IJC

International Journal of Cancer

Prophylactic salpingectomy for the prevention of ovarian

cancer: Who should we target?
1,2 1,2
Joanne Kotsopoulos and Steven A. Narod
1
Women’s College Research Institute, Women’s College Hospital, Toronto, Ontario, Canada
2
Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada

Invited Review Series on Personalized Prevention

Ovarian cancer is the most fatal gynecologic malignancy (50% 5-year survival) due to a typically advanced stage at diagnosis
and a high rate of recurrence. Chemoprevention options are limited, and few interventions have been shown to reduce cancer
risk or mortality. Emerging data support the model that fallopian tubes are the site of origin for a proportion of high-grade
serous cancers. This implies that a subset of cancers may be prevented by removing the fallopian tubes while leaving the
ovaries intact. Accordingly, there has been shift in clinical practice for average risk women; some now recommend removal of
both the fallopian tubes only instead of tubal ligation for sterilization or at the time of benign gynecologic surgery. This has
been termed opportunistic salpingectomy and represents a means of decreasing the burden of ovarian cancer by preventing
cancers that arise in the fallopian tubes. There have been no detailed, prospective reports that have estimated ovarian cancer
risk reduction with opportunistic salpingectomy, neither among women at baseline population risk nor among women at a high
risk of developing the disease. The situation is complicated for women with a BRCA mutation—bilateral salpingo-oophorectomy
is a proven means of risk reduction and salpingectomy alone is not the standard of care. Based on the existing data,
salpingectomy alone should only be reserved for women with a lifetime risk of ovarian cancer of less than 5%.

Ovarian Cancer ultrasound imaging among women in the general population.11

In a recent publication of the worldwide evidence by the Interna-
tional Agency for Research on Cancer, ovarian cancer was the
seventh most common cancer among women and eighth most
common cause of death.1,2 Ferlay et al. reported that there were
295,400 newly diagnosed ovarian cancer cases and 184,800 deaths
due to ovarian cancer worldwide.2 The cumulative risk of ovarian
cancer to age 75 is estimated at 0.75%, but varies by geographic
location.3 Among the invasive epithelial subtypes, the histologic
distributions of ovarian cancer are serous (62%), endometrioid
(20%), clear cell (8%), mucinous (5%) and other histopathological
types (5%).4 The majority of serous tumors are diagnosed at an
advanced stage (due to local spread outside the pelvis and into the
peritoneum and/or intestine) and are high grade (collectively
referred to as high-grade serous ovarian cancer).5,6 Serous ovar-
ian cancer is the most common subtype and is responsible for
80% of all ovarian cancer deaths.7 The 5-year survival rate for
advanced-stage serous ovarian cancer is 15%,8 and there has been
little change in this over the past three decades.7, 9,10
With regard to screening, the combined evidence from three
large clinical trials does not support a reduction in mortality asso-
ciated with annual cancer antigen 125 (CA125) and/or
Key words: salpingectomy, oophorectomy, prevention, fallopian tube
cancer, ovarian cancer
DOI: 10.1002/ijc.32916
History: Received 12 Nov 2019; Accepted 31 Jan 2020;
Online 9 Feb 2020
Correspondence to: Joanne Kotsopoulos, E-mail: joanne.
kotsopoulos@wchospital.ca
Oral contraceptive use has consistently been associated with a
dose-dependent reduction in the risk of ovarian cancer that per-
sists after cessation of use.12,13 Nevertheless, given the changes in
the formulations and patterns of use of oral contraceptives, along
with the increased uptake of intrauterine devices for contracep-
tion, whether these recent changes may impact ovarian cancer
risk is not yet known.14 In addition, the rarity of this disease along
with the potential increased risks of breast cancer and venous
thromboembolism among current users has not led to a universal
recommendation for chemoprevention of ovarian cancer with
oral contraceptives.15,16 There is some limited epidemiologic data
to support an inverse association between aspirin use and the risk
of ovarian cancer; however, the data are not definitive.17,18 Given
the scarcity of highly effective prevention options, preventive (or
risk-reducing) bilateral salpingo-oophorectomy (BSO) remains
the only option; however, given the nature of the surgery and the
well-established negative consequences of early surgical meno-
pause (discussed below),19-21 BSO is currently only rec-
ommended to women at a high-risk of developing ovarian
cancer.22
Despite extensive study, the etiology of ovarian cancer is not
fully understood, and there has been minimal progress in preven-
tion and treatment, leading to little change in the mortality and
morbidity associated with this disease.7,9,10 Given the high case-
fatality rate, primary prevention of this subtype of disease is of
critical importance. Data from molecular, epidemiologic and
pathologic investigations have provided new insight into the
pathogenesis of ovarian cancer and are indicative of novel

Int. J. Cancer: 147, 1245–1251 (2020) © 2020 UICC


1246
avenues for prevention.23-25 Specifically, is the emerging para-
digm of the fallopian tubes as the site of origin for a subset of
high-grade serous ovarian cancer and the potential to decrease
the burden from ovarian cancer with fallopian tube removal
(i.e., salpingectomy) instead of tubal ligation for sterilization or at
the time of benign gynecologic surgery. An overview of the data
supporting this shift in clinical practice and for whom
salpingectomy is indicated are the focus of this study.
Fallopian Tubes as the Site of Origin of Ovarian
Invited Review Series on Personalized Prevention
Cancer
Ovarian tumors have long been thought to arise from the
ovarian surface epithelium or from ovarian surface inclusion
cysts and were classified based on pathological features such
as histology, grade and stage.26,27 In recent years, a new multi-
pathway model has been proposed which is based on precur-
sor lesions, gene mutation analysis and histology.23-25 This
classification is centered on the hypothesis that high-grade
serous ovarian tumors can arise from either the fallopian tube
or the ovarian surface epithelium.28 This paradigm proposes
that the fallopian tube is the site of origin for a large propor-
tion of high-grade serous tumors that later spread to the ovary
and/or the peritoneum.29-33 Consequently, in 2014, the Inter-
national Federation of Gynecology and Obstetrics (FIGO)
staging system for high-grade serous cancers was modified to
classify the primary site of disease collectively as ovarian,
fallopian tube and primary peritoneal.34
A tubal origin of ovarian cancer was first proposed after
extensive examination of the distal fallopian tubes of asymp-
tomatic BRCA mutation carriers undergoing prophylactic sur-
gery by sectioning and extensively examining the fimbriated
end protocol (reviewed in References 35 and 36). The first
studies identified invasive, occult ovarian or fallopian tube
cancers in 5–15% of BRCA cancer patients diagnosed with
high-grade serous cancer; later studies identified a serous tubal
intraepithelial carcinoma (STIC) and proposed this as the
putative precursor to high-grade serous ovarian cancer, in
5–6% of these patients.37 Early support for the hypothesis was
based on the study of occult lesions in BRCA mutations car-
riers; however, this sequence was subsequently demonstrated
in studies of sporadic cancers which similarly support the the-
ory that high-grade serous ovarian cancers originate in the
fallopian tubes and subsequently implant on the ovarian or
peritoneal surfaces.36 Importantly, molecular sequencing stud-
ies of p53 and other genes have shown genetic identity
between STICs and accompanying high-grade serous tumors,
demonstrating a shared lineage.25,38,39 More detailed molecu-
lar profiling showed similarities between high-grade serous
ovarian cancers and the distal fallopian tube in oophorectomy
with and without an associated STIC lesion, suggesting that
the presence of a STIC may not be obligatory.40
Whether the fallopian tube is the source of all high-grade
serous tumors (including those with and without a genetic
predisposition) is debatable, given that (i) not all women with
10970215, 2020, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ijc.32916 by Venezuela Regional Provision, Wiley Online Library on [20/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Salpingectomy and ovarian cancer prevention
high-grade tumors have a STIC or other precursor lesion
(i.e., p53 signature) identified in their fallopian tubes and rates
of STICs in both sporadic and hereditary cases vary
substantially,40,41 and (ii) it is not clear if STICs are causally
associated with the subsequent risk of developing invasive
cancer, although an increased risk of high-grade serous perito-
neal carcinoma following a diagnosis of a STIC has been
observed in some (but not all) women.42,43 Other caveats to
the fallopian tubes as the sole origin of all high-grade serous
cancers have been discussed.44,45
Preventing Ovarian Cancer with Salpingectomy
among Women in the General Population
The recognition that the fallopian tubes are the site of origin
for a subset of high-grade serous ovarian cancers has led to
the promotion of opportunistic salpingectomy throughout the
gynecologic community. This procedure involves the complete
removal of both fallopian tubes only while leaving both ova-
ries intact (i.e., bilateral salpingectomy) at the time of surgery
for benign disease or in lieu of tubal ligation for sterilization
among women at baseline population risk.37,46-48 The premise
is that salpingectomy alone represents a safe and feasible
opportunity to potentially prevent a subset of serous cancers
that initially arise in the fallopian tubes while mitigating the
adverse effects associated with early surgical menopause,
including menopausal symptoms, an increase in all-cause
mortality and other comorbidities.21,49-51 The potential for
bilateral salpingectomy to prevent ovarian cancer and the fac-
tors which influence uptake have been discussed extensively in
the literature in recent years.52-57 Despite much interest, there
have been very few reports on the impact of salpingectomy on
subsequent risk of ovarian cancer or other potentially impor-
tant outcomes such as menopausal symptoms.
Salpingectomy at the time of a benign, gynecologic surgery is
considered a safe procedure and is not associated with an
increased rate of perioperative or postoperative complica-
tions.45,55,56 By removing the fallopian tubes and leaving the ova-
ries intact, it has been proposed that ovarian hormone
production is not impeded, and thus, women should not
experience typical symptoms of oophorectomy. Unfortunately,
the latter is based on a few studies that have quantified levels of
anti-Mullerian hormone (AMH), follicle-stimulating hormone or
estradiol as markers of ovarian function shortly after sur-
gery.37,58-60 There has been some suggestion that salpingectomy
may diminish AMH levels leading to an earlier age at menopause,
although this has yet to be demonstrated.59 A recent Swedish
registry-based study reported a significant increase in meno-
pausal symptoms 1-year following salpingectomy with hysterec-
tomy (n = 1,433) versus hysterectomy alone (n = 3,473) (relative
risk = 1.33; 95% CI 1.04–1.69).61 To our knowledge, there have
been no other large-scale prospective studies evaluating the long-
term impact of salpingectomy on ovarian function or other out-
comes, especially among women who are premenopausal at the
time of surgery.
Int. J. Cancer: 147, 1245–1251 (2020) © 2020 UICC

Kotsopoulos and Narod
To date, three studies have evaluated the impact of
salpingectomy and other gynecologic surgeries on ovarian cancer
risk (reviewed in References 59, 60 and 62). The key features of
these studies are summarized in Table 1. The first report was a
population-based case–control study of 194 cases and 388 con-
trols.63 Lessard-Anderson et al. reported a borderline significant
decreased risk of cancer among women who had an excisional
tubal sterilization (i.e., complete salpingectomy, distal fim-
briectomy and partial salpingectomy) versus women without ster-
ilization or nonexcisional tubal sterilization (odds ratio
[OR] = 0.36; 95% confidence interval [CI] 0.13–1.02; p = 0.05). In
comparison, any tubal sterilization was also associated with a
reduced risk; however, the association did not achieve statistical
significance (OR = 0.59; 95% CI 0.29–1.17; p = 0.13). This study
included only serous ovarian or primary peritoneal cancers. In
the second case–control study, Madsen et al. used the Danish
nationwide registry to evaluate the relationship between
salpingectomy and risk of ovarian cancer.64 They found a 42%
decreased risk of epithelial ovarian cancer with bilateral
salpingectomy (OR = 0.58; 95% CI 0.36–0.95); however, this was
based on 17 exposed cases and 411 exposed controls. Finally, in a
retrospective population-based study,65 Falconer et al. reported a
65% decreased risk of ovarian cancer among women who under-
went a bilateral salpingectomy (hazard ratio [HR] = 0.35; 95% CI
0.17–0.73). This estimate was based on seven exposed cases.
Although the limited data suggest a protective role of
salpingectomy, it is important to note that none of these reports
evaluated “opportunistic salpingectomy” but rather focused on
salpingectomy for specific indications. Large-scale, prospective
studies that explicitly evaluate the impact of opportunistic
salpingectomy on cancer incidence, mortality and other long-
term effects such as menopausal symptoms are warranted. There
is also a need to take into consideration age and time since sur-
gery, as well as underlying risk or the impact of surgery on the risk
of developing specific histologic subtypes of disease.
Preventing Ovarian Cancer in High-Risk Women
The strongest risk factor for ovarian cancer is the inheritance of a
deleterious mutation in various genes, predominantly, BRCA1 or
BRCA2. Women who inherit a deleterious BRCA1 or BRCA2
mutation face a very high lifetime risk of developing ovarian can-
cer.66 Specifically, the lifetime risk (i.e., cumulative risk to age 80)
of ovarian cancer among BRCA1 mutation carriers is estimated at
44–49%, and the corresponding estimate is 17–21% for BRCA2
mutation carriers.66,67 These risks of ovarian cancer are substan-
tially higher than the population risk (1.3–1.5%).68 Approxi-
mately 15–20% of all ovarian cancers are attributed to an
inherited BRCA mutation,69 and the majority of ovarian cancers
arising in BRCA mutation carriers are of the serous histology,
followed by the endometrioid subtype.70 Mutations in other
genes including RAD51C, RAD51D, BRIP1, STK11 and the Lynch
Syndrome genes (i.e., MLH1, MSH2, MSH6, PMS2) are also
implicated and predispose to a lifetime risk of 5% or more; how-
ever, these are responsible for a smaller proportion of cases
Int. J. Cancer: 147, 1245–1251 (2020) © 2020 UICC
10970215, 2020, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ijc.32916 by Venezuela Regional Provision, Wiley Online Library on [20/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
1247
(collectively <5%).71,72 Women with a strong family history of the
disease but no inherited genetic mutation are also at an elevated
risk of developing ovarian cancer. Specifically, one or more first-
degree relative diagnosed before age 40 or two or more first-
and/or second-degree relatives of the same lineage with ovarian
cancer constitutes a strong family history.73
Screening for early detection of ovarian cancer remains prob-
lematic, and patients are typically asymptomatic (presenting at
advanced stage with extensive peritoneal spread).74,75 Thus, sur-
gical removal of both the ovaries and fallopian tubes (i.e., prophy-
Invited Review Series on Personalized Prevention
lactic or risk-reducing BSO) is widely recommended to women
with a BRCA1 or BRCA2 mutation.75-77 The current 2019
National Comprehensive Cancer Network guidelines for the
management of hereditary cancer recommend oophorectomy
between the ages of 35–40 for BRCA1 mutation carriers and
between the ages of 40–45 for BRCA2 mutation carriers.22 These
recommendations are based on the age at which the risk of diag-
nosis (either clinically or as an occult cancer at the time of oopho-
rectomy) becomes substantial (i.e., greater than lifetime risk of
5%).76 Preventive BSO significantly reduces the risk of developing
ovarian, fallopian and peritoneal cancers in women with a BRCA
mutation, with estimates of risk reduction ranging from 75 to
96%.76,78-80 Women who carry mutations in other moderately
penetrant genes that confer a lifetime risk of 5% or more are also
candidates for preventive BSO but at a slightly later age
(45 years).22 Along with reducing cancer incidence, oophorec-
tomy is also associated with a highly statistically significant 77%
reduction in all-cause mortality among women with a BRCA1 or
BRCA2 mutation (HR = 0.23; 95% CI 0.13–0.39).81 Furthermore,
BSO has become an important treatment option for BRCA muta-
tion carriers following a diagnosis of breast cancer. For example,
Metcalfe and colleagues have demonstrated that oophorectomy
confers a significant reduction in breast cancer mortality among
BRCA mutation carriers with a personal history of breast cancer
(HR = 0.46; 95% CI 0.27–0.79).82
Given the potential negative consequences associated with
early surgical menopause (i.e., vasomotor symptoms, decline
in sexual functioning, worsening in overall quality of life),83
there has been interest in the role of salpingectomy with del-
ayed oophorectomy (completed closer to menopause) among
BRCA mutation carriers. This offers an opportunity to prevent
early cancers that arise from the fallopian tubes. This option
is acceptable for women who refuse surgery because of their
concerns regarding early surgical menopause. To our knowl-
edge, there have been no evaluations of salpingectomy with
ovarian cancer incidence (or mortality) among high-risk
women including those with a BRCA1 or BRCA2 mutation.
We have identified two independent trials currently recruiting
BRCA mutation carriers with the goal of evaluating the impact
of salpingectomy (with delayed oophorectomy) on noncancer
endpoints including safety, acceptability, menopausal symp-
toms and quality of life.84,85
Several questions come to mind when evaluating the
impact of salpingectomy on health outcomes in a high-risk
 Invited Review Series on Personalized Prevention

Table 1. Characteristics of three epidemiologic studies evaluating bilateral salpingectomy and risk of epithelial ovarian cancer
Cases/controls
1248

or exposed/
Reference Study design Country Study period unexposed Comparison Risk estimates Comments
Retrospective
Lessard-Anderson et al.63 Population-based, United States 1966–2009 Serous epithelial ovarian Any tubal sterilization ORany = 0.59 (95% Only serous ovarian
nested (Rochester cancer or primary versus no sterilization CI 0.29–1.17); cancer or primary
case–control Epidemiology peritoneal cancer; or nonexcisional tubal p = 0.13 peritoneal
study Project) n = 194 sterilization OR excisional = 0.36 Excisional tubal
Age matched controls from (9 cases/21 controls) (95% CI sterilization included:
general population; Excisional tubal 0.13–1.02); complete
n = 388 sterilization versus no p = 0.05 salpingectomy, distal
sterilization or fimbriectomy or partial
nonexcisional tubal salpingectomy
sterilization Nonexcisional were all
(5 cases/25 controls) other methods of tubal
sterliziation
(coagulation, clips,
rings)
Madsen et al.64 Nested case– Denmark 1982–2011 Epithelial ovarian cancer History of salpingectomy: ORunilateral = 0.90 All histologic subtypes of
control study (n = 13,241); no Unilateral (95% CI ovarian cancer included
previous cancer salpingectomy: n = 89 0.72–1.12)
Age-matched; no previous cases/1,382 controls ORbilateral = 0.58
cancer or bilateral Bilateral salpingectomy: (95% CI
oophorectomy 17 cases/411 controls 0.36–0.95)
(n = 194,689)
Prospective
Falconer et al.65 Population-based Sweden 1973–2009 Ovarian and tubal cancers History of salpingectomy: ORunilateral = 0.71 Salpingectomy for benign
cohort study Women with previous Unilateral (95% CI indication; all histologic
surgery on benign salpingectomy: 0.56–0.91); subtypes of ovarian
indication (sterilization, n = 19,552; 68 cases p = 0.005 cancer included
salpingectomy, Bilateral salpingectomy: ORbilateral = 0.35
hysterectomy, BSO) n = 3,051; 7 cases (95% CI
(n = 251,465) versus 0.17–0.73);
unexposed p = 0.004
(n = 5,449,119)
Salpingectomy and ovarian cancer prevention

Int. J. Cancer: 147, 1245–1251 (2020) © 2020 UICC

10970215, 2020, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ijc.32916 by Venezuela Regional Provision, Wiley Online Library on [20/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
 10970215, 2020, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ijc.32916 by Venezuela Regional Provision, Wiley Online Library on [20/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Kotsopoulos and Narod 1249

population such as BRCA mutation carriers. This includes the
impact on risk of developing ovarian or fallopian tube cancer,
the impact on the ensuing menopausal symptoms, and
whether women who are at a substantially elevated risk of
developing serous cancer return for ovarian removal within
the recommended limits that maximize cancer prevention and
prevent death. An additional question of interest is which
women are electing salpingectomy vs. standard of care, and
whether their perceived risk of cancer and cancer-related dis-
tress differs. Importantly, in a series of studies conducted
lifetime risk of 5% or a strong family history)—in particular, for
women delaying or refusing surgery because of concerns of early
surgical menopause and the associated comorbid conditions or
because childbearing is not complete. An important caveat is
whether women who elect salpingectomy will return for a delayed
oophorectomy within the appropriate timeframe to ensure the
established beneficial effects of oophorectomy on cancer risk and
survival. Given the anecdotal evidence of an increase in the num-
ber of high-risk women being offered salpingectomy with delayed
oophorectomy, there is a potential false sense of decreased risk

Invited Review Series on Personalized Prevention

among BRCA mutation carriers and their providers, Metcalfe
et al. have shown that uptake of preventive BSO is suboptimal
and that differences in uptake may be related to personal pref-
erences or health care provider recommendations.86-88
Who is and Who is not a Candidate for
Salpingectomy?
Due to evidence supporting the fallopian tubes as the site of origin
of a proportion of high-grade serous cancers, opportunistic
salpingectomy should continue to be offered to women at average
population risk as an approach to prevent the most aggressive
subtype of ovarian cancer and potentially prevent a subset of
deaths due to this highly fatal disease.89,90 Imminent prospective
evaluations will provide the empirical evidence to support this
hypothesis along with the role of the fallopian tubes in the patho-
genesis of ovarian cancer.
For women with the highest lifetime risk of developing ovar-
ian cancer due to an inherited BRCA mutation, “salpingectomy
alone is not the standard of care for risk reduction.”22 Despite
this, there has been interest in the role of salpingectomy as an
ovarian cancer prevention method for BRCA mutation carriers
(and potentially other high-risk women such as those with a
perception they may be experiencing which may ultimately
impede on their return for ovary removal. Salpingectomy should
not be offered to women with a BRCA mutation and a history of
breast cancer as the therapeutic benefit of oophorectomy is
increasingly being recognized. In conclusion, salpingectomy-
alone should not be offered to high-risk women as a prevention
strategy or those with a personal history of breast cancer outside
of a research study until prospective data on risk and mortality, as
well as non-cancer outcomes such as menopausal symptoms and
quality of life, are available. At the same time, we recognize the
importance for women who undergo the operation to be enrolled
in prospective studies with these goals in mind.
Acknowledgments
Steven A. Narod is the recipient of a Canada Research Chair (Tier I).
Joanne Kotsopoulos is a recipient of a Tier II Canada Research Chair. This
study was supported by a Canadian Cancer Society Research Institute
Grant (703058) and the Peter Gilgan Foundation Tour de Bleu.
Conflict of Interest
The authors have no conflicts of interest to disclose.

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