• Discuss any “take-away” thoughts from the article.
• What are the ethical dilemmas to consider with prophylactic surgeries?
• Discuss the screenings/interventions/options/education that you would provide to a patient that has a strong family history of ovarian cancer.
• What if the patient has no health insurance?
• What resources could you offer to assist the patient?

MOLECULAR AND CLINICAL ONCOLOGY 3: 267-273, 2015

Abstract. Risk-reducing surgery (RRS) is defined as a
prophylactic approach with removal of organs at high risk of
developing cancer, which is performed in cases without lesions
or absence of clinically significant lesions. Hereditary gyneco-
logical cancers for which RRS is performed include hereditary
breast and ovarian cancer (HBOC) and Lynch syndrome. For
HBOC, RRS in the United States (US) is recommended for
women with mutations in the breast cancer susceptibility
(BRCA)1 and BRCA2 genes and bilateral salpingo-oopho-
rectomy (BSO) is generally performed. This procedure may
reduce the risk of breast, ovarian, Fallopian tube and primary
peritoneal cancer, although ovarian deficiency symptoms
occur postoperatively. For Lynch syndrome, RRS in the US
is considered for postmenopausal women or for women who
do not desire to bear children and BSO and hysterectomy
are usually performed. This approach may reduce the risk of
endometrial and ovarian cancer, although ovarian deficiency
symptoms also occur. For RRS, there are several issues that
must be addressed to reduce the risk of cancer development
in patients with HBOC or Lynch syndrome. To the best of our
knowledge, this is the first review to discuss RRS with a focus
on hereditary gynecological cancer.

Contents

1. Introduction

2. Indications for RRS

3. Techniques of RRS

4. Effects of RRS

5. Complications and surveillance following RRS

6. Current status of RRS worldwide

7. Conclusions

1. Introduction

Hereditary gynecological cancers include ovarian cancer
associated with hereditary breast and ovarian cancer (HBOC);
endometrial and ovarian cancer associated with Lynch
syndrome; endometrial, cervical and ovarian cancer associated
with Peutz-Jeghers syndrome; and ovarian cancer associ-
ated with Cowden disease. HBOC is an autosomal dominant
hereditary disease that may cause breast, ovarian, Fallopian
tube and peritoneal cancer.

Mutations of the breast cancer susceptibility (BRCA)1 and
BRCA2 genes have been identified in ~8‑13% of patients with
ovarian cancer (1,2). By the age of 70 years, the estimated risks
of developing ovarian cancer are 35‑60 and 10‑27% in BRCA1
and BRCA2 mutation carriers, respectively (2). The mean
ages at diagnosis of ovarian cancer are 54, 62 and 63 years
for BRCA1 and BRCA2 mutation carriers and non-carriers,
respectively, indicating that BRCA1 mutation carriers are
more likely to be affected by ovarian cancer at a younger
age (3). Clinicopathologically, the majority of ovarian cancers
that are BRCA1/2 mutation-positive are of serous histology
and are poorly differentiated (grade 3) stage III-IV tumors,
according to the International Federation of Gynecology and
Obstetrics (FIGO) staging criteria, as defined in 1988 (4,5).
In BRCA1/2 mutation-positive and -negative cases, the rates
of serous adenocarcinoma are 63‑86 and 57‑58%, those of
poorly differentiated tumors 68‑87 and 48‑58% and those of
stage III‑IV tumors 72‑88 and 62‑70%, respectively.

Lynch syndrome, also referred to as hereditary non-polyp-
osis colorectal cancer, is an autosomal dominant hereditary
disease that may lead to colorectal, endometrial, gastric and
ovarian cancer. Lynch syndrome is caused by germline muta-
tions in DNA mismatch repair (MMR) genes, which include
mutL homolog 1 (MLH1), mutS homolog 2 (MSH2), MSH3,
MSH6, postmeiotic segregation increased 1 (PMS1) and PMS2.
High mutation rates of MLH1, MSH2, or MSH6 have been

Risk-reducing surgery in hereditary gynecological cancer:
Clinical applications in Lynch syndrome

and hereditary breast and ovarian cancer (Review)
MASATAKA ADACHI, KOUJI BANNO, MEGUMI YANOKURA, MIHO IIDA, KANAKO NAKAMURA,

YUYA NOGAMI, KIYOKO UMENE, KENTA MASUDA, IORI KISU, ARISA UEKI,
AKIRA HIRASAWA, EIICHIRO TOMINAGA and DAISUKE AOKI

Department of Obstetrics and Gynecology, School of Medicine, Keio University, Tokyo 160‑8582, Japan

Received April 10, 2014; Accepted October 15, 2014

DOI: 10.3892/mco.2014.460

Correspondence to: Dr Kouji Banno, Department of Obstetrics and
Gynecology, School of Medicine, Keio University, 35 Shinanomachi
Road, Shinjuku‑ku, Tokyo 160‑8582, Japan
E-mail: kbanno@z7.keio.jp

Key words: risk-reducing surgery, Lynch syndrome, hereditary
breast and ovarian cancer, hysterectomy, salpingo-oophorectomy

ADACHI et al: RISK-REDUCING SURGERY IN HEREDITARY GYNECOLOGICAL CANCER268

identified in Lynch syndrome (6), with 50% of women in fami-
lies with Lynch syndrome carrying a MLH1 mutation, 39% a
MSH2 mutation and 7% a MSH6 mutation. The majority of the
cases of endometrial cancer associated with Lynch syndrome
have germline mutations of MSH6 and MLH1 (7). However,
Lynch syndrome may also occur without a pathogenic mutation
in MMR genes (8) and may instead be due to an epimutation in
the promoter region of MLH1 or MSH2, with different levels
among family members and tissues (9). For patients with
MMR gene mutations, the estimated risk of developing endo-
metrial, colorectal and ovarian cancer at the age of 70 years
is 42‑60, 30‑54 and 12%, respectively (10,11). Compared to
sporadic endometrial cancer, the histological characteristics of
endometrial cancer in Lynch syndrome include a lower rate of
endometrioid tumors (86.0 vs. 97.6%) that are more often found
in FIGO stage I-II disease (88.0 vs. 73.8%) (12) and are more
commonly surface epithelial stromal tumors (95.9 vs. 83.6%),
including endometrioid (18.3 vs. 9.6%) and clear cell tumors
(18.3 vs. 3.6%) (13).

Genetic tests may be used to determine whether an indi-
vidual is at high risk of developing cancer; however, screening
methods for ovarian cancer and Lynch syndrome have not been
established. Therefore, risk-reducing surgery (RRS) may be an
important approach to such cases. RRS was originally defined
as an operation performed in cases without lesions or absence
of clinically significant lesions to remove organs at high risk
of developing cancer, for the purpose of reducing the mortality
risk from cancer or from the side effects of treatment. The
benefits of RRS for gynecological cancers associated with
Peutz-Jeghers syndrome or Cowden disease have not been
investigated. In this review, we examined the conditions for
performing RRS for HBOC and Lynch syndrome, the methods
and outcomes of surgery, postoperative management and the
current status of RRS for these diseases worldwide.

2. Indications for RRS

The indications for RRS in HBOC are summarized in the
guidelines published by the National Comprehensive Cancer
Network (NCCN) (14). Due to the absence of a reliable
method for early detection and the poor prognosis associated
with advanced ovarian cancer, these guidelines recommend
‘risk-reducing bilateral salpingo-oophorectomy (RRSO)
for women with known BRCA1/2 mutations, ideally aged
35-40 years and upon completion of child bearing or at an
individualized age based on earliest age of ovarian cancer diag-
nosed in the family’ (14). Since 95% [95% confidence interval
(CI): 0‑16%] of women in hereditary breast cancer families,
including patients with ovarian cancer, carry BRCA muta-
tions (15), the majority of women in such families are eligible
for RRS. King et al (16) observed that the risk of developing
ovarian and breast cancer at the age of 40, 50 and 60 years
was 3, 21 and 40%, respectively, in BRCA1 mutation carriers
and 2, 2 and 6%, respectively, in BRCA2 mutation carriers;
they also reported that the risk of developing breast cancer
at these ages was 21, 39 and 58%, respectively, in BRCA1
mutation carriers and 17, 34 and 48%, respectively, in BRCA2
mutation carriers. Finch et al (17) reported that the prevalence
of occult carcinoma was 1.5% for BRCA1 mutation carriers
who underwent oophorectomy at <40 years of age and 3.8%

for women who underwent surgery between 40 and 49 years.
This led to the recommendation that BRCA1 mutation carriers
should undergo RRSO by the age of 35 years. Finch et al (17)
also observed that the rate of diagnosis of ovarian cancer was
4.0% if a BRCA1 mutation carrier chose to delay RRSO until
the age of 40 years and that this rate increased to 14.2% with a
delay until the age of 50 years.

Regarding the indications for women without gene muta-
tions in hereditary breast cancer families, the Breast Cancer
Linkage Consortium in 1998 collected data on 237 families,
each with ≥4 cases of breast cancer diagnosed by the age
of 60 years (15). A case of ovarian cancer was found to be
associated with mutations of BRCA1 or BRCA2 in 90% of
the families. These results indicated that a woman in a family
with at least 1 case of ovarian cancer should be managed in
a manner similar to women with BRCA1/2 mutations. In a
study of 165 BRCA mutation-negative hereditary breast cancer
families at the Memorial Sloan‑Kettering Cancer Center (18),
the risk of breast cancer in women in these families was 3.13
(95% CI: 1.88‑4.89) compared to that in the general popula-
tion. However, those families did not exhibit a significantly
increased risk for ovarian cancer. This suggests that RRSO for
the prevention of ovarian cancer may be unnecessary in patients
with BRCA mutation-negative hereditary breast cancer.

The NCCN guidelines also include an indication for
RRS in Lynch syndrome and state that ‘when postmeno-
pausal or not desiring to bear children, total abdominal
hysterectomy̸bilateral salpingo‑oophorectomy (TAH/BSO)
should be considered’ (19). In patients with Lynch syndrome,
Schmeler et al (20) found that the median age at diagnosis of
endometrial and ovarian cancer was 46 and 42 years, respec-
tively, with diagnosis at ≥35 years in 94 and 83% of the cases,
respectively. These findings suggested that the more appro-
priate indication for RRS is ‘a woman aged 35 years or older
not desiring to bear children, or a postmenopausal woman
with suspected Lynch syndrome from family history or known
DNA mismatch repair gene mutation’ (21). Moreover, since
endometrial cancer in Lynch syndrome is mainly detected
at an early stage (12), treatment initiated following early
detection may be curative (22). Therefore, further studies are
required to elucidate the appropriate indications for RRS (23).
Of note, performing an RRSO in Japan requires approval from
an Ethics Committee, as symptoms have not yet developed; in
addition, the patient must have sufficient financial resources, as
RRSO is not covered by public health insurance in Japan (24).

3. Techniques of RRS

RRS performed in HBOC is basically BSO. The benefits of
laparoscopic RRSO are reduced invasiveness, a lower rate of
postoperative complications and a shorter median hospital
stay compared to laparotomy, although laparoscopy may be
converted to laparotomy in case of a major intraoperative
complication, such as adhesion or perforation (25). Over
the last few years, laparoscopic single-port RRSO has been
introduced and this procedure has the advantage of further
decreased invasiveness compared to conventional laparos-
copy (26). Occult cancers are detected at a frequency of 1‑4%
in cases in which RRSO is performed; thus, both the ovaries
and Fallopian tubes should be removed (27,28). In HBOC, the

MOLECULAR AND CLINICAL ONCOLOGY 3: 267-273, 2015 269

risk for developing endometrial cancer in BRCA1 mutation
carriers is 2.6-fold higher compared to that in non-carriers (29)
and the relative risk for endometrial cancer is 11.6 following
tamoxifen treatment in BRCA1/2 mutation carriers (30). Since
the uterus is non-functional following BSO, a hysterectomy
should be performed at the same time as BSO (31). However,
with regard to prevention of malignant transformation, the
incidence of gynecological malignancies was not found to
differ significantly between women who did and those who did
not undergo hysterectomy with BSO (2.8 vs. 0%) (32). Based
on those results, the benefits and risk of simultaneous hysterec-
tomy must be discussed with the patient prior to RRSO.

The NCCN guidelines state that the RRS performed in
Lynch syndrome is TAH̸BSO (19); however, laparoscopic
assisted vaginal hysterectomy (LAVH) and BSO are also occa-
sionally performed (30). Care must be taken when performing
LAVH due to the higher risk of injuring the urinary tract
during this procedure (odds ratio = 3.13; 95% CI: 1.06‑9.28)
compared to abdominal hysterectomy (33). Among women
with Lynch syndrome, 13% are diagnosed with endome-
trial/ovarian cancer and colon cancer synchronously or
metachronously (20): endometrial/ovarian cancer is diagnosed
first in 41‑43%, endometrial and ovarian cancer are diagnosed
synchronously in 7‑14% and colon cancer is diagnosed first
in 42‑51% of the cases (20,34). If colon cancer is diagnosed
first, the next tumor to develop is endometrial and ovarian
cancer in 84 and 14% of the cases, respectively (34). Based on
those results, RRS following initial diagnosis of colon cancer
may prevent the onset of endometrial or ovarian cancer (20).
Thus, in patients with Lynch syndrome, TAH/BSO may be
performed at the same time as surgery for colon cancer (32).

4. Effects of RRS

Over a mean follow-up of 24.2 months following RRSO for
HBOC, the hazard ratio for breast or gynecological cancers,
such as ovarian, Fallopian tube and primary peritoneal cancer,
was found to be 0.25 (95% CI: 0.08‑0.74) (28). A meta‑analysis
of 10 studies on the efficacy of RRSO reported hazard ratios
of 0.21 (95% CI: 0.12‑0.39) for onset of ovarian and Fallopian
tube cancer and 0.49 (95% CI: 0.37‑0.65) for onset of breast
cancer, indicating that the risk of developing these cancers
was reduced following RRSO (35). Over a mean follow-up
period of 3 years, the overall mortality was also found to be
reduced in patients who underwent RRSO compared to those
who did not (3 vs. 10%, respectively) (36). Finch et al (17)
observed 5,783 women with a BRCA1 or BRCA2 muta-
tion prospectively for an average of 5.6 years and reported
hazard ratios for all-cause mortality following RRSO of 0.30
(95% CI: 0.24‑0.38) and 0.33 (95% CI: 0.22‑0.50) for BRCA1
and BRCA2 mutation carriers, respectively.

In patients with Lynch syndrome, Schmeler et al (20)
observed a significantly decreased incidence of endometrial
cancer over a mean follow-up period of 13.3 years following
RRS compared to that over a follow-up of 7.4 years in
non-RRS patients (0.000 vs. 0.045 per woman-year; P<0.001). For ovarian cancer, the incidence did not differ significantly in a follow-up of 11.2 years following RRS compared to that in a follow-up of 10.6 years in non-RRS patients (0.000 vs. 0.005 per woman-year; P=0.09). Those results indicated that RRS

significantly reduced the risk of endometrial cancer in Lynch
syndrome, but did not affect the risk of ovarian cancer. In a study
of RRS at the age 30 years for women with Lynch syndrome
with an annual gynecological examination, Chen et al (37)
observed that surgical management increased survival by
2.5 years. When comparing RRS with annual screening
(transvaginal ultrasound + endometrial biopsy + measuring
serum CA125 levels), it was estimated that 75 surgeries were
required to save one life and that 28 and 6 RRS procedures
were required to prevent one case of ovarian cancer and endo-
metrial cancer, respectively (37).

5. Complications and surveillance following RRS

There are few complications associated with RRSO for HBOC.
Kauff et al (28) reported complications in 4 of 98 women
following RRSO, including 1 case each of infection; perfora-
tion of the bladder, from which the patient recovered in 5 days;
distal obstruction of the small bowel, which developed 8 weeks
following RRSO; and perforation of the uterus by a uterine
manipulator. All these events were caused by BSO alone and
no complications occurred in the 11 women who underwent
hysterectomy at the time of RRSO. Postoperative follow-up
commonly includes bone densitometry with dual-energy X-ray
absorptiometry, yearly CA125 serum testing and yearly pelvic
examination; however, there is no consensus on the optimal
approach and standardized postoperative methods for follow-up
are required (38). Tumors may develop following RRSO, with
a particular residual risk of breast, ovarian and Fallopian tube
cancer (35). The cumulative incidence of primary peritoneal
cancer has been estimated to be 4.3% at 20 years following
RRSO, including 4 of 7 women who succumbed to their
disease, with an average survival of 3 years (39). A mean of
5.3 years had elapsed between RRSO and cancer diagnosis
(median, 3 years). Finch et al (17) estimated the risk of peri-
toneal cancer in the 20 years following RRSO to be 3.9% for
BRCA1 and 1.9% for BRCA2 mutation carriers. A proportion
of these cases were metastases of subclinical disease present at
the time of surgery and, thus, the authors recommended earlier
RRSO to prevent peritoneal cancer.

Complications of TAH/BSO in Lynch syndrome are also
rare. Schmeler et al (20) reported only one case of ureteral
injury following creation of a Hartmann pouch, together with a
ureterovaginal fistula and a ureteroenteral fistula to the pouch.
The common complications associated with hysterectomy and
BSO are bleeding, infection and injuries to the urinary tract
and bowel, with complication rates of 1‑9% associated with
hysterectomy and BSO for benign conditions (20). There is no
report of follow-up after RRS in Lynch syndrome; however,
surveillance for patients with Lynch syndrome with or without
RRS is recommended as follows (40): For colorectal cancer,
lower gastrointestinal endoscopy should be performed every
1-2 years with removal of precancerous polyps, beginning at
20-25 years, or at an age 10 years younger compared to the
youngest age of diagnosis in the family; for gynecological
diseases, annual cytology and histological examinations of
the endometrium, transvaginal ultrasound and serum CA125
measurement are recommended; and for urinary system
diseases, routine urinalysis with cytology should be performed.
Recurrence of endometrial and ovarian cancer has not been

ADACHI et al: RISK-REDUCING SURGERY IN HEREDITARY GYNECOLOGICAL CANCER270

reported following RRS in Lynch syndrome (20). Primary
peritoneal cancer has been reported following hysterectomy
and BSO in 2 patients with Lynch syndrome (41); however, in
those cases the procedures were performed following occur-
rence of benign disease and endometrial cancer, respectively;
thus, no case of primary peritoneal cancer following RRS has
been reported. In a study of 223 patients with Lynch syndrome,
a digestive system tumor developed after the initial diagnosis
of endometrial cancer and ovarian cancer in 46 and 6 cases,
respectively (34); however, no case with a digestive system
tumor following RRS has been reported.

BSO is commonly performed in RRS for HBOC as well as
Lynch syndrome. Ovarian deficiency symptoms may develop
and they present a major concern, particularly in premenopausal
women (24). These symptoms begin with vasomotor effects
and mood disorders caused by menopausal symptoms and lead
to atrophic vaginitis, incontinence, osteoporosis, dyslipidemia
and associated arteriosclerotic diseases. Therapeutic methods
for ovarian failure syndrome include hormone replace-
ment therapies (HRTs), such as estrogen therapy (ET) and
estrogen̸progesterone therapy (EPT) (42). Bone density should
be measured within 1 year following surgery to evaluate the
risk of osteoporosis; risk factors for cardiovascular diseases,
such as hypercholesterolemia, hypertension, diabetes mellitus
and smoking history, should also be evaluated (43).

The side effects of HRT include endometrial, breast and
ovarian cancer and ET has been found to cause endometrial
cancer with a relative risk of 2.3 (95% CI: 2.1‑2.5) with
estrogen use compared to non-use (44). However, in a study
in which patients were randomly assigned to ET or placebo
following hysterectomy for stage I or II endometrial cancer,
with or without lymph node dissection, the recurrence
rates were 1.9% in the placebo and 2.3% in the ET group,
whereas mortality was 0.6% in the placebo and 0.8% in the
ET group (45). Based on those results, ET may be administered
in stage I or II endometrial cancer under careful observa-
tion. EPT does not increase the risk of endometrial cancer,
with a relative risk of 0.71 (95% CI: 0.56‑0.90) compared to
non-HRT patients (46). Therefore, the preferred regimen in
these patients is EPT, comprising 0.625 mg of conjugated
estrogen daily and 5-10 mg of medroxyprogesterone acetate
for ≥10 days over 28 days (47). However, EPT may increase
the risk of breast cancer and HRT in patients with breast
cancer may induce tumor cell proliferation; therefore, its use
is contraindicated (24). In a study with a follow-up of 11 years,
an increased risk of breast cancer was found with EPT, but not
with ET (48), with hazard ratios of 1.25 (95% CI: 1.07‑1.46)
with EPT and 0.77 (95% CI: 0.62‑0.95) with ET. Eden (49)
demonstrated that ET did not increase the risk of breast cancer
for at least 7-10 years. A study with a short-term follow-up of
3.6 years following RRSO in women with a BRCA1/2 muta-
tion demonstrated that HRT did not significantly increase
breast cancer risk compared to that in non-HRT patients, with
a hazard ratio of 1.35 (95% CI: 0.16‑11.58) (50). In BRCA1
mutation carriers, the hazard ratios for breast cancer risk are
0.63 (95% CI: 0.34‑1.16) within 3 years after HRT and 0.51
(95% CI: 0.24‑1.08) at >3 years after HRT. These results indicate
that ET or EPT may reduce breast cancer risk compared to no
HRT (51). The hazard ratio for ET was 0.51 (95% CI: 0.27‑0.98)
and that for EPT was 0.66 (95% CI: 0.34‑1.27).

In patients with Lynch syndrome, the risk of developing
breast cancer was reportedly 4-fold higher compared to that
of sporadic breast cancer (52), although a variation of breast
cancer risk following HRT has not been reported. However,
in postmenopausal women following hysterectomy, the hazard
ratio for breast cancer was found to be 0.77 (95% CI: 0.59‑1.01)
with HRT compared to placebo (42). Selective estrogen
receptor modulator (SERM) treatment reduces the risk of
breast cancer by 65% compared to no HRT (53) and the risk of
endometrial hyperplasia has been found not to differ between
combination therapy with ≥20 mg/day bazedoxifene, a
third-generation SERM, and 0.625 mg/day conjugated estrogen
for 1 year, compared to placebo (54). These results indicated
that HRT using a combined regimen may be used without risk
of increased breast and endometrial cancer. In patients with
HBOC who cannot undergo HRT, selective serotonin reuptake
inhibitors or serotonin noradrenaline reuptake inhibitors may
be used to improve vasomotor symptoms (55) (Table I).

Pearce et al (56) reported that the relative risk (hazard ratio)
of developing ovarian cancer was 1.22 (95% CI: 1.18‑1.27)
with ET and 1.10 (95% CI: 1.04‑1.16) with EPT, but remained
significantly increased compared to non-users. By contrast,
Lacey et al (57) observed a risk of developing ovarian cancer
of 1.89 (95% CI: 1.22‑2.95) with ET for >10 years and a rela-
tive risk of 3.09 (95% CI: 1.68‑5.68) for EPT therapy with
progestin used sequentially (progestin for <15 days per cycle) for >5 years. Those findings led to the conclusion that EPT
was significantly associated with the development of ovarian
cancer and to a more significant extent compared to ET (57).
However, another study reported that ET was associated
with a significant relative risk of 2.07 (95% CI: 1.50‑2.85),
whereas EPT had a relative (and non‑significant) risk of 1.18
(95% CI: 0.79‑1.76) (58). Therefore, there is currently no
consensus on whether ET or EPT is better for reducing the
risk of ovarian cancer.

6. Current status of RRS worldwide

The status of RRSO differs in Asia compared to Europe and
the United States (US). Miller et al (59) reported that the
percentage of carriers of BRCA1/2 mutations who underwent
RRSO ranged between 10 and 78% in Europe and the US,
but that the overwhelming majority of women were satis-
fied with their decision to undergo the surgery (86.4‑97%).
Factors positively associated with undergoing RRSO included
demographic variables, such as age, having had children
and educational level; medical variables, including family
history of ovarian cancer, personal history of ovarian cancer
and previous risk-reducing mastectomy; and psychosocial
variables, including beliefs, higher perceived ovarian cancer
risk and increased cancer-related distress. Regarding costs,
in the US, the rate of prophylactic oophorectomy covered by
health insurance was 18% in women with an ovarian cancer
family history and 20% in women with a known BRCA muta-
tion (60). Anderson et al (61) reported that the cost of RRSO
was 118,605 and 116,213 US$ per BRCA1 and BRCA2 muta-
tion carrier, respectively, which were lower compared to the
respective screening costs of 135,858 and 124,016 US$. The
quality-adjusted life years (QALYs) following RRSO were
18.39 and 17.69 in BRCA1 and BRCA2 mutation carriers,

MOLECULAR AND CLINICAL ONCOLOGY 3: 267-273, 2015 271

respectively and QALYs with screening were only 15.64 and
16.42, respectively. Those results indicated that, in patients
with HBOC, RRSO is cost-effective compared to annual
screening.

Yurgelun et al (62) reported that 21‑65% of patients with
Lynch syndrome selected RRS. The percentage of women who
were satisfied with their decision to undergo this type of surgery
was not reported. Total hysterectomy and BSO performed as
RRS in Lynch syndrome had a cost of 23,422 US$ per case
and the QALY value was 25.71, while annual screening cost
68,392 US$, with a QALY value of 25.17 and annual examina-
tions cost 100,484 US$, with a QALY value of 24.60. Those
results suggested that RRS in Lynch syndrome is highly
cost-effective compared to the other methods.

The findings of Miller et al (59) and Yurgelun et al (62)
clearly support RRS as an option for patients in Europe and
the US. By contrast, the number of studies on Asian patients is
limited. In Japan, RRS has rarely been performed in HBOC or
Lynch syndrome. In 2005, a woman in an HBOC family who
did not desire BRCA1/2 genetic diagnosis underwent RRSO at
the Cancer Institute Hospital in Tokyo (63). Reports of RRSO
in patients with HBOC include a case at Keio University
Hospital in 2008 (24) and a case at the Cancer Institute
Hospital in 2011 (64). In Lynch syndrome, modified radical
hysterectomy and BSO were performed as an early interven-
tion at the stage of atypical endometrial hyperplasia in a case
at Keio University Hospital in 2011 (65). In that case, a woman

aged 46 years with an MLH1 mutation, who wanted to bear
children, did not undergo surgery after endometrial hyper-
plasia was found in initial screening, but underwent surgery
following a histological examination that detected complex
endometrial hyperplasia with atypia. RRS is not common
in Japan, due to the limited number of genetic counseling
units and facilities that perform BRCA1/2 genetic tests, the
lack of coverage of RRS for HBOC and Lynch syndrome by
the health insurance system and insufficient knowledge and
experience of medical staff regarding genetic diagnosis (24).
In China, 12 patients with BRCA mutations were treated with
RRSO (66), but RRS for Lynch syndrome has not yet been
reported. In Asia, RRS is most common in Korea, based on a
study on RRSO in 21 patients with HBOC (67).

7. Conclusions

RRS may reduce the risk of ovarian and breast cancer in
patients with HBOC and the risk of endometrial and ovarian
cancer in patients with Lynch syndrome. The benefits of RRS
are a lower rate of complications and higher cost-effectiveness
compared to annual screening and routine examinations.
However, ovarian deficiency symptoms occur postoperatively
and tumors may still develop following surgery. Thus, RRS for
patients with HBOC or Lynch syndrome should be performed
only after informed consent is obtained, following detailed
explanation of the benefits and concerns. There are several

Table I. RRS for HBOC and Lynch syndrome.

Postoperative
considerations HBOC Lynch syndrome

Surgical Infection Ureteral injury
complications Perforation of the bladder Ureterovaginal fistula
Distal obstruction of the small bowel Ureteroenteral fistula
Perforation of the uterus
Treatment 20 mg/day bazedoxifene + 0.625 mg/day conjugated 20 mg/day bazedoxifene + 0.625 mg/day
of ovarian estrogen, as HRT reduces the risk of breast cancer conjugated estrogen, as HRT reduces risk of
deficiency and endometrial cancer. In cases with breast cancer, breast and endometrial cancers
symptoms an SSRI or SNRI is initiated.
Postoperative No consensus No information. As follow-up for Lynch syndrome
management Bone densitometry with or without RRS, the following are recommended:
Annual measurement of serum CA125 level Lower gastrointestinal endoscopy every 1-2 years
Annual internal examination and removal of precancerous polyps
Any of the above may be combined Annual cytology and histological examination
of the endometrium, transvaginal ultrasound
and serum CA125 level measurements
Routine urinalysis with cytology
Postoperative Breast cancer No information
occurrence Ovarian cancer
of tumors Fallopian tube cancer
Primary peritoneal cancer

HBOC, hereditary breast and ovarian cancer; HRT, hormone replacement therapy; SSRI, selective serotonin reuptake inhibitor; SNRI, sero-
tonin noradrenaline reuptake inhibitor; RRS, risk-reducing surgery.

ADACHI et al: RISK-REDUCING SURGERY IN HEREDITARY GYNECOLOGICAL CANCER272

problems associated with RRS that require further investiga-
tion, including the indications for Lynch syndrome, whether
hysterectomy should be combined with RRSO and follow-up
measures after surgery. Addressing these issues is expected
to make RRS more common and reduce the risk of cancer
development in patients with HBOC or Lynch syndrome.

Acknowledgements

We would like to thank Dr M. Moriya, Dr T. Kotani and
Dr K. Yuki for their helpful assistance. The authors gratefully
acknowledge grant support from the Japan Society for the
Promotion of Science through a Grant‑in‑Aid for Scientific
Research (KAKENHI), a Grant‑in‑Aid for Scientific Research
(C) (22591866) and a Grant‑in‑Aid for Young Scientists (B)
(24791718); the Medical Research Encouragement Prize of The
Japan Medical Association; and the Keio Gijuku Academic
Development Fund. The funders had no role in data collection
and the decision to publish.

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