DOI: 10.1111/tog.

12107 2014;16:185–91
The Obstetrician & Gynaecologist
Review
http://onlinetog.org

Risk-reducing surgery for women at high risk of epithelial

ovarian cancer
a,
Eve Maria Geraldine Gaughan BSc MB BCh BAO MRCOG MRCPI, * Thomas Anthony Walsh BSc MB BCh BAO MRCOG
b
MRCPI
a
Clinical Fellow in Gynaecology Oncology, Mater Miseracordiae Hospital, Eccles Street, Dublin 1, Ireland
b
Consultant Gynaecologist Oncologist with special interest in gynaecology oncology, Mater Miseracordiae Hospital, Eccles Street, Dublin 1, Ireland
*Correspondence: Eve Maria Geraldine Gaughan. Email: evegaughan@yahoo.co.uk

Accepted on 25 February 2014

Key content  To be able to appropriately counsel those at high risk of ovarian

 The lifetime risk of ovarian cancer in the general population is 1.4% cancer regarding modifiable risk factors, screening and the role of
but women with hereditary ovarian cancer syndromes have a lifetime risk-reducing surgery, including prophylactic bilateral
probability as high as 25–60% for developing epithelial ovarian cancer. salpingo-oophorectomy and its alternatives such as tubal ligation
 Screening has not been found to be associated with a statistically and salpingectomy.
significant reduction in mortality from ovarian cancer and cannot  To understand the limitations of current screening modalities for
be routinely recommended even for women at high risk. Serum the reduction of ovarian cancer risk.
CA125 levels are only elevated in 50–60% of stage I ovarian cancers
Ethical issues
and interval cancers may develop between screening visits. 
 Studies show a 4–20% risk of finding an occult malignancy at the
Ethical concerns exist pertaining to the performance of screening
modalities, which have not been found to significantly
time of risk-reducing bilateral salpingo-oophorectomy.
reduce mortality from ovarian cancer and can cause harm
 Studies support the efficacy of risk-reducing bilateral
in terms of psychological and surgical morbidity from
salpingo-oophorectomy in significantly reducing the risk of
false-positive results.
gynaecological and breast cancer in women who carry BRCA1 or  For those with a positive family history of ovarian cancer but no
BRCA2 mutations.
 Women undergoing risk-reduction bilateral salpingo-
genetic cancer syndrome, the discussion to perform risk-reducing
surgery should be balanced against the risk of surgical morbidity
oophorectomy should be counselled about the effects of early
and early menopause. Individual patient risk factors must be
menopause and the available management options including
considered in the decision-making process.
hormone replacement therapy.
Keywords: bilateral salpingo-oophorectomy / BRCA gene / cancer /
Learning objectives

epithelial ovarian cancer / risk-reducing surgery
To be able to identify those women at increased risk of
ovarian cancer.

Please cite this paper as: Gaughan EMG, Walsh TA. Risk-reducing surgery for women at high risk of epithelial ovarian cancer. The Obstetrician & Gynaecologist
2014;16:185–91.

survival rate is largely due to the spread of cancer beyond the

Introduction
ovary at time of diagnosis in 75% of patients.2
Ovarian cancer is the second most common gynaecological
malignancy and the most common cause of gynaecological
cancer death. The majority of ovarian tumours (90%) arise
Risk factors
from epithelial cells and the remainder are derived from The strongest known risk factor is a family history of the
other ovarian cell types (germ cell and sex cord disease, which is present in about 10–15% of women with
stromal tumours). ovarian cancer.3 The risk of ovarian cancer is increased when
The lifetime risk of ovarian cancer in the general the family history suggests a sporadic case but is substantially
population is 1.4%. The median age at diagnosis is 57.1 greater when there is a hereditary cancer syndrome. Women
Despite the good prognosis associated with early-stage with a single family member affected by epithelial ovarian
disease, overall 5-year survival is less than 45%. This poor cancer have a 4–5% risk, while those with two affected

ª 2014 Royal College of Obstetricians and Gynaecologists 185

 Risk-reducing surgery for women at high risk of epithelial ovarian cancer

relatives have a 7% risk of developing the disease. In contrast, 30 years after cessation of OCP use although the effect
women with hereditary ovarian cancer syndromes defined as attenuated over time. For women with 5 years’ use of OCP
having at least two first-degree relatives with epithelial the risk reduction in ovarian cancer within 10 years of
ovarian cancer, have a lifetime probability as high as discontinuing OCPs versus 20–29 years after discontinuing
13–50% for developing epithelial ovarian cancer.3 OCPs was 29% and 15%, respectively.9
Hysterectomy was associated with a 34% reduction in the
Breast ovarian cancer syndrome risk of ovarian cancer in a meta-analysis of 12 case–
Women with BRCA gene mutations have a greatly increased control studies.10
risk of ovarian and breast cancer. The estimated risk of Women who had undergone tubal ligation had a 34%
ovarian cancer is 35–46% for BRCA1 mutation carriers and reduction in ovarian cancer risk in a meta-analysis of 13
13–23% for BRCA2 mutation carriers.3 BRCA mutations may case–control studies.11 In addition, a case–control study by
account for up to 90% of hereditary ovarian cancers. the Hereditary Ovarian Cancer Clinical Study Group12 found
Tumours in BRCA carriers are more likely to be invasive that tubal ligation lowered the rate of ovarian cancer among
serous adenocarcinomas when compared with non-BRCA BRCA1 carriers by 60%, after adjustment for oral
age-matched controls (odds ratio [OR] 1.84, 95% confidence contraception use, parity, history of breast cancer and
interval [CI] 1.21–2.79) and unlikely to be borderline ethnic group. A history of both OCP use and tubal ligation
or mucinous.4 was even more protective, with 72% risk reduction. The
The stage at presentation of ovarian cancer is similar for mechanism for this reduction is unknown but may coincide
BRCA carriers and the general population – approximately with research that suggests that tubal neoplasia is a precursor
70% of patients present with stage III/IV disease.5 Ovarian for serous ovarian cancer.13
cancers in BRCA mutation carriers are more likely to be of Breastfeeding for a cumulative duration of more than
higher grade than ovarian cancers in age-matched controls.4 12 months compared with never breastfeeding is associated
However, BRCA mutation carriers, particularly BRCA2 with a statistically significant decrease in the risk of epithelial
carriers, have a better prognosis than non-carriers. Studies ovarian cancer (OR 0.72, 95% CI 0.54–0.97).14
have shown that stage, grade and histology-adjusted 5-year Current available data suggest that an association between
all-cause mortality was 45% in BRCA1 carriers versus 47% in ovulation induction and ovarian cancer does not indicate
non-carriers (hazard ratio [HR] 0.73, 95% CI 0.64–0.84) and necessarily a causal effect. Infertility alone is an independent
36% versus 47% for BRCA2 carriers versus non-carriers (HR risk factor. Nulliparous women may harbour a higher risk of
0.49, 95% CI 0.39–0.61).6 ovarian cancer irrespective of their use of fertility drugs. A
2013 Cochrane review by Rizzuto et al.15 concluded that
Other high-risk genetic syndromes there was no convincing evidence of an increase in the risk
Lynch syndrome, also called hereditary nonpolyposis of invasive ovarian tumours with fertility drug treatment.
colorectal cancer (HNPCC), is associated with cancer There may be an increased risk of borderline ovarian
diagnosis at an early age and the development of multiple tumours in subfertile women treated with in
cancer types, particularly colon and endometrial cancer. vitro fertilisation.
Women with Lynch syndrome have a 3–14% lifetime risk of The risk of ovarian cancer is slightly increased in women
ovarian cancer.7 HNPCC carriers account for 1% of ovarian with a history of endometriosis. The risk of malignant
cancers.8 Peutz–Jeghers syndrome is associated with a 20% transformation of ovarian endometriosis was estimated at
risk of developing ovarian cancer but many of these are 2.5%.16 Endometriosis-associated ovarian cancer appears to
non-epithelial sex cord stromal tumours. occur in younger and nulliparous patients. These tumours
are well-differentiated low-stage carcinomas that have a
Other risk factors higher survival rate.
The risk of ovarian cancer appears to be decreased in There is a small increased risk associated with polycystic
women with a history of pregnancy, use of the oral ovary syndrome (OR 2.52, 95% CI 1.08–5.89).17
contraceptive pill (OCP), breastfeeding, tubal ligation Obesity appears to increase the ovarian cancer risk. A
and hysterectomy. systematic review reported a small, but statistically
A history of ever using the OCP is associated with a significant, association between obesity and ovarian cancer
significant reduction in risk of developing ovarian cancer (OR 1.3, 95% CI 1.1–1.5).18
(risk reduction [RR] 0.73, 95% CI 0.70–0.76).9 Larger
reductions in ovarian cancer risk occurred with increasing
Screening
duration of OCP use: RR decreased by about 20% for each
5 years of use; by 15 years the risk of ovarian cancer was Screening for ovarian cancer with CA125 or ultrasound is
halved. Importantly, the protective effect persisted for not recommended for premenopausal and postmenopausal

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 Gaughan and Walsh

women without a family history of ovarian cancer.19 The High-risk family history
predictive value of either test alone (less than 3%) yields Women with a suspected hereditary ovarian cancer syndrome
an unacceptably high rate of false-positive results and should be referred to a genetic counsellor for consideration of
attendant morbidity and costs. The combination of annual testing for BRCA mutations or HNPCC if appropriate.
CA125 testing with ultrasound did not decrease mortality The United Kingdom Familial Ovarian Screening Study
at 13-year follow-up in the Prostate, Lung, Colorectal and (UK FOCCS) study,26 looking at the effectiveness of
Ovarian (PLCO) Cancer Screening Randomized Controlled screening in high-risk populations is due to report in 2015.
Trial20 and screening caused harm related to adverse Even though evidence for screening effectiveness has not been
effects from surgery for false positive findings. The demonstrated to date, the decision to screen this patient
continuing United Kingdom Collaborative Trial of population is based on their very high lifetime risk of ovarian
Ovarian Cancer Screening (UKC-TOCS)²¹ involves cancer and is usually undertaken in women who decline
202 638 low-risk postmenopausal women and is due to risk-reducing surgery.
report in 2015. For women declining risk-reducing surgery, some expert
The potential of screening for any cancer is limited by groups have recommended screening with transvaginal
the clinical biology of the particular disease. At diagnosis, ultrasound plus CA125 assays every 6 months, starting at
the majority of patients with advanced ovarian cancer have the age of 35 years or 5–10 years earlier than the earliest age
multiple nodules of cancer involving different peritoneal of first diagnosis of ovarian cancer in the family. While this
sites.22 While it has generally been assumed that each may be a reasonable option, the evidence indicates limited
peritoneal nodule represents a metastasis from a primary effectiveness of screening in this population, and clinicians
ovarian cancer, the disease might, in fact, be multifocal. and patients should not be falsely reassured by negative
Hereditary ovarian cancer is frequently multifocal rather screening results. Most groups advise risk-reducing surgery
than clonal.22,23 Anecdotal cases indicate that widespread for this group by age 35–40 or when childbearing is
disease can be diagnosed 3 months after a negative complete.27 See Table 1 for guidance on the management
transvaginal ultrasound and normal serum CA125 values for those at increased risk of ovarian cancer.
have been obtained.24 As screening has not been associated
with a statistically significant reduction in mortality from
Chemoprevention
ovarian cancer, its use cannot be routinely recommended
even in women deemed at high risk. Interval cancers can The combined oral contraceptive pill (COCP) has been
develop between screening visits and are often advanced at found to reduce the ovarian cancer risk in BRCA carriers. A
presentation. Serum CA125 levels are only elevated in history of ever using the COCP in these women was
50–60% of stage I ovarian cancers.25 For these reasons it is associated with significantly reduced risk of ovarian cancer
not appropriate to use screening to reassure high-risk (RR 0.50, 95% CI 0.33–0.75).25 The protective effect
women and it should only be offered in women increased with longer duration of use. There has been
declining risk-reducing surgery, in the absence of a concern that COCP may increase the risk of breast cancer in
better alternative. mutation carriers. Studies have shown an increased risk of
breast cancer with oral contraceptive formulations used
before 1975. However, studies have not shown a significantly
Women at increased risk
increased risk of breast cancer in users overall, or in the first
It is important to differentiate those with a possible rare 10 years after cessation of use of recent oral contraceptive
familial cancer syndrome and those with the more common formulations.28 Given the available data, it has been
presentation of an isolated family member with ovarian suggested that women with a hereditary ovarian cancer
cancer, without evidence of a hereditary pattern. syndrome who have not elected for risk-reducing surgery
and who are not trying to conceive should consider
Lower-risk family history COCP use.
Women with a family history but without evidence of a
hereditary pattern should be counselled about their
Risk-reducing surgery
individual risk – considering age, parity and history of oral
contraceptive pill use – about the limited evidence for Lack of efficacy of ovarian cancer screening has prompted
effectiveness of screening and about the potential adverse many clinicians to recommend risk-reducing bilateral
effects of screening. There is no evidence to support screening salpingo-oophorectomy (rrBSO) at the completion of
in this group and decisions regarding screening and childbearing rather than intensified screening for ovarian
risk-reducing surgery should be based on individualised cancer. Studies support the efficacy of rrBSO in significantly
considerations involving the patient and clinician. reducing the risk of gynaecological and breast cancer in

ª 2014 Royal College of Obstetricians and Gynaecologists 187

 Risk-reducing surgery for women at high risk of epithelial ovarian cancer

Table 1. Guidance for the management of women at increased risk of ovarian cancer

Risk of ovarian cancer Suggested management

Increased risk

Positive family history, single member affected No evidence to support screening in this group
not suggestive of a hereditary cancer syndrome
Risk of ovarian cancer: 4–5% Could consider risk-reducing bilateral salpingo-oophorectomy
based on individualised considerations involving patient
and clinician
(General population risk: 1.7%)

High risk

Family history suggestive of a hereditary cancer No evidence to support screening in this group
syndrome Can offer screening to those who decline risk-reducing surgery
Risk of ovarian cancer: 13–50% Offer risk-reducing surgery
BRCA1 has lifetime risk of ovarian cancer of 35–46% Offer risk-reducing bilateral salpingo-oophorectomy after age
35 when childbearing is complete
BRCA2 has lifetime risk of ovarian cancer of 13–23% Offer risk-reducing bilateral salpingo-oophorectomy after age 35.
May be delayed until age 45 because of later age of onset in this
group but this would mean losing the benefit of the associated
reduction in breast cancer risk
HNPCC (hereditary nonpolyposis colorectal cancer, or Offer risk-reducing bilateral salpingo-oophorectomy with concurrent
Lynch syndrome) has lifetime risk of ovarian cancer of 3–14% hysterectomy once family is complete because of risk of ovarian
and endometrial cancer

women who carry BRCA1 or BRCA2 mutations. BSO in An observational study of nearly 30 000 women enrolled in
premenopausal women with BRCA mutations has the the Nurse’s Health study, (median follow-up of 24 years),
additional benefit of significantly reducing the risk of breast concluded that, ‘compared with ovarian conservation,
cancer by 30 to 75%.29,30 As an example, in one study the bilateral oophorectomy at the time of hysterectomy for
relative risk of ovarian/fallopian tube/peritoneal cancer after benign disease is associated with a decreased risk of breast
rrBSO was 0.04% (95% CI 0.01–0.16) and in another study and ovarian cancer but an increased risk of all-cause
the relative risk of breast/ovarian/fallopian tube/peritoneal mortality, and fatal and nonfatal coronary heart disease’. At
cancer was 0.25% (95% CI 0.08–0.74).29,30 no age was oophorectomy associated with increased survival,
Data regarding the finding of occult fallopian tube cancers but equally, it was not associated with a decreased survival in
in women who have undergone rrBSO suggest that at least women over the age of 55 at the time of hysterectomy
some apparent ovarian cancers were initiated in the tubes.31 and oophorectomy.32
The possibility that the fallopian tubes are the primary site of A further prospective cohort study of over 24 000 women,
carcinogenesis in ovarian cancer has led to some experts with a shorter duration of follow-up (median 7.6 years),
advocating salpingectomy at the time of hysterectomy in the concluded that, whilst oophorectomy at the time of
general population to reduce ovarian cancer risk. hysterectomy decreased the risk of ovarian cancer
Removal of healthy ovaries does not add significantly to compared to hysterectomy alone, it was not associated with
the operating time or immediate surgical complications of an increased risk of coronary heart disease, hip fracture
hysterectomy, but may have significant implications for or death.33
short- and long-term health. Clearly there is conflicting evidence and therefore the
Lack of evidence from high-quality randomised clinical decision for oophorectomy must consider the individual
trials limits the ability of surgeons and patients to make an consequences for each woman with regard to her baseline risk
informed decision about the relative merits of ovarian for developing breast and ovarian cancers, coronary artery
removal or conservation in those who are not at increased disease, osteoporosis, non-compliance and/or poor clinical
inherited risk of ovarian cancer. response to HRT. In postmenopausal women, there is no
The postmenopausal ovaries are physiologically active and consensus about whether ovaries should be removed or
continue to produce estradiol (at low levels) and retained and decisions should be made following patient
testosterone. The relative risks and benefits of consultation on an individualised basis.
oophorectomy at the time of hysterectomy can be difficult In view of the literature on ovarian carcinogenesis, Leblanc
to estimate on an individualised basis. et al.34 have proposed radical fimbriectomy for ovarian

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 Gaughan and Walsh

cancer risk reduction, for women who wish to retain their All ovarian tissue should be removed. All ovarian adhesions
fertility and ovarian function. Radical fimbriectomy consists should be removed in their entirety to ensure no residual
of removing all of the fallopian tube and the fimbrio-ovarian ovarian cells remain.35 The ovarian artery and vein should be
junction. The safety and effectiveness of radical fibriectomy clamped at least 2 cm proximal to the ovary, and preferably at
for reducing ovarian carcinoma in the BRCA population has the pelvic brim to avoid leaving any ovarian tissue behind.41
not been assessed in clinical trials. Leblanc et al. proposed The surgeon should remove as much of the fallopian tube as
this option for women who wish to retain their ovarian possible but cornual resection does not appear to be necessary.
function and fertility in preference to having no prophylactic Although the intramural portion of the fallopian tube is
surgery at all. typically left behind after BSO, there have been no reports of
It is important to remember that rrBSO is not completely malignant transformation in the tubal remnant after this type
protective and BRCA carriers still have a risk of developing of surgery.42
primary peritoneal cancer (approximately 2% risk).35
Concurrent hysterectomy
Timing of surgery Hysterectomy may be performed at the same time as BSO
This can be a difficult decision involving balancing the when there are other gynaecological indications. This increases
procedure-related consequences of sterility and premature the associated morbidity and length of hospital stay.
menopause against the risk of ovarian and tubal cancer. Risk-reduction hysterectomy is beneficial in some groups,
BRCA1 carriers develop ovarian cancer at a younger age than for example women with Lynch syndrome who are at
BRCA2 carriers. Of women with a BRCA1 mutation and increased risk of endometrial cancer (40–60% lifetime risk).43
ovarian cancer, 54% are diagnosed before the age of 50 years. Some BRCA carriers wish to take tamoxifen for
Diagnosis before the age of 40 is uncommon (2–3%) and chemoprophylaxis of breast cancer. Tamoxifen use is
under the age of 30 is rare.36,37 Given that the age of onset is associated with an increased risk of endometrial pathology
usually over 40 it is appropriate to consider rrBSO for BRCA1 and therefore these women may consider risk-reduction
carriers after the age of 35 once childbearing is completed. hysterectomy at the time of BSO.
BRCA2 carriers reach a 2–3% incidence a decade later, by age Women who wish to take unopposed estrogen therapy
50 years and the average age at diagnosis is 60 years – similar may consider concurrent hysterectomy. Combined estrogen
to the general population. Based on this difference in the and progestin therapy for those who require hormone
likely age of onset of ovarian cancer, BRCA2 carriers may replacement therapy (HRT) is associated with a
wish to delay their risk-reducing surgery but by doing this significantly increased risk of breast cancer in
they would not benefit from the reduction in breast cancer postmenopausal women, whereas no such association has
afforded by salpingo-oophorectomy.38 been noted with unopposed estrogen in this group.44,45 The
Women considering rrBSO who have not completed ability to generalise these data to premenopausal women who
childbearing should be counselled about alternative undergo rrBSO is unclear.
reproductive options including embryo cryopreservation.
Preservation of ovarian tissue is under investigation.
Premature menopause
Surrogacy is an option for those undergoing
concurrent hysterectomy. Women undergoing rrBSO should be counselled about the
effects of premature menopause and the available
Preoperative evaluation management options. Menopausal effects include
There is a 4–8% chance of detecting an occult malignancy at menopausal symptoms such as hot flushes, sleep
the time of rrBSO. Over the age of 45 the risk rises to disturbance, mood change and hair and skin changes.
approximately 20%.35,39–41 Pelvic ultrasound and CA125 Sexual-health-related effects include dyspareunia secondary
level to evaluate for the presence of an ovarian malignancy to vaginal atrophy and decreased libido. Long-term health
should therefore be performed prior to surgery. An effects include osteoporosis, cardiovascular disease and
intraoperative finding of malignancy necessitates full effects on cognitive and psychological function.
surgical staging and patients should be appropriately Surgical menopause differs from natural menopause in
counselled and consented about the possible need for that hormone levels drop abruptly and hormone production
additional surgery. ceases completely, as opposed to a gradual decline in
hormone level and continued production of androgens as
Surgical procedure occurs with natural menopause. Women who undergo rrBSO
The laparoscopic route is preferable to the open approach as it are typically younger than the average age of menopause of
is associated with less morbidity. The minimum surgery 51 and are therefore exposed to the detrimental effects of
required for risk reduction is bilateral salpingo-oophorectomy. hypoestrogenism for longer.

ª 2014 Royal College of Obstetricians and Gynaecologists 189

 Risk-reducing surgery for women at high risk of epithelial ovarian cancer

The Scottish Intercollegiate Guidelines Network’s Decisions regarding screening and risk-reducing surgery
guidelines on ovarian cancer46 have recommended giving should be based on individualised considerations involving
HRT after rrBSO up to the age of 50 as there is no decrease in the patient and clinician.
the benefit in terms of breast cancer risk reduction. Although
there is a small increase in the rate of breast cancer in women Disclosure of interests
on HRT, they are usually of a lower grade and HRT has no The authors of this article have no conflict of interest
impact on breast cancer mortality.47 to disclose.
The type of BRCA mutation may impact on HRT breast
cancer risk. Breast cancers in BRCA1 carriers are typically Contribution to authorship
negative for estrogen and progestin receptors, and thus are TW came up with the idea to review the subject. EG
potentially less likely to be influenced by hormones than the performed the literature search on the subject and compiled
breast cancers that develop in BRCA2 carriers which are the review with TW as supervisor. Both authors approved the
usually positive for these receptors.48 final version of this article.
A shared decision-making process regarding the
management of menopausal symptoms and effects should
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