Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / @xirurgi_2025 / @xirurgi_2025 - 625 - файл
.pdf
26 Histopathological Findings inProphylactic Surgical Specimens
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
299
practice guidelines in oncology. J Natl Compr
Cancer Netw. 2008;6(8):766–94.
192. Soslow RA, Han G, Park KJ, Garg K, Olvera N,
Spriggs DR, etal. Morphologic patterns associated
with BRCA1 and BRCA2 genotype in ovarian carcinoma. Mod Pathol. 2012;25(4):625–36.
193. Bartosch C, Clarke B, Bosse T.Gynaecological neoplasms in common familial syndromes (Lynch and
HBOC). Pathology. 2018;50(2):222–37.
194. Lavie O, Moskoviz MG, Auslender R, Gemer O,
Bitterman A, Younes G, etal. Clinical and pathological characteristics of ıncidental diagnostic early
occult malignancy after risk-reducing salpingooophorectomy in BRCA mutation carriers. Int J
Gynecol Cancer. 2016;26(2):233–9.
195. Powell CB, Chen L, McLennan J, Crawford B,
Zaloudek C, Rabban JT, et al. Risk-reducing
salpingo- oophorectomy (RRSO) in BRCA mutation
carriers: experience with a consecutive series of 111
patients using a standardized surgical-pathological
protocol. Int J Gynecol Cancer. 2011;21(5):846–51.
196. Lee YJ, Lee SW, Kim KR, Jung KH, Lee JW, Kim
YM.Pathologic ndings at risk-reducing salpingooophorectomy (RRSO) in germline BRCA mutation
carriers with breast cancer: signicance of bilateral
RRSO at the optimal age in germline BRCA mutation carriers. J Gynecol Oncol. 2017;28(1):e3.
197. Manchanda R, Abdelraheim A, Johnson M, Rosenthal
AN, Benjamin E, Brunell C, etal. Outcome of risk-
reducing salpingo-oophorectomy in BRCA carriers
and women of unknown mutation status. BJOG Int J
Obstet Gynaecol. 2011;118(7):814–24.
198. Callahan MJ, Crum CP, Medeiros F, Kindelberger
DW, Elvin JA, Garber JE, et al. Primary fallopian
tube malignancies in BRCA-positive women undergoing surgery for ovarian cancer risk reduction. J
Clin Oncol. 2007;25(25):3985–90.
199. Bethan Powell C, Kenley E, Chen L-M, Crawford
B, McLennan J, Zaloudek C, et al. Risk-reducing
salpingo-oophorectomy in BRCA mutation carriers:
role of serial sectioning in the detection of occult
malignancy. J Clin Oncol. 2005;23(1):127–32.
200. Hirst JE, Gard GB, McIllroy K, Nevell D,
Field M. High rates of occult fallopian tube
cancer diagnosed at prophylactic bilateral
salpingo- oophorectomy. Int J Gynecol Cancer.
2009;19(5):826–9.
201. Reitsma W, de Bock GH, Oosterwijk JC, Bart J,
Hollema H, Mourits MJE.Support of the “fallopian
tube hypothesis” in a prospective series of riskreducing salpingo-oophorectomy specimens. Eur J
Cancer Oxf Engl. 2013;49(1):132–41.
202. Zhong Q, Peng H-L, Zhao X, Zhang L, Hwang
W-T.Effects of BRCA1- and BRCA2-related mutations on ovarian and breast cancer survival: a metaanalysis. Clin Cancer Res. 2015;21(1):211–20.
Prophylactic Surgery forGenetic
Predisposition ofFemale Organs
NuriYildirim, DuyguGuzel, andAliAkdemir
27
27.1 Introduction
Currently, rapid developments in molecular biology techniques allow the identication of mutations and the inherited diseases with which they
are associated. Determination of risk groups for
germline mutations is possible with genetic
counseling. Thus, before the disease occurs, it
can be decided which patient population will be
screened and whether they are candidates for
risk-reducing prophylactic treatment.
The most common clinical-related hereditary
syndromes in gynecological oncology are hereditary breast ovarian cancer syndrome due to
BRCA 1/2 mutation [1]. After the identication
of BRCA 1 and 2 genes in 1994 and 1995, respectively [2], many patients have had the opportunity
of early diagnosis and preventive treatment for
breast and ovarian cancer with the detection of
mutations in these genes. With the identication
of other hereditary syndromes such as Lynch
(MLH1, MSH2, MSH6, PMS2), Li–Fraumeni
(TP53), Cowden (PTEN), and Peutz–Jeghers
N. Yildirim · D. Guzel
Division of Gynecologic Oncology, Department of
Obstetrics of Gynecology, Faculty of Medicine,
Ege University, Izmir, Turkey
e-mail: nuri.yildirim@ege.edu.tr;
duygu.guzel@ege.edu.tr
A. Akdemir (*)
Department of Obstetrics of Gynecology, Faculty of
Medicine, Ege University, Izmir, Turkey
e-mail: ali.akdemir@ege.edu.tr
syndromes (STK11), effective screening and prophylactic surgery recommendations for gynecological cancers with genetic predisposition have
been published by various guidelines.
There are many prophylactic surgery options
described in the literature. Effective screening
programs, prophylactic risk reduction surgery,
and its timing are discussed in this chapter in the
light of the literature.
27.2 Hereditary Breast
andOvarian Cancer
The majority of hereditary breast and ovarian
cancers are caused by mutation of BRCA1 and
BRCA2 tumor suppressor genes that are inherited autosomal dominantly [3] and located on
chromosomes 17q21 and 13q12-13, respectively
[4]. Women who are carriers of the BRCA 1/2
mutations have an increased risk of developing
breast and ovarian cancer. At least 5–10% of all
ovarian cancers were found to be associated with
BRCA mutations [5]. The overall prevalence of
BRCA1/2 mutations has been estimated from
1:300 to 1:500 [6]. While 81% of the hereditary
breast and ovarian cancer cases occur due to
BRCA1 and 14% due to BRCA2 mutation,
BRCA2 is responsible for 76% of all familial
breast cancers [7]. In the meta-analysis of 22
studies, the average cumulative risks in BRCA1
and BRCA2 carriers by age of 70 were calculated
as 65% and 45% for breast cancer and 39% and
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021
O. N. Dilek et al. (eds.), Prophylactic Surgery, https://doi.org/10.1007/978-3-030-66853-2_27
301
302
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
N. Yildirim et al.
11% for ovarian cancer, respectively [8]. BRCA
mutation carriers have also been shown to have
an increased risk for male breast cancer, melanoma, pancreatic, prostate, colon, fallopian tube
and primary peritoneal carcinoma [9–13]. The
incidence of BRCA 1/2 mutations differs in various ethnic groups and populations. Ashkenazi
Jews, Icelanders, Norwegians, Finns, French,
Swedes, Dutch, Italians, Pakistanis, South
Africans, Hispanics, French-Canadians, and
Afro-Americans are known to have founder
mutations [14]. In Ashkenazi Jews, 1in 40 individuals carry one of the three founder mutations
of BRCA 1 or 2 [6].
High grade serous carcinoma (HGSC) is the
most frequently reported histological type (76.7–
93%) in women with hereditary breast ovarian
cancer syndrome [15]. The risk for HGSC is less
than 2% in the general population, up to 40% in
BRCA1 carriers and up to 25% in BRCA2 carriers [16]. Studies have found that mucinous carcinomas and ovarian tumors with low malignancy
potential are not associated with the BRCA1/2
mutation [17]. Ovarian cancer patients with
BRCA mutations have higher sensitivity to platinum and poly (ADP ribose) polymerase (PARP)
inhibitors [18, 19]. Patients with ovarian cancer,
who are BRCA1 carriers, have a longer survival
and better chemotherapy response [20].
Breast cancers developed because of the
BRCA1 mutation are more aggressive and higher
grade compared to BRCA2 due to the hormone
receptor status. Approximately 78% of patients
with BRCA1 mutation are triple negative (hormone epidermal growth factor receptor 2 (HER-
2), estrogen receptors (ER), and progesterone
receptors (PR)) with worse prognosis [21].
27.2.1 Management
Identication of BRCA1/2 carriers helps to provide appropriate genetic counseling to the patient
and family, and to plan alternative treatment or
prophylactic risk-reducing surgery options
according to the fertility expectation of the
patient. Women who need genetic counseling and
testing for BRCA1/2 due to the risk of having a
predisposition to hereditary breast, ovarian, tubal,
and peritoneal cancer are as follows [
22]:
• Individuals with relatives who have a known
pathogenic or possibly pathogenic variant in
the cancer susceptibility gene.
• Individuals who meet the following criteria
but previously used limited testing and want
multi-gene testing.
• Diagnosed at ≤45years for breast cancer.
• Breast cancer diagnosed between 46 and
50years of age with limited or unknown family history, or a second breast cancer diagnosed at any age, or diagnosed for ovarian
carcinoma/fallopian tube/primary peritoneal
carcinoma, metastatic prostate cancer, pancreatic cancer at any age, in at least 1 close
relatives.
•
Triple-negative breast cancer diagnosed at
≤60years.
• Ashkenazi Jews diagnosed with breast cancer
at any age.
• Ovarian, pancreatic, or metastatic prostate
cancer at any age, or breast cancer diagnosed
at <50years.
• At any age, in at least 1 close relatives; diagnosed for ovarian carcinoma/fallopian tube/
primary peritoneal carcinoma, metastatic
prostate cancer, pancreatic cancer.
• ≥3 total diagnoses of breast cancer in patient
and/or close relative.
Diagnosed of male breast cancer in a close
•
relative at any age.
• For all patients with a history of ovarian carcinoma, pancreas, metastatic prostate, and male
breast cancer at any ages.
• Patients of any age with a history of high
grade prostate carcinoma (Gleason score≥7)
with any of the following: a history of ovarian,
pancreatic or metastatic prostate cancer at any
age in at least one relative or breast cancer
diagnosed at <50 years, two relatives diagnosed with breast or prostate cancer at any age
or Ashkenazi Jewish ancestry.
– Close relative is dened as a rst-, second-,
or third-degree blood relatives on the same
27 Prophylactic Surgery forGenetic Predisposition ofFemale Organs
303
side of the family (either maternal or paternal side).
– Limited family history includes fewer than
2 rst- or second-degree female relatives
surviving beyond 45 years on either the
maternal or paternal side.
27.2.2 Screening
The recommendations of the expert groups for
breast cancer screening in the National
Comprehensive Cancer Network (NCCN), the
American College of Obstetricians and
Gynecologists (ACOG), and the European
Society for Medical Oncology (ESMO) are as
follows [22–24].
27.2.2.1 Breast Cancer
Breast awareness training should be given to
women who are BRCA1/2 carriers from the age
of 18. All mutation carriers should be warned to
seek immediate medical attention if they detect
any changes in their breasts or axilla with regular
breast examination (BSE). BSE is recommended
to be performed especially at the end of the menses in women in the premenopausal period. A
clinical breast examination should be started
every 6 months from the age of 25. Women
should be screened with an annual contrasted
breast MRI (magnetic resonance imaging) or
annual mammography (only if MRI is not available) between the ages of 25–29. Screening can
be individualized if the family history includes
breast diagnosis before 30years of age. Although
MRI is more sensitive than mammography for
detection of breast cancer [1], the combined use
of MRI, clinical breast examination, and mammography has the highest sensitivity. Both contrasted breast MRI and mammography are
evaluated together between 30 and 75years of
age. Patients over 75years old should be evaluated individually. For women with BRCA1/2
mutations who are treated for breast cancer and
have not had bilateral mastectomy, annual mammography screening is recommended considering tomosynthesis and breast MRI.
27.2.2.2 Ovarian Cancer
For patients who have not elected to undergo
risk-reducing salpingo-oophorectomy or who are
postponing the procedure, a proven benet of the
combined use of transvaginal ultrasound and
serum CA-125 level starting at the age of
30–35years has not been demonstrated and may
be considered in a limited patient at the discretion
of the clinician. There is still no effective surveillance method for ovarian cancer [25].
27.2.3 Risk-Reducing Surgical
Procedures
The patient should be included in the screening
program as soon as the mutation is detected;
intensive surveillance, chemoprevention, or riskreducing prophylactic surgery for ovarian and
breast should be discussed. Prophylactic riskreducing surgical procedures signicantly reduce
the risk of developing cancer but cannot eliminate it completely. The treatment options and
their timing should be individualized to the
patient.
27.2.3.1 Breast Cancer
Bilateral prophylactic mastectomy is the most
effective risk-reducing method in BRCA carriers
[26]; studies show that this procedure decreases
the incidence of breast cancer by 90% or more
[23, 27]. Various surgical options are available,
such as total mastectomy, skin-sparing mastectomy (SSM), and nipple-sparing mastectomy
(NSM) [23]. Sentinel lymph node biopsy is not
indicated because of the probability of detecting
an occult breast cancer less than 5% at the time of
surgery [23]. In one study, nipple-sparing mastectomy performed on 346 women with BRCA1/2
carrier was found to be highly protective against
breast cancer. No patient developed breast cancer
in routine follow-up [28]. In women with
BRCA1/2 carriers once diagnosed with breast
cancer, the risk of developing cancer in the opposite breast has been shown to be 16–55% in
25years [29]. Although contralateral prophylactic mastectomy has been shown to reduce this
304
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
risk by about 95%, in the other breast, no survival
benet has been demonstrated yet by prospective
randomized studies [30].
In studies that evaluate patient satisfaction
after prophylactic mastectomy, while negative
effects on quality of life were not found, undesirable results were reported in terms of sexuality
and body image perception [31]. It is the preferred approach to offer breast reconstruction to
the patient immediately after mastectomy [26].
Multidisciplinary counseling service should be
provided to the patient, and long- and short-term
complications and psychological effects should
be explained in detail [24].
N. Yildirim et al.
Fig. 27.1 Serous tubal intraepithelial carcinoma (STIC)
with irregular luminal surface, epithelial stratication, and
nuclear atypia in the fallopian tube epithelium (H&E,
200×)
27.2.3.2 Ovarian Cancer
The most effective primary prevention in
BRCA1/2 carriers is bilateral salpingooophorectomy, which reduces the risk of ovarian
cancer by 80–90% and breast cancer by 40–50%,
and has also been shown to reduce overall mortality [23, 32–34]. The incidence of occult ovarian
cancer in BRCA1 carriers was 1.5% before the
age of 40, and 3.8% between the ages of 40 and
49; in BRCA2 carriers, only 1% was reported
before the age of 50 [23]. NCCN guideline recommends risk-reducing salpingo-oophorectomy
(RRSO) for all BRCA1 carriers between the ages
of 35 and 40. For BRCA2 carriers, since the age
of onset is usually later, RRSO can be delayed
until the age of 40–45, unless the age of diagnosis
in the family requires an earlier time for this operation. This suggestion should be considered only
after childbearing is completed [22]. Hysterectomy
is not routinely recommended [35].
At the beginning of the operation, all organ
and peritoneum surfaces should be carefully
evaluated for the presence of tumoral implants
and pelvic washing uid should be taken [24,
36]. A biopsy should be taken from suspicious
areas. Infundibulopelvic ligament should be
ligated 2cm proximal to the ovary. Ovaries and
fallopian tubes should be completely removed
[24, 37]. And then, they should be scanned with
microscopic serial sections for occult tumors
[24]. Occult malignancies were found in 2–10%
of patients who underwent prophylactic riskreducing surgery [38]. The majority of this
tumors have been shown to be located in the fallopian tube [39]. In BRCA mutation carriers, the
incidence of serous tubal intraepithelial carcinoma (STIC) has been shown to be 0.6–7%
(Figs.27.1 and 27.2) [40]. Women with BRCA1/2
mutation have less than 5% risk of developing
primary peritoneal carcinoma after RRSO [41,
42]. If hysterectomy will not be performed, the
fallopian tube should be divided from its junction
with the uterus corn. When the operation is performed laparoscopically, specimens should be
taken out of the abdomen with endoscopic bag.
Routine intraoperative frozen section procedure
is not recommended [24]. It is not clear which
surgical technique (e.g., laparotomy versus laparoscopy) should be chosen [20, 43]. Minimally
invasive surgery has been shown to be an effective and safe option in BRCA carriers [38].
Women with the BRCA1 mutation have an
increased risk for ovarian and breast cancer as
well as serous endometrium cancer so concurrent
hysterectomy option should be considered in
women with BRCA1 mutation [44]. In a study
carried out, in 40-year-old women who are
BRCA1 carrier, the addition of a hysterectomy to
the risk-reducing salpingo-oophorectomy was
shown to be cost-effective and associated with a
mean additional 4.9-month survival [45]. The
Cochrane review, which included 10 cohort studies with participants carrying the BRCA1/2
mutation, showed that overall survival was longer
in patients undergoing RRSO compared to those
without RRSO [46].
27 Prophylactic Surgery forGenetic Predisposition ofFemale Organs
305
a
b
c
Fig. 27.2 (a) In serous tubal intraepithelial carcinoma
(STIC), the atypical mitosis cell between the cells with
nuclear pleomorphism is marked by an arrow (H&E,
600×). (b) High Ki67 proliferation index in immune staining in STIC. (c) Complete loss of nuclear p53 expression
in serous tubal intraepithelial carcinoma (null pattern)
The results of risk-reducing surgical procedures in women with BRCA mutation carriers
indicated the presence of early tubal malignancy
in 1–5% of patients. Supporting retrograde menstruation theory, tubal ligation has been shown to
be protective against endometrioid and clear cell
ovarian carcinomas [47]. In BRCA carriers, prophylactic salpingectomy and delayed oophorectomy (PSDO) can be considered as an alternative
to RRSO against early menopausal risks [39]. In
a study comparing RRSO and bilateral salpingectomy in women with BRCA mutations, BSO was
shown to be the most effective risk-reducing procedure and was associated with the highest life
expectancy and lowest cost [48].
Patients in the premenopausal period may
experience acute surgical menopausal symptoms
after RRSO, which causes a decrease in quality
of life (QoL) such as hot ashes, night sweats,
sleep disturbances, cognitive changes, vaginal
dryness, and loss of sexual interest [49, 50].
However, some studies have shown that RRSO
has no negative effect on quality of life (QoL) in
high-risk women [51, 52]. Nevertheless, symptoms that decrease sexual satisfaction after prophylactic surgery and lead to a decrease in sexual
functions have been reported more frequently
[52]. RRSO has been shown to be associated with
some long-term adverse effects such as changes
in lipid prole, coronary heart disease, and osteoporosis, as it reduces the age of onset of menopause [20].
Several studies have reported that short-term
use of HRT is safe in alleviating symptoms that
develop after surgical menopause. Regardless of
the hormone receptor status, HRT is not recommended in patients previously diagnosed with
breast cancer [23].
In the postoperative follow-up, the patient
should be evaluated twice a year with transvaginal ultrasound and CA125 levels [27].
27.2.3.3 Chemoprevention
The use of tamoxifen, which inhibits the action
of estrogen on breast tissue, has been shown to
increase disease-free survival and reduce the risk
306
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
N. Yildirim et al.
of contralateral breast cancer in patients with
estrogen receptor positive breast cancer [53].
Chemoprevention with tamoxifen is associated
with increased endometrial cancer, thromboembolic events, cataracts, and menopausal symptoms [54]. Studies have shown that the use of oral
contraceptives (OKS) reduces the risk of ovarian
cancer in BRCA1/2 carriers [55, 56].
27.3 Lynch Syndrome
Lynch syndrome (LS) or hereditary nonpolyposis colorectal cancer (HNPCC) is a
genetic syndrome dened by Lynch in 1966,
inherited as an autosomal dominant and responsible for 3–5% of colorectal cancers [57, 58].
Lynch syndrome, which constitutes 10–15% of
hereditary ovarian cancers [59], is characterized
by the presence of a mutation in one of four
DNA mismatch repair (MMR) genes such as
MLH1, MSH2, MSH6, and PMS2 [58, 60]. The
expression loss of MSH2 has also been associated with mutations in EPCAM [60]. Unlike
hereditary breast ovarian cancer syndrome,
genetic assessment in Lynch syndrome can be
performed by immunohistochemically evaluating the tumor for mismatch repair proteins [61].
Studies show that LS causes predisposition not
only for colorectal carcinomas, but also for
endometrium, ovary, stomach, small intestine,
hepatobiliary tract, pancreas, renal pelvis, ureter,
breast, brain (glioblastoma) and prostate cancers
[59]. The lifetime risk in women with LS is
40–60% for endometrium and colon cancer,
while it is 9–12% for ovarian cancer [61].
Endometrial and ovarian cancers associated with
Lynch syndrome are usually diagnosed at an earlier age than the general population. The mean
age of diagnosis for both cancers is in the fth to
sixth decade of life [57]. The most common histological subtype of endometrial cancer is the
endometrioid type, but the presence of others
(such as clear cell, papillary serous, and MMMT)
has been demonstrated. The risk of lower uterine
segment involvement is higher [62].
27.3.1 Management
Surveillance, detailed screening, chemoprevention, and risk reduction surgery are available for
women with Lynch syndrome to prevent or detect
endometrium and ovarian cancer early [63].
Genetic evaluation recommended by Society of
Gynecologic Oncology (SGO) for increased risk
of Lynch syndrome [61]:
• Patients with endometrium or colorectal can-
cer with loss of a DNA mismatch repair pro-
tein or microsatellite instability (MSI) in
immunohistochemistry.
• Patients whose rst-degree relatives were
affected by endometrium or colon cancer,
either diagnosed before the age of 60, or found
to be at risk for Lynch syndrome by system-
atic clinical screening.
• Patients with known mismatch repair gene
mutations in their rst- or second-degree
relatives.
The current NCCN guideline recommendations for Lynch syndrome are as follows [64]:
Endometrium cancer: Since early detection of
endometrial cancer is often possible based on
symptoms, women should be made aware of the
importance of any abnormal uterine bleeding or
postmenopausal bleeding. These symptoms must
be evaluated with an endometrial biopsy.
Although prophylactic hysterectomy does not
decrease mortality in endometrial cancer, it can
reduce the incidence of cancer. Therefore, hysterectomy can be considered as a risk-reducing procedure. The timing of hysterectomy can be
individualized according to conditions such as
the completion of childbearing, comorbidities,
the pathogenetic variant of the LS gene, and family history.
The benet of endometrial cancer screening in
women with Lynch syndrome has not been demonstrated. However, since endometrial biopsy is
highly sensitive and specic in diagnosis, screening with an endometrial biopsy may be considered every 1–2years.
27 Prophylactic Surgery forGenetic Predisposition ofFemale Organs
307
The benet of screening with transvaginal
ultrasonography has not been demonstrated in
postmenopausal women. It can be considered at
the clinician’s discretion. It is not recommended
in women in the premenopausal period due to the
changes in endometrial thickness.
Ovarian cancer: Bilateral salpingooophorectomy (BSO) can be considered a riskreducing procedure in women who have
completed childbearing because of the potential
to reduce the incidence of ovarian cancer. The
timing of BSO can be customized according to
conditions such as completion of childbearing,
comorbidities, pathogenetic variant of the LS
gene, and family history. There is insufcient evidence to perform risk-reducing salpingooophorectomy (RRSO) in those with MSH6 and
PMS2 pathological variants.
Since there is no effective screening for ovarian cancer, patients should be informed about
possible symptoms such as abdominopelvic pain,
bloating, weight loss, and early satiety.
Routine ovarian cancer screening is not supported in patients with LS.Transvaginal ultrasonography and serum CA125 levels are not
sensitive or specic enough for ovarian cancer;
their use may be considered according to the doctor’s discretion.
European Society for Medical Oncology
(ESMO) and the American College of
Gastroenterology (ACG) guidelines recommend
all women with LS follow-up with an annual
transvaginal ultrasound and endometrial biopsy
from the age of 30–35. Hysterectomy and bilateral salpingo-oophorectomy should be offered to
women between the ages of 40–45 who have
completed childbearing [23, 65]. A study by
Schmeler et al. revealed that prophylactic total
hysterectomy and bilateral salpingooophorectomy is an effective method of preventing endometrium and ovarian cancer in women
with LS [66]. It should be remembered that
patients undergoing prophylactic surgery have a
risk of occult malignancy [60]. Cases of primary
peritoneal carcinoma have been reported after
oophorectomy for Lynch syndrome [63].
There is no consensus yet for endometrium and
ovarian cancer surveillance and screening in
women with Lynch syndrome. The sensitivity of
transvaginal ultrasonography in screening for
endometrial cancer has been shown to be low [62].
Several studies have shown that the use of oral
contraceptives in high-risk women with Lynch
syndrome can provide an effective chemoprevention for ovarian and endometrial cancer [62]. The
risks associated with HRT use in women with LS
have been shown to be lower compared to patients
with BRCA mutations [58].
27.4 Peutz–Jeghers Syndrome
Peutz–Jeghers syndrome (PJS) is a rare disease
characterized by mutation in the STK11 (LKB1)
gene, with an autosomal dominant inheritance,
clinically susceptible to gastrointestinal hamartomatous polyps, mucocutaneous pigmentation,
and susceptibility to various malignancies [67].
The presence of two of the three criteria is diagnostic for PJS: mucocutaneous pigmentation of
the mouth, lips, nose, eyes, genitalia, or ngers;
family history for PJS; and presence of 2 or more
hamartomatous polyp in the gastrointestinal tract
[59, 63]. The average age of diagnosis for PJS
has been reported to be 26years in women [68].
The lifetime risk of cancer in PJS was 32–54%
for the breast, 18–21% for the ovary, 10% for the
cervix, and 9% for the uterus, respectively [64].
Sex cord tumors with annular tubules (SCTATs)
associated with PJS typically occur in young
adults with signs of menstrual irregularity and
hyperestrogenism. Unlike sporadic cases, they
are usually bilateral and microscopic [67].
27.4.1 Management
Patients should be screened for breast cancer
from the age of 25, with annual mammography
and breast MRI, and a clinical breast examination
every 6months. For the screening of gynecological malignancies, it is sufcient to perform an
annual pelvic examination and pap smear from
the age of 18–20 [64].
ESMO guidelines recommend clinical breast
examination every 6–12 months starting from
308
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
N. Yildirim et al.
20–25years old, annual breast MRI between 20
and 29 years old, annual mammography and/or
MRI between 30 and 75 years old, and annual
gynecological follow-up. In addition, riskreducing mastectomy should be considered [23].
27.5 Li–Fraumeni Syndrome
Li–Fraumeni syndrome (LFS) is an autosomal
dominant inherited disease caused by the germline mutation of the TP53 gene located on chromosome 17p13.1. Because the TP53 gene
mutation causes loss of function in P53, patients
face many early-onset risks of malignancy [69].
LFS has been associated with many malignancies: brain tumors, adrenocortical carcinoma, soft
tissue sarcomas and bone tumors, hematologic
malignancies, breast cancer (generally very early
in onset), lung, skin, gastrointestinal tract, kidney,
thyroid and neuroblastoma [70]. Approximately
50% of TP53 mutation carriers have a risk of
developing cancer by age 30. While the lifetime
risk is 70% for men, it is almost 100% for women
[71]. Breast cancer accounts for about 25–30% of
LFS-related tumors. Unlike hereditary breast cancers associated with the BRCA mutation, it affects
only women with LFS [72]. Cumulative incidence
rate for breast cancer by age 70years was reported
as 54% among women [73]. Patients with LFS are
at risk for second malignancies arising from the
radiation eld [74].
27.5.1 Management
According to current NCCN guideline recommendations [22], the patient should be made conscious in terms of breast awareness from the age
of 18. Clinical breast examination should be done
every 6–12 months from the age of 20. Breast
should be screened with an annual contrast breast
MRI between the ages of 20–29 and an annual
contrast breast MRI and mammography between
the ages of 30–75. If over 75years old, screening
can be individualized. Patients diagnosed with
breast cancer who do not have bilateral mastectomy and are carriers of the TP53 variant are rec-
ommended with annual breast MRI and
mammography. Considering genetic counseling,
reconstruction options, degree of protection, and
possible risks, the risk-reducing mastectomy
option should be discussed in detail. Psychosocial
aspects and its effect on quality of life should be
shared with the patient.
ESMO recommends avoiding ionizing radiation (e.g., CT), risk-reducing mastectomy, and
PGD options before pregnancy to patients with
Li–Fraumeni syndrome [23].
27.6 Cowden Syndrome
Cowden syndrome (CS), which is inherited as an
autosomal dominant and occurred due to germline disorders in the PTEN (The phosphatase and
tensin homolog) tumor suppressor gene located
on chromosome 10, is a rare disease characterized by multiple hamartomatous lesions [75, 76].
Women with Cowden syndrome have an
increased risk for malignancies such as breast,
thyroid, bladder, ovarian, endometrium and cervical cancer [77, 78]. The most common accompanying malignancy is breast cancer. Lifetime
cancer risk has been shown to be 25–50% [77].
27.6.1 Management
According to the NCCN guideline recommendations [22], women with CS should be trained
about breast awareness from the age of 18.
Clinical breast examination, every 6–12months
should be recommended starting at age 25years
or 5–10 years before the earliest known breast
cancer in the family. Breast screening should be
performed with mammography and breast MRI
starting from the age of 35 or 5–10years before
the earliest known breast cancer in the family.
After 75years of age, patients should be evaluated individually. It is recommended that PTEN
pathological and possible pathological variant
carriers that are treated for breast cancer but have
not had a bilateral mastectomy should be screened
with annual mammography and breast MRI.Riskreducing mastectomy should be discussed.
27 Prophylactic Surgery forGenetic Predisposition ofFemale Organs
309
For endometrial cancer, screening should be
started by the age of 35. Patients should be
advised to keep a calendar to detect menstrual
cycle irregularities. Also, they should be informed
of symptoms such as abnormal uterine bleeding
and postmenopausal bleeding. If these ndings
are present, patient should be evaluated by endometrial biopsy. Although endometrial cancer
screening has no proven benet in women with
CS, screening with an endometrial biopsy may be
considered every 1–2years due to the high sensitivity and specicity. The benet of transvaginal
ultrasound in screening in patients in the premenopausal period has not been demonstrated. It
can be used in the postmenopausal period at the
discretion of the doctor.
ESMO guideline recommends that the patient
be offered risk-reducing mastectomy, riskreducing hysterectomy, and PGD before possible
pregnancy [23].
References
1. Petrucelli N, Daly MB, Feldman GL. Hereditary
breast and ovarian cancer due to mutations in BRCA1
and BRCA2. Genet Med. 2010;12(5):245–9.
2. Eisen A, etal. Prophylactic surgery in women with a
hereditary predisposition to breast and ovarian cancer.
J Clin Oncol. 2000;18(9):1980–95.
3. Enomoto T, etal. The rst Japanese nationwide mul-
ticenter study of BRCA mutation testing in ovarian cancer: CHARacterizing the cross-sectionaL
approach to Ovarian cancer geneTic TEsting of
BRCA (CHARLOTTE). Int J Gynecol Cancer.
2019;29(6):1043–9.
4. Wooster R, etal. Localization of a breast cancer sus-
ceptibility gene, BRCA2, to chromosome 13q12-13.
Science. 1994;265(5181):2088–90.
5. Alsop K, et al. BRCA mutation frequency and pat-
terns of treatment response in BRCA mutation–positive women with ovarian cancer: a report from the
Australian Ovarian Cancer Study Group. J Clin
Oncol. 2012;30(21):2654.
6. Rosenthal E, et al. Incidence of BRCA1 and
BRCA2 non-founder mutations in patients of
Ashkenazi Jewish ancestry. Breast Cancer Res Treat.
2015;149(1):223–7.
7. Ford D, et al. Genetic heterogeneity and penetrance
analysis of the BRCA1 and BRCA2 genes in breast
cancer families. Am J Hum Genet. 1998;62(3):676–89.
8. Antoniou A, etal. Average risks of breast and ovarian
cancer associated with BRCA1 or BRCA2 mutations
detected in case series unselected for family history:
a combined analysis of 22 studies. Am J Hum Genet.
2003;72(5):1117–30.
9. Thompson D, Easton DF. Cancer incidence in
BRCA1 mutation carriers. J Natl Cancer Inst.
2002;94(18):1358–65.
10. Lecarpentier J, etal. Prediction of breast and prostate
cancer risks in male BRCA1 and BRCA2 mutation
carriers using polygenic risk scores. J Clin Oncol.
2017;35(20):2240.
11. Del Chiaro M.Cancer risks in BRCA2 mutation carriers. J Natl Cancer Inst. 1999;91:1310–6.
12. Brose MS, et al. Cancer risk estimates for BRCA1
mutation carriers identied in a risk evaluation program. J Natl Cancer Inst. 2002;94(18):1365–72.
13. Tai YC, etal. Breast cancer risk among male BRCA1
and BRCA2 mutation carriers. J Natl Cancer Inst.
2007;99(23):1811–4.
14. Ferla R, et al. Founder mutations in BRCA1 and
BRCA2 genes. Ann Oncol. 2007;18:vi93–8.
15. Schrader KA, et al. Germline BRCA1 and BRCA2
mutations in ovarian cancer: utility of a histologybased referral strategy. Obstet Gynecol. 2012;120(2
Part 1):235–40.
16. Blok F, etal. Retrospective study of a 16 year cohort
of BRCA1 and BRCA2 carriers presenting for RRSO:
prevalence of invasive and in-situ carcinoma, with follow- up. Gynecol Oncol. 2019;153(2):326–34.
17. Pal T, etal. BRCA1 and BRCA2 mutations account
for a large proportion of ovarian carcinoma cases.
Cancer. 2005;104(12):2807–16.
18. Moschetta M, etal. BRCA somatic mutations and epigenetic BRCA modications in serous ovarian cancer.
Ann Oncol. 2016;27(8):1449–55.
19. Fong PC, etal. Poly (ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier
ovarian cancer correlating with platinum-free interval.
J Clin Oncol. 2010;28(15):2512–9.
20. Rosen B, et al. Systematic review of management
options for women with a hereditary predisposition to
ovarian cancer. Gynecol Oncol. 2004;93(2):280–6.
21. Piszczek C, et al. Cancer risk-reducing opportunities
in gynecologic surgery. J Minim Invasive Gynecol.
2018;25(7):1179–93.
22. National Comprehensive Cancer Network. Genetic/
familial high risk assessment: breast and ovarian.
Version 1.2020—December 4, 2019. NCCN clinical
practice guidelines in oncology. https://www.nccn.
org/professionals/physician_gls/pdf/genetics_bop.
pdf. Accessed 06 June 2020.
23. Paluch-Shimon S, et al. Prevention and screening
in BRCA mutation carriers and other breast/ovarian
hereditary cancer syndromes: ESMO clinical practice
guidelines for cancer prevention and screening. Ann
Oncol. 2016;27(suppl_5):v103–10.
24. Committee on Practice Bulletins–Gynecology,
C. Practice bulletin no 182: hereditary breast
and ovarian cancer syndrome. Obstet Gynecol.
2017;130(3):e110.
25. Hirasawa A, et al. Experience of risk-reducing
salpingo- oophorectomy for a BRCA1 mutation
Соседние файлы в папке @xirurgi_2025