Accepted Manuscript

New insights in the pathophysiology of ovarian cancer and implications for screening
and prevention
Farr R. Nezhat, MD, Radu Apostol, DO, Camran Nezhat, MD, Tanja Pejovic, MD,
PhD
PII:

S0002-9378(15)00325-7

DOI:

10.1016/j.ajog.2015.03.044

Reference:

YMOB 10332

To appear in:

American Journal of Obstetrics and Gynecology

Received Date: 24 November 2014

Revised Date:

31 January 2015

Accepted Date: 20 March 2015

Please cite this article as: Nezhat FR, Apostol R, Nezhat C, Pejovic T, New insights in the
pathophysiology of ovarian cancer and implications for screening and prevention, American Journal of
Obstetrics and Gynecology (2015), doi: 10.1016/j.ajog.2015.03.044.
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New insights in the pathophysiology of ovarian cancer and implications for

screening and prevention

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The authors report no conflict of interest.

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Corresponding Author
Farr R. Nezhat, MD, FACOG, FACS

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Farr R. Nezhat1, MD, Radu Apostol1, DO, Camran Nezhat2, MD and Tanja Pejovic3 MD,
PhD
1
Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Mount
Sinai St Luke's and Mount Sinai Roosevelt, New York, NY, 2Center for Special
Minimally Invasive and Robotic Surgery, Palo Alto, CA and 3Division of Gynecologic
Oncology, Oregon Health and Science University, Portland, OR

Professor, Dept. of Obstetrics, Gynecology & Reproductive Science | Icahn School of

Medicine at Mount Sinai

Director, Div. & Fellowship in Minimally Invasive Gynecologic Surgery & Robotics
Div. of Gynecologic Oncology, Dept. of Obstetrics & Gynecology | Mount Sinai St.

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Luke's and Mount Sinai Roosevelt

OBGYN Administration | 1000 Tenth Avenue, Ste 10-C | New York, NY 10019
P: 212 523-7337 | F: 212 523-8066 | e-Mail: [email protected]

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[email protected]

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ABSTRACT:
Despite advances in medicine, ovarian cancer remains the deadliest of the gynecologic
malignancies. Herein, we present the latest information on the pathophysiology of
ovarian cancer and its significance for ovarian cancer screening and prevention. A new

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paradigm for ovarian cancer pathogenesis presupposes two distinct types of ovarian

epithelial carcinoma with distinct molecular profiles: Type I and Type II carcinomas.
Type I tumors include endometrioid, clear cell carcinoma, and low grade serous

carcinoma and mostly arise via defined sequence either from endometriosis or from

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borderline serous tumors, mostly presenting in early stage. More frequent Type II

carcinomas are usually high grade serous tumors, and recent evidence suggests that the

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majority arise from the fimbriated end of the fallopian tube. Subsequently, high-grade
serous carcinomas usually present at advanced stages, likely as a consequence of the
rapid peritoneal seeding from the open ends of the fallopian tubes. On the other hand
careful clinical evaluation should be performed along with risk stratification and targeted
treatment of women with premalignant conditions leading to Type I cancers, most
notably endometriosis and endometriomas. Although the chance of malignant

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transformation is low, understanding of this link offers a possibility of prevention and

early intervention. This new evidence explains difficulties in ovarian cancer screening
and helps in forming new recommendations for ovarian cancer risk evaluation and

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prophylactic treatments.

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BACKGROUND:
Ovarian cancer is the second most common gynecologic malignancy in developed
countries, and the most lethal. In the United States, there are approximately 22,000 new
cases of ovarian cancer diagnosed each year and 14,000 cancer-related deaths.[1] The

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majority of ovarian cancers are of epithelial origin, while fewer ovarian cancers develop
from the remaining cell types, such as sex-cord stromal, germ cell or mixed cell type

tumors.[2] The most common histologic subtypes of epithelial ovarian carcinomas are:

serous (68-71%), endometrioid (9-11%), clear cell (12-13%), mucinous (3%), transitional

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(1%) and mixed histologies (6%).[3] At the time of diagnosis, the majority of epithelial
ovarian cancers are advanced stage high grade serous carcinomas and have a poor

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prognosis compared to early stage carcinomas.

In the last 50 years, despite advances in cytoreductive radical surgery and cytotoxic
chemotherapy, marginal improvement has been seen in the overall survival of patients
with ovarian cancer. Attempts at early detection strategies in the last two decades have
failed to provide survival benefit. Although the potential benefit of an effective screening

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strategy for ovarian cancer is great, to date studies have not shown any decrease in
morbidity and mortality. The best example is the Prostate, Lung, Colorectal and Ovarian
(PLCO) Cancer Screening Trial, that evaluated the effect of combined modality screening
(ie: transvaginal ultrasound and CA-125 serum level) for ovarian cancer.[4] The PLCO

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trial did not find any reduction in ovarian cancer mortality using screening with cancer
antigen 125 and transvaginal ultrasound. Another large multicenter, randomized

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controlled trial is currently looking not only at mortality but also cost, acceptance by
patients, and physical and psychosocial morbidities associated with transvaginal
ultrasound and CA-125 screening is the United Kingdom Collaborative Trial of Ovarian
Cancer Screening (UKCTOCS).[5]
New evidence suggests that high grade serous carcinoma, frequently presenting as
advanced stage, often originates from the fimbriated end of the fallopian tube. This is in
contrast to low grade serous endometrioid and clear cell histology, which mostly present
in early stage and mostly originate from borderline serous carcinoma or
endometriosis.[6,7] Herein will discuss new perspectives in the pathophysiology of

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different histologies of epithelial ovarian cancer, present possible preventative steps in

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decreasing the risks of this malignancy and possible future screening methodologies.

ETIOLOGY:

The etiology of ovarian cancer remains poorly understood, and the source population of
epithelial ovarian cancer progenitors has become a matter of controversy. Traditionally,

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the ovarian surface epithelium was thought to be the primary source of ovarian

malignancies. Indeed, the theory of incessant ovulation presupposes that repetitive

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involvement of the ovarian surface in the process of ovulation is a risk factor for ovarian
cancer. Factors associated with ovulation include injury and repair of the ovarian surface
epithelium in response to follicle rupture, inflammatory effects of the ovarian
environment surrounding ruptured follicle, entrapment of ovarian surface epithelium cells
within the ovary with resulting inclusion cyst formation, and steroid hormone effects of
the uniquely high concentrations of progesterone, androgens and estrogen in the local

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ovarian environment during each menstrual cycle.[8] Evidence has accumulated,

however, to suggest that many cases of epithelial ovarian cancer originate in the distal
portion of the fallopian tube, more precisely, the fimbrial epithelium. The initial
evidence implicating the fimbrial epithelium came from risk reducing salpingo-

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oophorectomies in women who had either BRCA gene mutations or a strong family
history of ovarian cancer.[9] When the entire tube was serially examined, foci of small in

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situ tubal intraepithelial carcinoma (TIC) were found.[10,11] These are regions of
dysplasia within tubal epithelium that demonstrate high levels of TP53 mutations. Later
on, similar lesions were found in fimbrial epithelium of a significant number of cases of
sporadic ovarian carcinomas.[11] Przybycin et al. identified TIC in 60% of consecutive
ovarian cancer cases when tubes were systematically examined. Yet, these precursor
lesions were not found in the fimbrial epithelium of non-serous types of ovarian
carcinoma.[12]

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CLASSIFICATION AND NEW THEORIES:

Several groups have now convincingly established that there are two distinct types of
epithelial ovarian carcinoma: Type I and Type II.[13,14,15] Type I tumors arise via well
recognized sequence either from borderline serous tumors or from endometriosis, and

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include low grade serous carcinoma, endometrioid, and clear cell carcinoma. These

tumors are often early stage, and low-grade tumors, with a relatively indolent disease

course. Type II carcinomas are more frequent, usually of serous histology, are high grade,
and seem to originate from the fimbrial epithelium in up to 60% of the cases.[12]

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Subsequently, high-grade serous carcinomas present clinically as stage 3 or 4 disease

consistent with the hypothesis of peritoneal seeding by malignant cells from the

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fimbriated end of the tubes.

The molecular profile of the two types are different and correlate well with the distinct
nature of Type I and Type II carcinomas. Type I carcinomas are characterized by KRAS,
BRAF, ERBB2, CTNNB1, PTEN, PIK3CA, ARID1A, PPP2R1A and BCL2
mutations.[15,16,17] On the other hand, the majority of Type II tumors are characterized

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by TP53 mutations. Indeed, the TP53 mutations are present in almost 96% of high-grade
serous ovarian carcinomas of The Cancer Genome Atlas data set.[18]

Role of the Fallopian Tube and High Grade Serous Carcinoma

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Today we understand that the rapid progression of high-grade serous carcinomas is

consistent with seeding of the peritoneal cavity by malignant cells from the fimbriated

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ends of the fallopian tubes. What not so long ago was thought to be a precursor lesion in
the fimbrial epithelium of BRCA carriers, is now found in up to 60% of all cases of
epithelial ovarian cancer.[12] The precursor lesion, serous tubal intraepithelial carcinoma
(TIC), has now been defined and it typically consists of secretory cells, lacks the ciliated
cells of a normal fallopian tube, has a TP53 signature, and is associated with a high
degree of DNA repair pathway alterations including BRCA and BRCA-like mutation.[11]
The Gynecologic Oncology Group is currently completing a non-randomized
prospective trial comparing longitudinal screening with CA-125 and ultrasound to
risk-reducing bilateral salpingo-oophorectomy in a high genetic risk population.

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The results from the surgical intervention arm of Gynecologic Oncologic Group
(GOG-0199) found that 2.6% of women undergoing risk reducing salpingooophorectomy were diagnosed ovarian/tubal neoplasms (4.6% of BRCA 1 mutation

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carriers, 3.5% of BRCA 2 mutation carriers and 0.5% of noncarriers). Overall, 56%
of women with ovarian/tubal neoplasia had serous TIC or stage I or II invasive

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cancer.[19]

Role of Endometriosis and Endometrioid and Clear Cell Carcinoma

The association between endometriosis and ovarian cancer has perplexed clinicians and

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scientists for many years, since it was first reported by Sampson.[20] Several
epidemiologic studies have suggested the link between endometriosis and ovarian cancer.
This was recently corroborated by the study assessing the association between selfreported endometriosis and risk of ovarian cancer.[21] Data collected from 13 original
studies, analyzed a total of 13, 226 controls and 7,911 women with invasive ovarian
cancer, out of which 818 (6.1%) and 738 (9.3%) respectively reported a history of

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endometriosis. Self-reported endometriosis was associated with significantly increased

risk for clear cell cancer (OR 3.05), endometrioid cancer (OR 2.21), and low-grade
serous invasive ovarian cancers (OR 2.21). There was no association between
endometriosis and risk for high-grade serous carcinoma. In another meta-analysis, Kim

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et al investigated the impact of endometriosis on the risk and prognosis for ovarian
cancer, and evaluated clinicopathologic characteristics of endometriosis associated

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ovarian cancer in comparison with non-endometriosis associated ovarian cancer.[22]

Again, it was confirmed that endometriod and clear cell carcinomas are more common in
endometriosis associated ovarian cancer (RRs: 1.759 and 2.606, respectively), whereas
serous carcinoma was less frequent in endometriosis associated ovarian cancer than in
non-endometriosis associated group (RR: 0.733).

The causes of malignant transformation of endometriosis are not clear, but several
genetic, immunologic and hormonal factors have been implicated.[8,15,23] Recent
evidence links the role of microenvironment to the process of malignant transformation

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of endometriosis. Indeed endometriosis is an inflammatory state, as a result of retrograde

menstruation. Suryawanshi et al. implicated a role of complement system in malignant
transformation.[24] Specifically the group has reported for the first time the up-

endometriosis and its pro-tumorigenic role.

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CLINICAL IMPLICATIONS:

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regulation of chronic activation of the complement pathway in women with

Keeping in mind these new findings, it is not surprising that early detection of high-grade

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serous carcinoma of the ovary is extremely challenging using current methods of mainly
pelvic ultrasound and serum CA-125. The occult early lesion in the fallopian tube and the
rapid seeding of the peritoneal cavity via the tubes are some of the theories proposed to
describe the emergence of impressive ovarian masses as well as other peritoneal tumors.
Thus, at the time of diagnosis clinicians are faced with already advanced disease. In light
of these findings, we need to focus on new strategies for early detection of high-grade

fallopian tube.

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serous carcinomas, shifting our thinking towards the earliest precursor lesion within the

Similarly, the methods for early detection of Type I ovarian carcinomas parallel our

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understanding of their precursor lesions and biology of their development.

Endometriosis, defined as the presence of endometrial-like glands and stroma at

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extrauterine sites, is a chronic disease occurring in approximately 10% of women.[25]

While endometriosis is considered a benign disease, it has several features that are
characteristic of invasive cancers. Some of these features include invasion of the stroma
of the organ in which it involves, development of local and distant foci, and high
recurrence rate after treatment. One of the most common sites of endometriosis is the
ovary. Ovarian endometriosis is of particular interest, as a proportion of ovarian cancers
arise from ovarian endometriotic lesions, particularly clear cell and endometrioid ovarian
carcinomas.[26,27] Although useful, both serum CA-125 and transvaginal ultrasound are
poor screening modalities in differentiating malignant tumors from benign ones. [28]

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Clinical presentation of ovarian cancer associated with endometriosis includes symptoms

that are typically attributed to endometriosis, including pelvic pain, exacerbation of
dysmenorrhea, dyspareunia, and vaginal bleeding.[29] In a series reported by Deligdisch
et al, all stage I non-serous ovarian carcinomas were diagnosed based on associated

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symptomatology, such as pelvic pain with endometriosis/adnexal masses or vaginal

bleeding associated with underlying endometrial pathology.[7] Pathology revealed an

endometriotic ovarian cyst in 39 of 54 women with stage I non-serous ovarian carcinoma

compared to 1 of 22 with stage I serous ovarian carcinoma. Further, 33 of 54 women

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with stage I non-serous ovarian carcinoma proved to have endometrial carcinoma,

hyperplasia or polyp, compared with 4 of 22 women with stage I serous ovarian

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carcinoma. Therefore, we recommend the evaluation of the endometrium in symptomatic

patients with endometriosis and an ovarian mass, to rule out possible coexisting
malignancies.[7,30] Endometrioid and clear cell ovarian carcinomas associated with
endometriosis usually present with an adnexal mass that may be associated with
endometrioma. It appears therefore that a discreet set of symptoms associated with
different ovarian carcinoma histologies exist, and may be helpful in establishing

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programs for early detection of cancers associated with endometriosis.

OPTIONS FOR PREVENTION:

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Both endometriosis and ovarian cancer share certain characteristics, valuable in

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developing strategies for future prevention and treatment.(Table 1)[31]

This becomes even more critical since now we understand that low grade serous
carcinomas originate from ovarian surface epithelium and most endometrioid and clear
cell histologic subtypes originate from endometriosis.[32]

Oral contraceptives are a potentially promising primary prevention strategy for ovarian
cancer. The majority of studies that have examined the relationship between combined
oral contraceptives use and ovarian cancer have reported a decreased risk with their use.
Beral et al looked at 23,257 cases and 87,303 controls and found a significant reduction

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of overall ovarian cancer risk (Relative Risk [RR] 0.73; 95% confidence interval 0.700.76) with an additional 20% reduction for every 5 years of use.[33] Furthermore, the
reductions in risk per 5 years of oral contraceptive use were broadly similar for epithelial
and non-epithelial tumors. Oral contraceptives also seem to have little effect on

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mucinous tumors.[33]

Two large collaborative studies have recently called attention to the role of tubal ligation

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on reducing the ovarian cancer risk. Tubal ligation has been known for a long time to

reduce the risk of ovarian cancer.[34] Most recent analyses show that this risk reduction

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is the greatest for endometrioid and clear cell carcinoma, rather than high grade serous
ovarian carcinoma, 52% and 48% versus 19% reduction, respectively.[35,36,37] The
protective effect of tubal ligation on these two subtypes of invasive ovarian cancer is
thought to be associated with prevention of retrograde menstruation, ovarian seeding by
endometrial cells, and inflammation.

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Given the overwhelming evidence suggesting the possibility of the fallopian tube as the
origin of high-grade ovarian cancer, salpingectomy should be considered as a method of
prophylaxis, even in women at average risk for ovarian cancer, instead of tubal ligation.

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The SGO recommends that women who have BRCA1 or BRCA2 germline mutations
should be counseled regarding bilateral salpingo-oophorectomy, after completion of

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childbearing, as the best strategy for reducing their risk of developing ovarian cancer. In
the event that these women opt to delay risk-reducing bilateral salpingo-oophorectomy,
they should be counseled regarding a two-step procedure: initial risk-reducing
salpingectomy followed by oophorectomy in the future, although the safety of this
approach has not been studied.[38] Serial sectioning of the ovaries and fallopian tubes,
especially the fimbriae, is crucial. Furthermore, the SGO also recommends that for
women at average risk of ovarian cancer, risk-reducing salpingectomy should also be
discussed and considered in patients at the time of abdominal or pelvic surgery, after
completion of childbearing.[38] This recommendation should also be considered by

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other disciplines, besides the gynecologist, especially when the fallopian tubes are found
to be damaged by endometriosis and/or pelvic inflammatory disease. Countries like
Canada even went so far as to initiate a province wide ovarian cancer prevention
initiative.[39] Obstetricians and gynecologists, in the province of British Columbia, were

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educated on the current evidence outlying the role of the fallopian tube in ovarian cancer
and explained the association of high-grade serous cancer with inherited BRCA 1 and 2
mutations. The interventions called for salpingectomy at the time of hysterectomy,

salpingectomy for permanent sterilization instead of tubal ligation, and referral for all

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patients with high-grade serous cancer for hereditary cancer counseling and genetic
testing for BRCA 1 and 2 mutations. Although still in its infancy, these 3

over the next 20 years.[39]

Pros and Cons of Salpingectomy

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recommendations are projected to reduce ovarian cancer rates in this province by 40%

Other advantages of complete bilateral salpingectomy include a decrease in the risk of

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hydrosalpinx, tubal ligation failure and ectopic pregnancies.

The Rochester Epidemiology Project evaluated women after hysterectomy with adnexal
preservation over a 56 year study period, and found that the incidence of women
requiring removal of one or both adnexa was 12.8%.[40] Furthermore, the risk of

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developing a hydrosalpinx was 2.6 per 1,000 women-years. Assuming 30 years of life
after hysterectomy, the lifetime risk of surgery for hydrosalpinx alone would be

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7.8%.[40]

Historically, post-partum salpingectomy has been considered to have the lowest failure
rate of all sterilization methods as well as the lowest cumulative probability of ectopic
pregnancies.[41,42] The feasibility and safety of postpartum distal salpingectomy has
recently been reported.[43].

Although a relatively simple procedure, that could potentially be implemented in women

who have completed childbearing, there is a concern that salpingectomy would
compromise collateral circulation to the ovaries and predispose women to early ovarian

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failure. However, multiple studies have failed to show the association between tubal
ligation and early ovarian failure. Findley et al, randomized 30 pre-menopausal women
undergoing laparoscopic hysterectomy with ovarian preservation for benign indication
into two groups: bilateral salpingectomy versus no salpingectomy. Anti-Mullerian

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hormone (AMH) levels were measured pre-operatively, and at 4-6 weeks and 3 months

post-operatively. Given that there was no statistical difference between the AMH levels,
they concluded that salpingectomy at the time of laparoscopic hysterectomy with ovarian
preservation is a safe procedure that does not appear to have any short-term deleterious

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effects on ovarian reserve.[44]

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In another recent study, Morelli et al. also compared ovarian function in pre-menopausal
women undergoing hysterectomy alone versus hysterectomy with bilateral salpingectomy
for benign disease. The authors found no difference in ovarian function between the
patient groups, as determined by AMH, FSH, antral follicle count, mean ovarian diameter
and peak systolic velocity. They also found no difference in operative time,
postoperative stay, time to return to normal activity, and post-operative hemoglobin

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between the 2 groups.[45]

One of the drawbacks of complete bilateral salpingectomy is eliminating the option of

future tubal re-anastomosis.[46] Subsequently, patients should be counseled regarding

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sterilization regret, especially for women under the age of 25. Furthermore, local and

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state policies should be reviewed and taken into consideration.

Based on the available evidence, we can hypothesize that a compromised collateral

circulation to the ovaries, resulting in early ovarian failure, would be caused only by poor
surgical technique. Therefore, salpingectomy at the time of hysterectomy, instead of
tubal ligation, and also at the time of other abdomino-pelvic surgery, would be in the best
interest of the patient.

Endometriosis management consideration

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As with the changes in our thinking about screening and preventative measures in highgrade ovarian cancer, there is also mounting evidence for Type I carcinomas associated
with endometriosis that requires new consideration for a possible change in clinical
practice guidelines regarding screening and prevention of endometriosis associated

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ovarian cancer. Although ovarian cancer develops in only 0.3-1.6% of women with

endometriosis [22], it is important to assess, document, and systematically follow the risk
factors that may predispose patients to developing ovarian cancer. These include: (i) long
standing endometriosis, (ii) endometriosis diagnosed at an early age, (iii) endometriosis

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characteristics and mural nodule formation.[15,47,48]

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associated with infertility, (iv) presence of enlarging ovarian endometrioma or changing

Women found to be at increased risk of ovarian endometrioma have options of medical

(hormonal) or surgical treatment. The treatment should be personalized based on patients
age, desire for child-bearing, family history, and type and characteristics of
endometriomas. Nezhat et al. have described two types of endometriomas: Type I and
Type II.[49] Type I endometriomas are characterized by small lesions that spread across

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peritoneal and ovarian surfaces, while Type II endometriomas originally start as

functional ovarian cysts that are invaded by cortical endometriosis and gradually develop
into endometriomas. Hormonal treatment often results in incomplete regression of
endometriotic lesions and recurrence of endometriomas. Additionally, in Type II

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endometriomas, adjuvant hormonal suppressive therapy that prevent ovulation can

decreases the risk of recurrent ovarian endometrioma formation.[50,51,52] Interestingly,

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Melin et al showed that women who underwent unilateral oophorectomy for

endometriosis had a significantly reduced risk of later development of ovarian cancer,
with an OR of 0.19 (95% CI, 0.08-0.46) compared with controls.[53] In addition,
ovarian cancer was significantly less likely to develop in women who underwent
radical surgical excision of all visible endometriosis, with an OR of 0.30 (95% CI,
0.12Y 0.74).[53] Considering the above information, different surgical strategies should
be employed at the time of surgical treatment of patients with pelvic endometriosis.

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CONCLUSION:
These clinical observations and the new recent evidence for the dual pathogenesis of
ovarian cancer have set ground for implementing new strategies for screening and
prevention programs to reduce the incidence of epithelial ovarian cancer. Until specific

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markers are developed, able to detect different histological epithelial ovarian cancers, it
seems reasonable to undertake certain steps, such as bilateral salpingectomy, to reduce
the risk of these types of cancers, based on the current evidence.

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In light of the accumulated data and observations regarding endometriosis and ovarian
cancer, we propose that it is time to establish criteria for identifying and monitoring

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women with endometriosis for risk factors, and to pursue risk reducing medical and
surgical treatment options in these women. At the time of surgical diagnosis and
treatment, consideration for complete resection of pelvic endometriosis, salpingectomy,
oophorectomy or hysterectomy should be individualized based on patients age, desire for
future fertility and preoperative consultation with the patient.

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These initiatives, if validated by level 1 evidence, should substantially reduce the risk of
ovarian cancer as well as total mortality risk. As new research becomes available, the

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recommendations may be refined both in terms of screening and prevention.

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Table 1: Similarities between endometriosis and ovarian cancer

Ovarian CA

Early menarche

Yes

Yes

Genetic
Predisposition

Yes

Yes

Infertility

Yes

Yes

Estrogen Exposure

Yes

Yes

Nulliparity

Yes

Yes

BTL

Protective

Protective

Hysterectomy

Protective

Protective

Progesterone
Exposure

Protective

SC

M
AN
U

TE
D
EP
AC
C

RI
PT

Endometriosis

Protective