today classied as
BOT.22,24,3740 In the retrospective study from the Norwegian Radium Hospital,41 370 BOT were treated
between 1970 and 1982 and the follow up was complete, with a median follow-up time of 152 months
(range 6354 months). By multivariate analysis, the only three independent prognostic factors for diseasefree and long-term survival were FIGO stage (P < 0.0001), histologic type (P < 0.05) and age (P < 0.005). In
another study of the same women, including DNA ploidy, the women could be divided into risk groups.41
The low-risk group (100% disease-free survival) was characterised by stage I disease, diploid serous BOT or
mucinous BOT and age less than 40 years. The high-risk group (75% or higher risk of dying of disease) had
aneuploid serous BOT or mucinous BOT, stage II-III disease and age older than 70 years. Deoxyribonucleic
acid ploidy was the strongest prognostic factor in BOT in the study by Kaern et al.,41 but this has unfortunately not been reproduced by others.42,43 Lymph-node involvement could not convincingly be conrmed
to be an independent risk factor.35,41,44,45
Symptoms
Limited information exists about symptom registration by women with BOT at diagnosis. Most
women may be asymptomatic and a pelvic mass discovered at routine pelvic examination. Symptoms
are less common compared with symptoms registered for women with invasive ovarian cancer,
although 75% of women with BOT may have at lease one symptom as abdominal pain or discomfort,
bowel irregularity and persisting fatigue or weight loss.46,47
Standard treatment
The diagnosis of BOT cannot be determined before surgery. Intraoperative frozen section diagnosis
of BOT is often difcult, even for experienced pathologists. Frozen sections may be useful for
discrimination between BOT and epithelial ovarian cancer and benign tumour (over-diagnosis less than
10%), but not for discrimination between BOT and epithelial ovarian cancer (under-diagnosis in 2530%
of women).48,49 Less than 50% of women with BOT will have a complete surgical staging, this without
obvious inuence on survival.
The standard guidelines for primary surgery in BOT are similar to these for invasive ovarian carcinomas;
removal of all macroscopic disease and proper surgical staging: hysterectomy with bilateral salpingooophorectomy, multiple peritoneal biopsies and peritoneal washing with cytology. For mucinous BOT,
appendectomy should also be carried out.33 Lymph-node sampling has not been part of the standard
procedure. A recently published German study reported systematic lymph-node dissection in 18.9% of
women with BOT.11 Involvement of lymph nodes, even with upstage, do not inuence recurrence or
survival rate.8,50 Lymph-node involvement is rarely seen in M-BOT. Lymphadenectomy can be omitted
even for stage II and III disease, as there is no difference in the recurrence or survival rate (Fig. 2).50,51
Restaging procedures
Despite the fact that experts have recommended comprehensive surgical staging for many years, most
women referred to university or comprehensive cancer centres after primary surgery have incomplete

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329

surgery. Another common event is that malignancy is not suspected at the initial operation, and therefore
the abdomen is not properly explored. Should this woman undergo re-operation? Snider et al.52 upstaged
ve out of 27 women with stage I disease. None of the 12 women with mucinous BOT were upstaged,
whereas ve out of 13 women with serous BOT were upstaged. Mucinous BOTgrossly conned to one ovary
are probably unlikely to be upstaged at a restaging procedure. If evidence of extra-ovarian disease exists,
complete surgical staging and appendectomy are indicated. Mucinous BOT with abdominal spread are in
50% claimed to arise in the appendix or simultaneously in one or both ovaries.53,54 For serous BOT, it is
reasonable to do a second operation, as lymph-node involvement has been reported in about 20% in
apparent stage I tumours, with even higher incidence in more advanced stages.45 At the Norwegian Radium
Hospital, we recommend restaging if the women are insufciently staged at primary operation, in agreement with Cadron et al.51 and Trimble and Trimble.55 We also believe that the decision to restage must be
individualised, taking into consideration the adequacy of the previous abdominal exploration, the tumour
subtype, and potential treatment of residual disease, as well as the level of concern for both the woman and
the clinician, even if there is little proof that restaging operations have an effect on survival.11,50,5658
Laparoscopy
Laparoscopic treatment has become an attractive approach for benign ovarian tumours (pelvic
mass). The development of the laparoscopic techniques, with the use of endo-bag, gives less risk of
spillage during surgery and less port-side metastases. For conservatively treated women wishing to
preserve fertility, this is a more favourable approach, and has short postoperative recovery, fewer
adhesions and improved cosmetic results.59 Cyst rupture and incomplete staging occur signicantly
more frequently by laparoscopy compared with laparotomy (33.9% v 12.4%),60,61 but do not inuence
survival. The laparoscopic treatment may result in higher recurrence rate, which must be discussed
with the woman. The woman should agree to close follow up and repeated surgery.51,62 Other concerns
are port metastases63 and improper staging.61
Postoperative treatment of borderline ovarian tumours
Today, there is no proven benet from adjuvant therapy (chemotherapy or radiotherapy) even in
advanced stage disease and in the presence of invasive implants.14,32 No randomised-controlled studies

Fig. 2. Recommendation: treatment of borderline ovarian tumours. Modied from Trillsch et al.11 and Cadron et al.51 with permission.

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have evaluated the efcacy of chemotherapy in advanced stage BOT with residual disease. Cisplatinbased therapy in serous BOT with residual disease have shown high response rates but modest
effect on long-term survival.14,64 In case of recurrences where transformation to an invasive histology
has occurred, consideration of platinum-taxane-based chemotherapy is reasonable. The molecular
changes transforming BOT to invasive ovarian carcinoma may be claried in the future with the
possibility of blocking the different steps in the carcinogenesis. Today, we know that both serous BOT
and low-grade serous carcinoma frequently present with B-raf and K-ras mutations.11
Survival
Overall survival for women with BOT is excellent: 90100% in most reports depending on age at
diagnosis, FIGO stage and histologic type.11,26,51,62,65,66 Trillsch et al.11 reported a 5-year overall survival
rate of almost 100% in early stage disease (FIGO I-II) and between 86% and 92% in more advanced
disease (FIGO III-IV). In a Norwegian population-based study,67 the age-adjusted 1-, 3-, 5- and 10-year
relative survival rates of women with mucinous BOT were 98%, 97%, 97%, and 95%, respectively, and for
women with serous BOT 96%, 93%, 90%, and 90%, respectively. The relative risk of dying increased with
higher age at diagnosis. The 5-year relative survival for women aged between 0 and 44 years was 99%
compared with 85% for women aged 7589 years. Nearly the same gures are reported by Sherman
et al.,12 with better survival for younger women and slightly better survival for serous tumours
compared with mucinous tumours, although mucinous tumours in advanced stage had the poorest
long-term survival (85.5%).12
Seidman and Kurman35 summarised 97 reports, including a total of 4129 women with serous BOT,
and showed a disease-specic survival rate of 99% for stage I disease, and 95.3% for stage III disease
(mean follow up of 7 years).35 The 5-year survival was 98% for women with serous BOT with noninvasive implants and 33% for those with invasive implants.68
Conservative surgery
The median age of diagnosis for women with BOT is 40 years, and nearly one-third are younger than
40 years. Thus, preservation of childbearing potential is an important issue for many of these women.
To select women for fertility-sparing surgery without risk of reduced long-term survival is a challenge
for the gynaecologic oncologist30,69 (Fig. 2). Conservative surgery is dened as complete staging in
which the uterus, and at least a part of one ovary, are preserved11,62 (Fig. 2).
Although the standard treatment for all women with BOT is at least bilateral salpingooophorectomy, many young women with stage Ia tumours who have not completed childbearing
can be safely treated with unilateral salpingo-oophorectomy after comprehensive surgical staging,
thereby preserving the fertility potential. At least as important as the fertility issue, however, is
whether we can reduce the morbidity caused by radical surgery and whether a more conservative
approach is a safe alternative regarding cancer prognosis.51 Recent studies from the Norwegian Radium
Hospital8 and Gynecologic Oncology Group65 have shown that preservation of reproductive organs is
feasible. Relapse rates after bilateral salpingo-oophorectomy range between 0% and 20%. This rate
varies between 12% and 58% for cystectomy and between 2.5% and 5.7% for radical surgery. Relapses
can also occur late, and recurrences as late as 39 years after initial treatment have been reported.51,34
Predictors of relapse are resection margins containing tumour cells.70 The frequency of persistence or
recurrence in 35 patients with serous-BOT treated by unilateral cystectomy, bilateral cystectomy or
unilateral cystectomy with contralateral oophorectomy or salpingo-oophorectomy was retrospectively
investigated by Lim-Tan et al.71 Conservative surgical treatment was carried out either because the
women were young and wanted to preserve their fertility or because the nature of the tumour was not
determined at the time of surgery. Thirty-three women had stage I disease (19 stage Ia, 10 stage Ib and
four stage Ic), and two had stage III disease. Although 60% of the women had additional and in some
cases denitive operations within relative short periods after initial cystectomy or cystectomies, 21 had
conservation of ovarian tissue and were followed on average for 7.5 years. All women with stage I
disease were alive without evidence of disease after surgical treatment alone. The presence of
persistent or recurrent disease correlated with multifocality and involvement of resection margins.

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Multifocality may be a strong predictor of failure of cystectomy to control the disease. No recurrence of
disease was seen in ovaries from which a single cyst had been removed with negative resection
margins. Extensive sampling of the resection margins of ovarian cysts is important.71
For many women with BOT, fertility is an important issue. It is, therefore, essential to discuss with
these young women the advantages and disadvantages between conservative and radical surgery.
Conservative surgery preserves fertility and hormonal function, but unfortunately with high risk of
recurrence.
In women with obvious stage I disease, unilateral salpingo-oophorectomy or cystectomy has from
previous studies been shown to be safe. This has also been conrmed for women with advanced-stage
disease on the assumption of close follow up.
Even for women with advanced disease, conservative surgery might be considered after informed
consent. The recurrence rate is high, and invasive and even non-invasive implants may recur up to 15%
as invasive OC without negative inuence on survival.34,56,72,73
Treatment at recurrent disease after conservative treatment
Early detected recurrences are curable with repeated surgery,11,34,51 and therefore conservative
treatment might again be considered in women with recurrent disease if fertility still is an issue and the
woman is informed about the high risk of recurrence, and agrees on close follow up, accepting repeated
surgery.51,62 If invasive implants are diagnosed, this procedure could not be recommended. In any case
of recurrent disease, secondary debulking surgery is important, as women suboptimally debulked have
poor survival.11,51,74
Fertility after conservative management of borderline ovarian tumour
Infertility is frequently observed in women with BOT. A history of infertility before diagnosis has been
reported in 1035% of women.7577 To allow conservative surgery, careful evaluation of the extent of
disease by the gynaecologist at the time of operation and meticulous examination of the cystectomy
specimen by the gynaecologist and pathologist are desirable to determine the prognosis after cystectomy. In a study by Morris et al.,76 one woman who had disease-related death was not staged properly.
In a meta-analysis by Maltaris et al.,78 1483 women had BOT, of whom 656 were treated conservatively
(44.2%). A total of 196 women became pregnant and 111 relapsed after unilateral salpingooophorectomy; only one woman died from the disease (0,15%). The investigators, therefore, suggest
that conservative surgery is justiable for some women with a good prognostic index. Unilateral
oophorectomy, omentectomy and appendectomy in stage Ia diploid mucinous BOT are indicated for
young women who wish to preserve fertility (Fig. 2). In stage Ia diploid serous BOT, the same procedure is
safe if the contralateral ovary is macroscopically normal. Careful inspection of a macroscopically normal
contralateral ovary should be sufcient in young women with stage Ia disease who wish to remain fertile.
Surgery itself can impair the fertility function by loss of ovarian tissue, pelvic scarring and adhesions
blocking the fallopian tube. Post-surgery fertility factors, such as ovulation, fallopian tubes and sperm
factors should be investigated and treated if necessary. About one-third of women undergoing
conservative surgery for BOT will be able to conceive with no negative inuence of pregnancy on the
disease.60,72,77,79 Ovulation induction is often required in order to conceive.80 The role of ovulation
(in-vitro [IVF] fertilisation) drugs in BOT is currently under debate.77,8084
Recently, a large nationwide cohort study of 19,146 subfertile women in the Netherlands who
received IVF drugs between 1983 and 1995 and a comparison group of 6,953 subfertile women who
were not treated was published. After a median follow up of 15 years, a total of 77 ovarian malignancies
were observed in the cohort, including 42 women with epithelial ovarian cancer and 35 women with
BOT. Sixty-one ovarian malignancies were observed in the IVF-group and 16 in the unexposed (control)
group. The ratio hazard for epithelial ovarian cancer and BOT was 1.67 (0.74 to 3.75) and 4.25 (1.27 to
14.18), respectively.85 The conclusion of Burger et al.85 was that IVF increases the risk of BOT.
A worrying nding of their study is the increased risk of epithelial ovarian cancer and BOT even after 15
years of follow up. Fasouliotis et al.80 found no perceptible negative effect of previous BOT on pregnancy rates after IVF. The same was shown by Fortin et al.84 in a study of 30 women treated with IVF

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drugs for infertility after conservative surgery. Thirteen pregnancies were observed. Disease in four
women recurred. All recurrences were BOT on a remaining ovary that had been treated by surgery
alone. All women are currently disease-free after secondary surgery. Fortin et al.84 concluded that IVF
drugs can be used safely in women who develop infertility after conservative treatment of BOT. Because
of the low number of women treated with IVF drugs, Norwegian Radium Hospital guidelines are to
proceed with caution, and only women with early stage BOT are permitted to be treated with IVF drugs.
The latest development regarding reproduction and BOT is cryopreservation.86 Women who have
their ovaries removed because of large stage Ib BOT now have a possibility of becoming pregnant.
Biopsies from normal ovarian cortex can be taken during the primary operation. In 2004, a live birth
after a fresh ovarian tissue transplant in a primate was reported.87 Donnez et al.86 described in 2004
a live birth after orthotopic auto-transplantation of cryopreserved ovarian tissue. Their ndings opened
new possibilities for young women facing premature ovarian failure.
Women with reduced fertility after surgery can consider ovarian stimulation, egg retrieval and egg
freezing. Ovarian stimulation and exposure to high oestrogen exposure do not seem to increase the risk
for recurrence. Nor do pregnancies have negative inuence on survival.72,77
To assure future fertility preservation in women with BOT, the gynaecologic oncologist should
collaborate closely with the reproductive endocrinologists even before surgery. Until more mature data
exist, the general recommendation is a limited number of stimulation cycles, only for stage I patients. In
case of bilateral salpingo-oophorectomy, cryopreservation of ovarian cortex biopsy from the less
affected ovary could be considered, although this is not always technically possible.11,51
Follow up
Follow up should be long term and lifelong, because recurrences may develop after more than 15 years.
In conservatively treated women, close follow up is crucial, with special attention to the remaining ovary. It
is still debated if the remaining ovary (and uterus) should be removed after the family is completed. For
low-risk BOT, there is no indication for this procedure, but in women with high-risk of recurrence, the
procedure is optional, the alternative being to wait until recurrence or carry out radical surgery. Many
women will choose radical surgery when the family is completed because of psychological stress.
The general recommendation is follow up every 3 months during the rst 2 years and then every 6
months for the next 3 years and annually thereafter. The women is followed with pelvic examination,
transvaginal ultrasound and calcium 125 measurement14,51 (Fig. 2).
Future direction of borderline ovarian tumour
A key issue for future research on BOT concerning epidemiology is the identication of risk factors for
invasive implants, recurrences and death, and also the identication of predisposing heritable factors.
For clinical management, improved methods for preoperative and intraoperative diagnosis should
be considered, in addition to the role of laparoscopic surgery in removal of complex cysts, improved
methods for distinguishing metastases from BOT, and determination of risk associated with conservative treatment.
For pathology and molecular biology, molecular studies are needed to assess the relationship
between serous BOT, low-grade serous carcinoma and high-grade serous carcinoma. Molecular studies
are also needed to aid in the characterisation of implants; and studies need to be conducted to
determine the biology of microinvasive BOT and the clinical signicance of long-term follow up.
Conclusion
Borderline ovarian tumours are ovarian tumours with good prognosis that account for 1020% of all
epithelial ovarian cancer. Historically, standard primary surgery included bilateral salpingo-oophorectomy,
omentectomy, peritoneal washing and complete peritoneal resection of macroscopic lesions or multiple
biopsies. In cases of M-BOT, women are also treated with appendectomy. As one-third of BOT are diagnosed
in women younger than 40 years, however, fertility-sparing treatment (i.e. preservation of the uterus and at
least part of one ovary) has been increasingly used in the past 10 years. Fertility drugs are well tolerated in

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333

women with infertility after fertility-sparing surgery. Careful selection of candidates is necessary. Laparoscopic techniques can be used, but are reserved for oncologic surgeons. This conservative treatment
increases the rate of recurrence but without any effect on survival. The spontaneous pregnancy rate is nearly
50%, and most are achieved spontaneously. Spontaneous pregnancy can occur after conservative treatment
of advanced-stage BOT (with non-invasive implants). These women should be closely followed up. Further
research has to concentrate on clinical risk-factors, histopathological markers and pathogenesis to guarantee the best clinical management for women with BOT.
Conict of interest statement
None declared.
Practice points
 BOT are ovarian tumours with good prognosis that account for 1020% of all epithelial ovarian
cancer.
 Historically, standard primary surgery included bilateral salpingo-oophorectomy, omentectomy, peritoneal washing and complete peritoneal resection of macroscopic lesions or
multiple biopsies.
 In case of mucinous BOT, women are also treated with appendectomy.
 Adjuvant therapy for the treatment of BOT has no proven benet.
 As one-third of BOT are diagnosed in women younger than 40 years, fertility-sparing treatment (i.e. preservation of the uterus and at least part of one ovary) has been increasingly used
in the past 10 years.
 Fertility drugs are well tolerated in women with infertility after fertility-sparing surgery.
Careful selection of candidates is necessary.
 Laparoscopic techniques can be used, but are reserved for oncologic surgeons.
 Spontaneous pregnancy can occur after conservative treatment of advanced stage BOT (with
non-invasive implants).
 These women should be closely followed up

Research agenda
Epidemiology
 Identify risk factors for invasive implants, recurrences and death.
 Identify predisposing heritable factors.
Clinical management
 Improve methods for preoperative and intraoperative diagnosis.
 Further explore the role of laparoscopic surgery in the removal of complex cysts
 Improve methods for distinguishing metastases from BOT and determine risk associated with
conservative treatment.
Pathology and molecular biology
 Conduct molecular studies to assess the relationship between serous BOT, low-grade serous
carcinoma, and high-grade serous carcinoma.
 Conduct molecular studies to aid in the characterisation of implants.
 Conduct studies to determine the biology of microinvasive BOT and the clinical signicance of
long-term follow up.

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Acknowledgement
We wish to thank Mrs. Gry Seppola for technical assistance and gratefully acknowledge the nancial
support from the Inger and John Fredriksen Foundation for Ovarian Cancer Research.
References
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results obtained in 19691972, inclusive. FIGO. Stockholm, Sweden, Editorial ofce, Radiumhemmet, 1973.
3. Serov SF, Scully RE & Sobin LH. International histological classication of tumors, no 9. Histoloigcal typing of ovarian tumours.
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