Describe Perioperative Management of Women Undergoing Risk-reducing Surgery for Hereditary Breast and Ovarian Cancer.

Describe Perioperative Management of Women Undergoing Risk-reducing Surgery for Hereditary Breast and Ovarian Cancer.
Review Article

Perioperative Management of Women Undergoing Risk-reducing Surgery for Hereditary Breast and Ovarian Cancer

D1X XMariam M. AlHilli, D2X XMD, and D3X XZahraa Al-Hilli, D4X XMD From the Division of Gynecologic Oncology, Women’s Health Institute (Dr. AlHilli), Cleveland Clinic, Cleveland, Ohio, and Department of General Surgery,

Digestive Diseases and Surgery Institute (Dr. Al-Hilli), Cleveland Clinic, Cleveland, Ohio

ABSTRACT C

The authors decla

Corresponding au

Euclid Avenue, A

E-mail: alhillm@

Submitted July 11

Available at www

1553-4650/$ — (http://creativeco

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arriers of genetic mutations that predispose to cancer syndromes are often faced with complex decisions. For women with

hereditary breast and ovarian cancer in particular, the decision to undergo risk-reducing mastectomy or bilateral salpingo-

oophorectomy is burdensome from a physical and psychological perspective. Although risk-reducing surgery is the most

effective preventative measure in reducing a genetic mutation carrier’s risk of breast or ovarian cancer, the success of these

procedures requires a multidisciplinary approach that centers on careful counseling regarding the risks and benefits of risk-

reducing surgery. The physical and psychological distress associated with risk-reducing surgery often makes a combined

surgical approach attractive to some patients. In this review, we present the evidence surrounding the comprehensive surgi-

cal care of women with hereditary breast and ovarian cancer syndromes and evaluate the perioperative factors that influence

surgical management. Journal of Minimally Invasive Gynecology (2019) 26, 253−265 © 2018 Published by Elsevier Inc. on behalf of AAGL. This is an open access article under the CC BY-NC-ND license.

(http://creativecommons.org/licenses/by-nc-nd/4.0/)

Keywords: R

isk-reducing surgery; Risk-reducing mastectomy; Hereditary breast and ovarian cancer syndrome; BRCA; genetic
screening

re that they have no conflict of interest.

thor: Mariam M. AlHilli, MD, Cleveland Clinic, 9500

81, Cleveland, OH 44195.

ccf.org

, 2018, Accepted for publication September 6, 2018.

.sciencedirect.com and www.jmig.org

see front matter © 2018 Published by Elsevier Inc. on behalf of AAGL. This is an open access article under the CC BY-NC-ND license. mmons.org/licenses/by-nc-nd/4.0/)

.1016/j.jmig.2018.09.767

Approximately 5% to 10% of breast cancers are attrib-

uted to deleterious mutations in BRCA1 or BRCA2 genes,

which are key genes in DNA repair through homologous

recombination [1]. The cumulative risk of breast cancer by

80 years of age is 67% in BRCA1 carriers and 66% in

BRCA2 carriers [2,3].

After a diagnosis of breast cancer, BRCA mutation

carriers continue to have a substantial risk of developing

a new breast cancer. The likelihood of developing breast

cancer in an unaffected BRCA mutation carrier is

influenced by multiple factors such as the presence of

affected family members with the gene mutation and

age (calculated lifetime risk). A study by Van Den

Broek et al [4] of 6294 women diagnosed with breast

cancer under 50 years of age (including 271 women

with BRCA1 or BRCA2 mutations) showed that the

10-year cumulative contralateral breast cancer risk was

5.1% for noncarriers, 21.1% for BRCA1 mutation

carriers, and 10.8% for BRCA2 mutation carriers (hazard

ratio = 3.31 for BRCA carriers compared with

noncarriers). Interestingly, the age of first cancer was a

significant risk factor for contralateral breast cancer. In

women with a gene mutation who were diagnosed with

breast cancer before 41 years, the risk of contralateral

breast cancer was 23.9% compared with 12.6% for those

diagnosed between 41 and 49 years. This risk was found

to be even lower in women with no family history of

breast cancer.

Approximately 3% to 5% of women assessed for

hereditary breast cancer through multigene panel testing

are found to have mutations in genes of moderate pene-

trance such as PALB2, CHEK2, and ATM (Table 1). In

relation to these breast cancer−related genes, providing accurate estimates for breast cancer risk based on age

and life expectancy has been challenging because of the

limited availability of data. Furthermore, the success of

breast cancer screening may mitigate some of the

increased risks. Risk-reducing surgery is currently

not recommended for carriers of low to moderate

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Table 1

Hereditary Syndromes Associated with Breast and Ovarian Cancer 1

Genetic Mutation/Syndrome Estimated Breast Cancer

Risk Up to Age 70 Years

Estimated Ovarian

Cancer Risk Up to Age 70

Years

Management Recommendations

BRCA1 »55%−70% »39%−46% Annual screening MRI (or mammogram with tomosynthe- sis) at age 25 years

Discuss RRM

RRSO by age 35−40 years Transvaginal ultrasound and CA 125 at age 30-35 years*

BRCA2 »45%−70% »10%−27% Annual screening MRI (or mammogram with tomosynthe- sis) at age 25 years

Discuss RRM

RRSO by age 40−45 years Transvaginal ultrasound and CA 125 at age 30−35 years*

BRIP1 No increased risk »7%−10% RRSO by age 45−50 years CDH1: hereditary diffuse

gastric cancer

Increased risk of lobular

carcinoma »60% No increased risk Annual screening mammogram

Breast MRI with contrast at age 30 years

Insufficient evidence for RRM

CHEK2 »37% No increased risk Annual screening mammogram Breast MRI with contrast at age 30 years

Insufficient evidence for RRM

MSH2, MLH1, MSH6, PMS2,

EPCAM: Lynch syndrome

Unknown risk MLH1 »11%−20% MSH2 »15%−24% MSH6 »1% PMS2 »0%

RRSO by age 40 years or after completion of childbearing

Transvaginal ultrasound and CA 125 at age 30−35 years*

ATM »24% No increased risk Annual screening mammogram Breast MRI with contrast at age 40 years

Insufficient evidence for RRM

PALB2 »35%−70% Unknown risk Annual screening mammogram Breast MRI with contrast at age 30

Insufficient evidence for RRM

PTEN: Cowden syndrome;

PTEN hamartoma tumor

syndrome

»50% No increased risk Annual screening mammogram Breast MRI with contrast at age 30 years

Discuss RRM

RAD51C Unknown risk »5%−12% RRSO by age 50−55 years RAD51D Unknown risk »5%−12% RRSO by age 45−50 years STK11: Peutz-Jeghers

syndrome

»45%−50% »18%−21% risk of none- pithelial ovarian cancer

Annual screening mammogram and breast MRI at age 25

Annual pelvic examination at age 18−20 years

TP53: Li-Fraumeni syndrome »50% No increased risk Annual breast MRI with contrast at age 20 years Breast MRI with contrast at age 30 years

Discuss RRM

CA 125 = cancer antigen 125; MRI = magnetic resonance imaging; RRM = risk-reducing mastectomy; RRSO = risk-reducing salpingo-oophorectomy.

* If RRSO not performed, transvaginal ultrasound/CA 125 are offered. There is insufficient evidence (National Comprehensive Cancer Network Clinical Practice Guidelines

in Oncology 2018; Genetics/ Familial High-Risk Assessment: Breast and Ovarian Cancer).

254 Journal of Minimally Invasive Gynecology. Vol 26, No 2, February 2019

penetrance genes. However, the available data do sup-

port risk-reducing mastectomy (RRM) for carriers of

BRCA1, BRCA2, PTEN, and TP53 mutations.

Ovarian Cancer Risk

Carriers of BRCA1 or BRCA2 mutations have a cumula-

tive lifetime risk of ovarian cancer of 15% to 40% [1].

Women with a BRCA1 mutation have a 39% to 46% risk

for ovarian, fallopian tube, or primary peritoneal cancer

(referred to cumulatively as ovarian cancer) by age 70.

Women with mutations in BRCA2 have a 10% to 27% risk

of ovarian cancer [5,6]. Additionally, up to 25% of women

with ovarian cancer may harbor germline mutations

in homologous recombination genes (e.g., RAD51C,

RAD51D, and BRIP1) other than BRCA1 and BRCA2 [3].

Table 1 shows other genes associated with hereditary

ovarian cancer and management recommendations. Given

the substantial risk of identifying a genetic mutation in

a patient diagnosed with ovarian cancer, genetic testing

is currently recommended for all women with epithelial

ovarian cancer [1,6].

AlHilli and Al-Hilli Perioperative Management of Women Undergoing Risk-reducing Surgery 255

Approach to the Management of Women with

Hereditary Breast and Ovarian Cancer

Genetic Risk Evaluation and Testing

Criteria for genetic risk evaluation for hereditary breast

and ovarian cancer (HBOC) include a personal history of

ovarian cancer; a personal history of breast cancer in the

setting of a known mutation in the family; breast cancer

diagnosed ≤ 50 years of age; triple-negative breast cancer; 2 breast primaries in a single individual; breast cancer with

multiple family members with breast, ovarian, or prostate

cancer; family history of male breast cancer; Ashkenazi

Jewish descent; family history of multiple primary cancers;

and a first- or second-degree relative with breast cancer

≤ 45 years of age [1]. Genetic counseling is a key component in the manage-

ment of women with HBOC. The primary goal of genetic

counseling is to formally assess a patient’s personal and

family history with respect to hereditary cancers and to

provide an estimate of the likelihood that an inherited

genetic mutation is present [1,6]. The patient’s knowledge,

concerns, goals, and needs are evaluated at the time of

genetic consultation and before genetic testing. Education

regarding differential diagnosis, inheritance patterns and

penetrance, possible outcomes of testing, screening, pre-

vention, and risk-reducing strategies is initiated at that time

[6]. Post-test counseling is an important aspect of patient

management and education. Details of the results, their sig-

nificance, and impact of recommendations should be

discussed; family members are to be informed, and testing

and resources should be provided [1].

At this time, most centers offer genetic testing through

commercially developed multigene panel tests instead of

single gene testing unless a specific inherited genetic

mutation has been previously identified in a family mem-

ber. Multigene panel tests are based on next-generation

sequencing and allow the simultaneous evaluation of

multiple genes including those with moderate penetrance

[16]. This approach has some limitations including uncer-

tainty regarding the management of genes of intermediate

penetrance, variants of uncertain significance, and individu-

als with negative testing but strong family histories [1].

Breast Cancer Screening

Recommendations for breast cancer screening for

women with HBOC include breast awareness, clinical

breast examinations, and breast imaging. In general, breast

awareness and regular monthly self-breast examinations

start at the age of 18 years. Clinical breast examinations

begin at 25 years of age. Between the ages of 25 and

29 years, annual breast magnetic resonance imaging (MRI)

with contrast is performed (this should be performed on

days 7−15 of the menstrual cycle) or annual mammograms if MRI is not available. Between the ages of 30 and

75 years, annual mammography is recommended,

alternating every 6 months with annual breast MRI. Tomo-

synthesis can be considered with or without 2-dimensional

mammography, particularly in women with increased

breast density, because it is superior to mammography in

the detection of abnormalities within the breast. However,

this is not routinely performed or may not be widely avail-

able. Screening beyond 75 years is unclear and is consid-

ered on a case-by-case basis based on patient current health

and life expectancy [1].

Mammography has a sensitivity and specificity of 77%

to 95% and 94% to 97%, respectively [7]. The most recent

update for the US Preventive Services Task Force included

a review of 8 randomized trials of mammographic screen-

ing [8]. Mammographic screening was found to reduce the

risk of breast cancer mortality for women between 39 and

69 years old. A reduction in cancer mortality of 15% was

observed for women aged 39 to 49 years (relative risk

[RR] = 0.85; 95% confidence interval [CI], 0.75−0.96). Data regarding women aged 70 years or older are lacking.

In comparison with mammography, MRI screening has

been shown to have a higher sensitivity. However, it is

important to note that MRI screening may be associated

with higher false-positive rates and a higher cost.

Ovarian Cancer Screening

In comparison with breast cancer screening, there are no

screening tests that have been deemed effective in improv-

ing the detection of ovarian or fallopian tube cancer [9].

Studies that evaluate ovarian cancer screening strategies

have not shown an improvement in survival [1]. The cur-

rently available screening modalities including transvaginal

ultrasound and cancer antigen 125 (CA 125) have not been

shown to reduce mortality related to ovarian cancer

[10,11]. Other large prospective studies in high-risk women

have suggested the possibility of early detection of ovarian

cancer through screening with transvaginal ultrasound and

CA 125 (using the risk of ovarian cancer algorithm) [12].

However, the impact on mortality in these patients has not

been established. As such, risk-reducing surgery is the rec-

ommended strategy for reduction in ovarian cancer risk in

carriers of genetic mutations. Based on National Compre-

hensive Cancer Network guidelines, performing CA 125

and pelvic ultrasound starting at age 30 to 35 years is left to

the provider’s discretion [1].

Chemoprophylaxis

Breast cancer risk reduction elements include lifestyle

modification, surgical prophylaxis, and chemopreven-

tion. Risk-reducing chemoprevention agents include the

selective estrogen receptor modulators tamoxifen and

raloxifene and the aromatase inhibitors anastrozole and

exemestane. (The latter 2 are yet to be Food and Drug

Administration approved for breast cancer risk reduction

purposes.) Tamoxifen is used for premenopausal

256 Journal of Minimally Invasive Gynecology. Vol 26, No 2, February 2019

women, whereas all 4 can be used for postmenopausal

woman; this choice will be influenced by patient comor-

bidities and risk considerations. The challenge with che-

moprevention recommendations in gene mutation

carriers is the limited data available on the use of these

agents for risk reduction in this cohort. Studies have

shown that the use of tamoxifen was associated with an

approximately 45% to 60% reduction in the risk of con-

tralateral breast cancer in affected women with BRCA1

and 2 mutations [13,14]. The National Surgical Adju-

vant Breast and Bowel Project Breast Cancer Prevention

Trial (P-1) was a randomized trial evaluating the role of

tamoxifen for the prevention of breast cancer in unaf-

fected women considered to be high risk for the disease

[15]. BRCA2 patients, who typically develop estrogen

receptor−positive tumors, achieved a 62% reduction in breast cancer risk with the use of tamoxifen compared

with placebo. On the other hand, BRCA1 mutation car-

riers did not achieve risk reduction with tamoxifen,

likely because of the propensity for developing estrogen

receptor−negative tumors in these patients. It is impor- tant to interpret chemoprevention benefit data in muta-

tion carriers with caution because of the small number

of patients included in studies. In addition, little is

known about the role of chemoprevention in non-BRCA

gene mutation carriers.

With regard to ovarian cancer risk reduction, the use

of combined oral contraceptive pills has been shown to

be associated with a 40% to 50% reduction in the risk

of ovarian cancer [16]. In a case-control study by Narod

et al [17], the use of oral contraceptives was associated

with a significant reduction in the risk of ovarian cancer

in both BRCA1 and BRCA2 mutation carriers [5]. This

risk decreased with increasing duration of the use of

oral contraceptives. As such, the use of combined oral

contraceptives is considered to be a potential chemo-

preventive strategy in women with BRCA mutations

[16]. Data on the effect of oral contraception on breast

cancer risk among BRCA1/2 mutation carriers have been

conflicting. Some case-control studies have reported a

modest increased risk of breast cancer among BRCA1

but not BRCA2 mutation carriers, whereas others have

reported no increased risk [17,18]. However, at least 2

meta-analyses showed no increased risk of breast cancer

in women with a BRCA1/2 mutation who used oral con-

traception [19,20].

Risk-reducing Surgical Options for Women with HBOC

Risk-reducing salpingo-oophorectomy (RRSO) has been

shown to reduce the risk of ovarian cancer by 96%, breast

cancer by 50% to 75%, and all-cause mortality in unaf-

fected women [5,21−23]. Therefore, RRSO is the most effective strategy for decreasing the incidence of ovarian

cancer and mortality in high-risk women with hereditary

mutations. For women identified to have a BRCA1

mutation, national guidelines recommend RRSO between

the ages of 35 to 40 years because risk begins to increase in

these patients in their late 30s [6,16]. Carriers of the

BRCA2 mutation have a later age of onset of ovarian can-

cer, and RRSO is recommended between ages 40 and

45 years in these patients. Prospective studies of women

with BRCA1 and BRCA2 mutations show that approxi-

mately 60% of women will opt for RRSO [24].

RRM reduces the risk of breast cancer by 90% to 97%.

RRM can occur in conjunction with or as an alternative to

high-risk screening. Bilateral RRM (BRRM) may be con-

sidered in women without a personal history of breast can-

cer. On the other hand, women with a diagnosis of breast

cancer continue to carry an elevated risk for breast cancer

in the affected or contralateral breast. Therefore, these

patients may consider contralateral RRM (CRRM).

In general, women with a confirmed genetic mutation in

BRCA1 or BRCA2 or other genes with an elevated risk for

breast or ovarian cancer are offered risk-reducing surgery.

Women with negative genetic testing but a first-degree rela-

tive with epithelial ovarian cancer are estimated to have a

risk of 5% of developing ovarian cancer and also qualify

for RRSO. In the absence of a pathogenic mutation, an ele-

vated risk based on family history assessment of breast and/

or ovarian cancer risk is an appropriate indication for risk-

reducing surgery [3] (Fig. 1).

RRSO

Preoperative Counseling

Investigations into the psychosocial impact of risk-

reducing surgery show that surgery is associated with a sig-

nificant decline in psychological morbidity and anxiety

without an increase in negative body impact or a decrease

in sexual functioning [9]. Nevertheless, the decision to

undergo RRSO is complex and requires early consultation

with a gynecologic oncologist as well as a provider with

expertise in genetic counseling and testing [6]. At the time

of counseling, a thorough discussion on the impact of

RRSO on reproduction, breast and ovarian cancer risk, and

the long-term risk of premature menopause (including oste-

oporosis, cardiovascular disease, and sexual concerns) must

be had. A review of the impact of this intervention on qual-

ity of life is of high importance [1]. In addition, hormone

replacement therapy (HRT) is encouraged in women with-

out contraindications for estrogen and/or progesterone

replacement. This strategy of HRT after surgical meno-

pausal minimizes and ameliorates the potential detrimental

consequences of surgical menopause [3]. Although con-

cerns have been raised about a possible increase in breast

cancer risk with the use of HRT in premenopausal women,

it is important to discuss with patients that HRT has been

deemed to be safe in women with BRCA1 mutations, and an

increase in the risk of breast cancer among women taking

HRT has not been observed in prospective studies [22,25].

Fig. 1

Evaluation and management of women with suspected or confirmed hereditary breast and ovarian cancer syndrome.

Personal history of high grade epithelial ovarian cancer Personal history of breast cancer:

– ≤50 years – Triple negative breast cancer – Two breast cancer primaries – Family history of breast or ovarian or other

cancers – Male breast cancer

Ashkenazi Jewish descent First or second degree family member with breast cancer ≤45 years Family history of breast or ovarian cancer Family history of multiple cancers

Referral for consulta�on with a gene�cs counselor

Gene�c tes�ng if indicated

Hereditary breast and ovarian cancer confirmed

Ovarian cancer risk managementBreast cancer risk management

Breast cancer high-risk screening Risk –reducing mastectomy when sufficient evidence to recommend

Offer screening with transvaginal ultrasound and CA125 age 30-35

Risk-reducing salpingo- oophorectomy between 35-40

years (BRCA1 muta�on carriers) and 40-45 (BRCA2 muta�on

carriers) or a�er comple�on of childbearing

AlHilli and Al-Hilli Perioperative Management of Women Undergoing Risk-reducing Surgery 257

Rebbeck et al [21] showed that the short-term use of HRT

until the average age of menopause in premenopausal

women undergoing RRSO generally did not increase the

risk of breast cancer. A strategy of limiting HRT duration to

the age of 51 years (the average age of menopause) is gener-

ally recommended. In a decision analytic model developed

by Armstrong et al [26], RRSO was found to be associated

with an increase in life expectancy in patients with a

BRCA1/2 mutation regardless of HRT use. A decrement in

life expectancy was noted when HRT was continued for life

versus when HRT was stopped at age 50 years [26].

Patients should be counseled about the risk of detec-

tion of occult ovarian, fallopian tube, or primary perito-

neal carcinoma at the time of risk-reducing surgery,

which would necessitate surgical staging [9,27].

Furthermore, women who opt for RRSO before the

completion of childbearing should be counseled about

alternative reproductive options and referred appropri-

ately to a reproductive endocrinology specialist. They

should be informed about the option of undergoing

embryo or ovarian cryopreservation as well as preim-

plantation genetic diagnosis [1].

258 Journal of Minimally Invasive Gynecology. Vol 26, No 2, February 2019

Decision Regarding Concurrent Hysterectomy

Counseling regarding the risks and benefits of con-

current hysterectomy at the time of RRSO is an impor-

tant point of discussion. Hysterectomy is currently

offered electively to women undergoing RRSO. Women

with a gynecologic indication for hysterectomy includ-

ing those with a known history of Lynch syndrome are

likely to benefit from the addition of hysterectomy. Pre-

menopausal women without a personal history of breast

cancer who undergo RRSO are also offered hysterec-

tomy to simplify hormone replacement [9]. The use of

estrogen alone after hysterectomy is considered to be

safer than combined estrogen and progesterone with

regard to breast cancer risk [28].

It has been suggested that concurrent hysterectomy at

the time of RRSO may provide long-term survival bene-

fits when the risk of uterine cancer is taken into consid-

eration [16]. Data regarding the increased risk of uterine

serous carcinoma among BRCA mutation carriers are

conflicting. BRCA1 mutation carriers have been pro-

posed to be at highest risk. In a prospective review of

1083 women with BRCA mutations who underwent

RRSO with uterine conservation, an increased risk of

serous endometrial carcinoma was noted in BRCA1

mutation carriers (observed:expected risk ratio = 22.2;

95% CI, 6.1−56.9; p < .001) [29,30]. However, at this time, the decision to perform hysterectomy at the time of RRSO is individualized after balancing the surgical risks and benefits of the procedure. Delayed Oophorectomy Delayed oophorectomy has been proposed to avoid premature menopause. The performance of risk-reducing salpingectomy alone in genetic mutation carriers who wish to preserve fertility and ovarian function is based on the accepted paradigm that serous tubal intraepithe- lial carcinoma is a precursor lesion for invasive carci- noma [31]. Although retrospective studies in low-risk women suggest a 35% to 42% reduction in the risk of ovarian cancer after salpingectomy, this is not consid- ered to be sufficient evidence to recommend salpingec- tomy in high-risk women [1]. Furthermore, carriers of BRCA1/2 mutations who undergo salpingectomy may not receive the benefit of a reduction of breast cancer risk (by 50%) if oophorectomy is delayed [1]. Other concerns include the possibility that serous tubal intrae- pithelial carcinoma lesions may represent metastases from ovarian primary lesions in about 50% of cases [3]. Furthermore, 70% of occult carcinomas are found to originate in the fallopian tubes, which implies that one third of occult carcinomas that arise outside of the fallo- pian tubes would not be prevented with salpingectomy. Therefore, despite its feasibility, bilateral salpingectomy alone is not considered the standard of care with regard to risk reduction because the role of this procedure in BRCA mutation carriers has not been adequately vali- dated. Prospective studies are currently underway including the TUBA study (NCT02321228), which explores the impact of bilateral salpingectomy with delayed oophorectomy on quality of life as well as ovar- ian and breast cancer risk [3,32]. Intraoperative Considerations As described by the Society of Gynecologic Oncology and the American College of Obstetrics and Gynecology, the opti- mal technique for RRSO involves a systematic approach [33]. This process involves minor modifications in comparison with standard bilateral salpingo-oopherectomy (BSO) per- formed for other indications. A laparoscopic approach is gen- erally undertaken [9]. An abdominal survey is performed, and all peritoneal surfaces are inspected. Peritoneal washings are routinely obtained [6,34]. To ensure complete removal of the adnexa, the retroperitoneal space is entered. If adhesions between the ovary and pelvic side wall are encountered, they must be resected along with the ovary [9]. Prevention of ovar- ian remnant syndrome is of high importance in this patient population. The fallopian tubes are removed at their insertion point in the uterus if hysterectomy is not performed. The importance of complete removal of the fallopian tube is attributed to the high rate of occurrence of fallopian tube can- cers among BRCA mutation carriers [35]. These patients have a 120-fold increased risk of fallopian tube cancer compared with the general population [9]. The ovarian vessels are ligated at the pelvic brim. Postoperatively, meticulous histologic evaluation of the fallopian tubes and ovaries with sectioning in 2 to 3 mm is performed. This protocol, known as Sectioning and Exten- sively Examining the Fimbriated End of the fallopian tube, has been shown to increase the detection of serous carcinoma that arises in the fimbriated end of the fallopian tube in 50% of patients regardless of BRCA status [22,36,37]. Box 1 describes best practice recommendations for RRSO. Adher- ence to these guidelines may impact prognosis and minimize the risk of missing an occult malignancy. In a retrospective study of 263 patients undergoing RRSO performed by gen- eral gynecologists compared with gynecologic oncologists, it was found that gynecologic oncologists are more likely to adhere to best practice guidelines and a meticulous RRSO technique [34,38]. Particularly, gynecologic oncologists were more likely to perform pelvic washings, include a description of the upper abdomen in the operative report, use a retroperi- toneal approach, and undergo careful pathologic examination of the specimens. In order to maximize the benefit from RRSO, referral of women desiring RRSO to surgeons with specialized training in pelvic surgery and those with expertise in caring for high-risk women is advocated. AlHilli and Al-Hilli Perioperative Management of Women Undergoing Risk-reducing Surgery 259 Box 1 Best Practice Recommendations for Risk-reducing Bilateral Sal- pingo-oophorectomy Preoperative � Pelvic ultrasound and cancer antigen 125 at least within 6 months of surgery � Counseling regarding reproductive desires, menopausal symp- toms, cancer risk, and hormone replacement Intraoperative � Abdominal and pelvic survey and close evaluation of peritoneal surfaces, bowel, and pelvic organs � Pelvic washings (50 mL normal saline instilled and aspirated) � Complete removal of the fallopian tube at isthmus � Ligation of ovarian vessels at pelvic brim (at least 2 cm proximal to ovary) � Removal of all peritoneum around ovaries/fallopian tubes, espe- cially if adhesions present Postoperative � Histologic evaluation and processing using the Sectioning and Extensively Examining the Fimbriated End of the fallopian tube approach (2- to 3-mm sections) � Referral to genetics and gynecologic or surgical oncology if occult malignancy or serous tubal intraepithelial carcinoma is diagnosed Risk of Occult Malignancy at the Time of RRSO The detection of an occult ovarian malignancy and sub- sequent management has important implications. The inci- dence of occult malignancy at the time of RRSO has been described to range between 0.6% and 18.5% [39,40]. An analysis of 966 RRSO procedures estimated a rate of inva- sive ovarian/tubal or peritoneal carcinoma of 4.6% in BRCA1 mutation carriers and 3.5% in BRCA2 carriers [39]. This risk increases with age to 20% over the age of 45 years [28]. It has been proposed that the surgical technique may account for the variability in the detection rate of occult malignancy at the time of RRSO, which has been described in the literature [27,34,38]. Given the elevated risk of occult malignancy in genetic mutation carriers, preoperative eval- uation with transvaginal ultrasound and CA 125 is warranted before RRSO. The risk of development of pri- mary peritoneal cancer after RRSO has been reported to be 2% to 4% in women over 20 years old [22]. Perioperative Morbidity Associated with RRSO A laparoscopic approach to RRSO is considered the standard of care in the management of women with an increased risk for ovarian cancer. This procedure is per- formed as an outpatient procedure, and over 98% of patients are able to be dismissed home on the same day as surgery [41]. Complications related to RRSO are rare. Reports vary with regard to the described compli- cation rates from RRSO. Kauff et al [24] reported 4 complications among 80 patients (5%) undergoing RRSO. Similarly, Bogani et al [42] recently reported a complication rate of 4.7% within 30 days of surgery, which included fever and postoperative ileus. Severe complications were not observed, and all complications were managed conservatively. In a review of all RRSO procedures performed during a 10-year period at Brigham and Women’s Hospital, Boston, MA, it was found that the conversion rate to laparotomy was 2% for laparoscopic RRSO (5 because of adhesions, 1 because of a difficult entry, and 1 because of malignancy) [41]. Other outcome measures studied included estimated blood loss, which was reported to be negligible (<50 mL in 97% of patients), and absence of intraoperative complications. RRM Extent of Cancer Risk Reduction and Mortality Associated with RRM A recently published Cochrane Review update reported on the effects of RRM on breast cancer incidence, overall mortality, breast cancer−related mortality, disease-free sur- vival, physical morbidity, and psychosocial outcomes [43]. The review included 61 studies (no randomized trials avail- able for analysis) of 15 077 women who underwent RRM. The data were analyzed separately for BRRM and CRRM. The publication concluded that BRRM was effective in reducing both the incidence and mortality from breast can- cer. On the other hand, although CRRM was found to reduce the incidence of contralateral breast cancer, there was insufficient evidence that CRRM improves survival because of ongoing risk of recurrence or metastases from the original cancer. A meta-analysis by Li et al [44] investigated the effec- tiveness of risk-reducing surgery in women with BRCA1 and BRCA2 mutations. In 2555 patients, breast cancer risk corresponded to a relative risk [RR] of 0.114 for gene muta- tion carriers undergoing BRRM compared with those who did not have surgery. BRRM decreased the incidence of breast cancer in BRCA1 (RR = 0.134; 95% CI, 0.019 −0.937) and BRCA2 gene mutation carriers (RR = 0.183; 95% CI, 0.072−0.468). Furthermore, CRRM decreased the incidence of contralateral breast cancer (BRCA1 and 2: RR = 0.072; 95% CI, 0.035−0.148) and significantly decreased all-cause mortality compared with patients who did not undergo CRRM (hazard ratio = 0.512; 95% CI, 0.368−0.714). Surgical Options for Breast Cancer Risk Reduction There are a number of techniques available, including total or simple mastectomy (removal of both breasts, nip- ple-areolar complex [NAC], and the overlying skin), skin- sparing mastectomy (removal of both breasts and NAC with preservation of the overlying skin), and nipple-sparing mastectomy (NSM) (removal of both breasts with 260 Journal of Minimally Invasive Gynecology. Vol 26, No 2, February 2019 preservation of the NAC and the overlying skin). Subcuta- neous mastectomy was a traditional approach that has been abandoned as a therapeutic or prophylactic option in breast surgery because of the risk of leaving a significant amount of residual tissue. Furthermore, modified radical mastec- tomy (total mastectomy with axillary lymph node dissec- tion) is not performed without an oncologic indication because of the risk of axillary and arm morbidity. NSM has emerged over recent decades as an option for the treatment and prevention of breast cancer in selected women (Fig. 2). This procedure has the advantage of pre- serving the NAC to optimize cosmesis after mastectomy and also facilitates the process of breast reconstruction [45,46]. Studies have shown high patient satisfaction with the procedure [45]. In addition, NSM is associated with higher patient psychosocial and sexual well-being when compared with patients having skin-sparing mastectomy with removal of the NAC [47]. There are several reports of bilateral NSM for breast cancer risk reduction focusing mainly on patients with mutations in the BRCA1 and BRCA2 genes [48−51]. The main concern with NSM and surgical prophylaxis is the insufficient oncologic follow-up data available compared with other procedures. In addition, it is unknown if the presence of residual terminal duct lobu- lar units in the NAC confers a potential risk of cancer. Despite this, NSM with reconstruction has become a favored option for select women undergoing RRM. Breast reconstruction is an integral part of breast sur- gery, both in the therapeutic and prophylactic setting. A multidisciplinary team approach to patient management, with inclusion of a reconstructive surgeon as part of the team, is key to ensuring appropriate patient and procedure selection. Reconstruction options broadly include immedi- ate or delayed reconstruction with 1 or 2 staged procedures that could involve the use of breast implants or autologous tissue reconstruction. In the setting of secondary Fig. 2 Bilateral nipple-sparing mastectomy. (a) The preoperative image. (b) The postop prevention, in women with a diagnosis of breast cancer, considerations to bear in mind include the potential need for radiation to the chest wall and/or nodal basins because this could potentially increase the risk of complications with reconstruction. Therefore, careful planning of timing and the type of procedure are important. More importantly, women should be counseled that RRM does not completely eliminate the risk of breast can- cer after mastectomy. Furthermore, although RRM may increase psychological peace of mind, it can be associated with surgical morbidity, potential for multiple surgical pro- cedures, reduced tactile sensation of the breast and NAC, and potential for diminished satisfaction with body image. The optimal surgical and reconstruction approach must be individualized, taking into consideration patient factors and, in the case of secondary prevention, oncologic and treatment factors. Risk of Occult Malignancy at the Time of RRM Occult cancers have been found in up to 15% of patients undergoing RRM [52−55]. As such, the role of sentinel lymph node biopsy with RRM has been debated, and rec- ommendations are conflicting. The finding of occult cancer would require additional axillary staging, which could mean a return to the operating room for a second surgery (axillary lymph node dissection). This second surgery can potentially add surgical and psychological morbidity to the patient. Some studies examining the rate of occult invasive breast cancer have suggested that the addition of MRI and sentinel lymph node biopsy are neither cost-effective nor do they reduce overall morbidity. A study investigating risk factors associated with the identification of occult malig- nancy in high-risk lesion women undergoing CRRM revealed that the rate of occult malignancy was similar among patients with a genetic mutation, those who test erative image. AlHilli and Al-Hilli Perioperative Management of Women Undergoing Risk-reducing Surgery 261 negative, and those who had no testing [52,56]. Further- more, neither MRI nor genetic testing were associated with the identification of a high-risk lesion or occult malignancy. Therefore, upon balancing the risks and benefits of the procedure, sentinel lymph node surgery is not routinely performed or recommended. Obtaining up-to-date imaging is recommended before surgery in order to help identify a potential occult breast cancer. Perioperative Morbidity Associated with RRM In general, breast surgery is associated with low postop- erative complication rates and an even lower mortality rate. Complication rates after mastectomy with reconstruction have been reported to be in the range of 2% to 49% [57−60]. Data from the American College of Surgeons National Surgical Quality Improvement Program database (including breast cancer patients with or without a genetic mutation) revealed a total complication rate of 11.2% in women undergoing immediate reconstruction compared with 9.2% in those undergoing mastectomy alone (p < .001). Predictors of complications included obesity, autologous reconstruction, smoking, bilateral procedures, patient comorbidity, and diabetes [61]. A limited number of studies report on morbidity associ- ated with RRM. Reoperation rates range from 4% in women undergoing RRM without reconstruction to 64% in women undergoing RRM with reconstruction [43,62−68]. Reported complications include wound infection, flap complications (skin necrosis, flap loss, and donor-site com- plications), hematoma, seroma, implant complications (including capsular contraction, implant loss or rupture, and expander port leakage), and pain. A higher risk of com- plications is noted to be associated with increasing body mass index and smoking. Concurrent RRM and BSO Rationale for Concurrent Risk-reducing Surgery RRSO can be performed before, concurrently, or after mastectomy and reconstruction as a staged procedure [69,70]. There is no consensus on the optimal sequence of procedures in women without a diagnosis of malignancy who are found to be carriers of a genetic mutation [69]. Practice patterns generally vary by provider and institution. From a patient perspective, the oncologic status often dic- tates the timing of surgery (i.e., some patients undergoing mastectomy for the treatment of breast cancer may not be aware of their genetic risk before surgery and cancer treat- ment). On the other hand, BRCA mutation carriers are often diagnosed in the setting of strong family history and usually undergo prophylactic procedures under elective conditions [69]. BRRM with immediate reconstruction is the most common procedure performed in this patient population. Breast reconstruction options can range from implant- based reconstruction to more complex autologous recon- struction options. Autologous breast reconstruction is the preferred reconstructive approach in young healthy patients where possible. These procedures are typically lengthy and technically complicated. Importantly, the timing of these procedures may have implications on abdominal wall com- plication risk. Performing a staged procedure (with RRSO at the staged procedure) can be coordinated with 1 of the secondary reconstructive procedures a few months after ini- tial surgery. The benefits of a staged procedure include potentially lowering of infection rates, protection of the myocutaneous flap, and allowing secure closure of the abdominal wall [71]. Feasibility of Breast Reconstruction after RRSO Prior abdominal surgery can hinder microsurgical breast reconstruction. Hysterectomy and BSO performed before breast reconstruction (particularly if through a midline inci- sion) place limitations on the use of an autologous flap as well as concerns regarding perfusion across the scar. Even after a laparoscopic or robotic approach, there is a theoretic risk that perforators of the deep inferior epigastric vessels would be injured during placement of ports or scarring of the rectus muscle, which would potentially compromise breast reconstruction [69]. Khansa et al [69] found that microsurgical breast reconstruction performed after hyster- ectomy and BSO did not increase the risk of abdominal wall hernia or the use of mesh. However, the ability to per- form an abdominal flap reconstruction is minimized. In addition, a prior Pfannenstiel incision can exclude a patient from autologous reconstruction because of injury to the superficial inferior epigastric vessels. Feasibility of RRSO after Breast Reconstruction Approximately 70% of patients undergoing RRSO have a personal history of breast cancer [24]. As such, some of these patients may have had prior abdominal flap recon- struction [24,72]. Although risk-reducing gynecologic sur- gery performed after breast reconstruction is feasible, the duration of surgery is significantly increased in this setting [69]. Abdominal insufflation during laparoscopy can be hindered by previous flap harvest. The increased tightness of the abdominal wall, particularly if fascia is harvested or mesh is placed, makes abdominal exposure difficult and increases the risk of conversion [69]. Studies that have evaluated the safety of RRSO after transverse rectus abdominus muscle (TRAM) flap recon- struction show high rates of success after gynecologic pro- cedures. Awtrey et al [72] reported on their experience with RRSO in 102 patients with prior history of breast cancer, 10 of whom had previously undergone TRAM flap recon- struction. No difference was noted in estimated blood loss, length of hospital stay, or intraoperative/postoperative 262 Journal of Minimally Invasive Gynecology. Vol 26, No 2, February 2019 complication rates. However, patients who had undergone prior TRAM were noted to have significantly longer opera- tive times (91 vs 70 minutes, p < .01) [72]. Concurrent RRSO with Mastectomy and Breast Reconstruction An increasing number of women undergoing RRM are electing to undergo immediate reconstruction [73]. Hence, performing concurrent RRSO with breast surgery is a ratio- nal choice. Patient satisfaction with combined procedures in general has been reported to be high without incurring an increase in postoperative morbidity [74]. Concurrent RRSO with mastectomy and breast reconstruction has important advantages. It provides patients with the convenience of having a single operation and recovery, shortens recovery time, and reduces cost of care [75]. It has been further pro- posed that the burden of having 2 separate procedures could impact a woman’s decision to undergo RRSO in the setting of a diagnosis of breast cancer, whereas coordinated sur- gery may mitigate this factor. Safety and Efficacy of Concurrent Risk-reducing Procedures Some potential risks of concurrent mastectomy with RRSO, particularly in the setting of breast reconstruction, have been raised. The placement of patients in the Trende- lenburg position after flap revascularization could also increase the risk of vascular compromise, flap avulsion, or compromise of vascular pedicle [69,72]. In addition, there is concern for an increase in the risk of wound infections after hysterectomy leading to infection and/or loss of tissue implant [69]. Batista et al [76] reported on a small series of high-risk women who underwent combined RRM and RRSO, 10 of whom had a history of prior breast cancer and 10 patients underwent autologous breast reconstruction. The mean operative time was 9.3 hours (range, 3−16 hours), and the mean postoperative hospitalization duration was 5.4 days (range, 4−8 days). In the largest series of patients undergoing simultaneous breast and gynecologic surgery, Ma et al [75] reported on 73 patients, 48 of whom (80%) underwent BSO (55% had a concurrent hysterectomy and 25% did not). The remainder of patients underwent other procedures for benign indica- tions. The mean operative time was 5.6 hours (range, 47 minutes−14.6 hours). The average hospital length of stay was 3.3 days (range, 0−9 day). The length of stay increased with the addition of reconstructive procedure with a median length of 2.4 days for those undergoing implant reconstruc- tion and 6.5 days for those undergoing autologous recon- struction. Chapman et al [77] showed that total operating times are increased in patients undergoing sequential surgery (median of 1 hour 52 minutes longer than concur- rent surgery). In addition, the length of hospital stay was found to be on average 1 day and 8 hours longer in the con- current surgery group. Postoperative Morbidity Associated with Concurrent Surgery In the series by Ma et al [75], the rate of postopera- tive complications was determined to be 37% within 30 days of surgery. The vast majority (80%) of compli- cations were considered to be minor and did not require hospitalization or surgical intervention. Del Corral et al [78] reported on 42 patients undergoing bilateral mas- tectomy, reconstruction, and BSO with or without hys- terectomy. Among 18 patients who experienced a complication in this series, 15 were noted to be minor, including delayed wound healing, fat necrosis, seroma, or superficial infection. Three major complications of postoperative thrombosis/ flap loss occurred. Although there may be a numeric increase in complication rates with concurrent surgery, this has not been shown to translate into a statistically significant difference in complication rates between concurrent surgery and indi- vidual procedures [77,78]. Batista et al [76] reported no major intraoperative complications in their review. However, postoperative morbidity included abdominal wound dehiscence, reoperation for flap congestion, 1 case of superficial epidermolysis, and 1 case of aspira- tion pneumonia. The rate of these complications is believed to be in line with previously reported rates of postoperative complications for autologous reconstruc- tion, which have been estimated to be approximately 24% (flap complications) and 15% (donor-site compli- cations). Therefore, the addition of gynecologic sur- gery, while increasing operative time, does not seem to significantly increase the risk of postoperative breast complications. Increased blood loss and need for postoperative blood transfusion have been reported in patients undergoing com- bined abdominoplasty and gynecologic surgery [79]. Ma et al [75] reported a rate of 15% of blood transfusion in their series. These patients received autologous reconstruc- tion and required blood transfusion because of intraopera- tive blood loss, and 1 patient developed a breast hematoma after discharge. However, it is noteworthy that the addition of laparoscopic BSO did not alter the risk for needing blood transfusion in these patients. To improve outcomes of combined procedures, Del Cor- ral et al [78] described the technique of raising abdominal flaps, transferring and anastomosing them to the chest, and finally setting the flaps. This allows the gynecologic proce- dure to be completed with adequate visualization and minimal risk of flap avulsion or vascular injury. RRSO is AlHilli and Al-Hilli Perioperative Management of Women Undergoing Risk-reducing Surgery 263 performed through an open incision in the posterior rectus sheath. The plastic surgery team then performs closure of the peritoneum and fascia with or without mesh. There was no difference in intraoperative complications, rate of flap loss, fat necrosis, or wound complications found in this study. Cost-effectiveness It is proposed that a single procedure provides economic benefit by decreasing postoperative visits, anesthesia charges, and total hospital charges. This would also allow faster return to work and improved productivity. Del Corral et al [78] performed a cost analysis of patients undergoing concurrent breast and gynecologic procedures. It was found that operating room direct variable cost and total direct var- iable cost did not differ significantly between the groups. However, the average total cost was higher in the concur- rent surgery group. Factors found to be predictive of increased cost were simultaneous procedures, body mass index, operating room time, and immediate major surgical complications [78]. Optimal Patient Selection Although performing a concurrent procedure is not rou- tine practice at this time, there is an opportunity for comb- ing the procedures with some technical refinements and adequate team coordination. It must also be noted that per- forming the procedure at high-volume centers may impact surgical outcomes of concurrent surgery. In a study of 62 BRCA mutation carriers, 43 (69%) of whom opted for con- current surgery, it was found that patients undergoing con- current surgery were more likely to be older (median age 45 vs 39 years) and were more likely to receive neoadjuvant chemotherapy. No difference in complication rates was noted between the 2 patient groups [77]. An individualized approach is preferred. Conclusion Breast and ovarian cancer risk reduction is an area of ongoing research. Enhanced efforts have been spent on risk reduction through risk estimation, lifestyle modification, surgical prophylaxis, and chemoprevention. A key chal- lenge lies in the development and use of breast cancer risk reduction modalities that are evidence based and provide maximum benefit with low and acceptable morbidity and minimal impact on quality of life. Women with HBOC ben- efit from a multidisciplinary discussion of individual risk (taking into account the type of gene mutation, age and life expectancy, and family history), degree of risk reduction offered by surgery, associated risk of surgical morbidity, and alternatives to surgery. Concurrent RRM with RRSO can be performed when resources are available. 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