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Endometriosis and Ovarian Cancer: A Systematic Review

Ahmad Sayasneh, Dimitris Tsivos, and Robin Crawford
Department of Obstetrics & Gynaecology, The Rosie Hospital, Cambridge University Hospital NHS Trust,
Hills Road, Cambridge CB2 2QQ, UK
Received 1 April 2011; Accepted 21 May 2011
Academic Editors: J. M. Goldberg, R. Kimmig, andW. Yeung

Introduction

Endometriosis is one of the most common benign disorders which affects 10–15% of all women in reproductive age. The association between endometriosis and ovarian cancer has been frequently described in the medical literature. Purpose. To evaluate the literature for evidence of a correlation between endometriosis and ovarian cancer. Method. the English language
literature was searched using the keywords endometriosis combined with cancer,
tumour, tumor, carcinoma, or adenocarcinoma. All abstracts between January 1985 and August 2010 were reviewed. Full relevant articles were critically assessed. Reference lists of included studies were checked.
Results. Seven out of the eight studies, included in our review, have shown an increased risk of ovarian cancer. However, the effect size is modest (OR, RR, and SIR) ranging between 1.32 and 1.9 (95% CI). A causative relationship between the two incidences cannot be confirmed. There is increasing evidence on the role of genetic mutations in ovarian clear-cell and endometrioid carcinoma developing from endometriosis.
Conclusion. More evidence is needed before suggesting any change in the current management of endometriosis.

Endometriosis is one of the most common gynaecological
disorders. It affects 10–15% of all women in the reproductive
years [1]. The incidence is 40–60% in women with
dysmenorrhoea and 20–30% in those with subfertility [1].
Although endometriosis is recognised as a benign disease,
its association with ovarian cancer has been frequently
described in the medical literature since 1925. In that
year, Sampson established the first histopathological criteria,
which are still in use, to identify malignant tumours rising
from endometriosis: (1) clear evidence of endometriosis
close to the tumour, (2) the carcinoma must be seen to
arise in endometriosis, and not to be invading it from other
sources, and (3) presence of tissue resembling endometrial
stroma surrounding characteristic glands [2]. Later in 1953,
Scott has added a fourth criterion which is the demonstration
of a histology-proven transition from benign endometriosis
to cancer [3]. The application of all these four criteria has
rarely been fulfilled in the literature, which supports the idea
that the malignant transformation of endometriosis is a rare
event [4]. Yet, their stringent use may lead to underestimate
the real frequency of this phenomenon [4].
The aim of this paper is to systematically review the
literature evidence of a correlation between endometriosis
and ovarian cancer.

Methods

A protocol-driven systematic review was conducted in
accordance with the Centre for Reviews and Dissemination
(CRD) guidance. [5] The English language literature was searched using the
keywords: endometriosis combined with cancer, tumour,
tumor, carcinoma, or adenocarcinoma. All abstracts between
January 1985 and August 2010 were reviewed and full articles
of relevant publications in English language were retrieved.
A further systematic analysis of the publications included
in the reference lists was performed. All up-to-date reviews
on the same topic in the literature were assessed according
to Glasgow appraisal tool [6]. Case reports and case series
studies were excluded from our review.

Results

Seven reviews were found in the literature [4, 7–12], which
have addressed the association between endometriosis and
ovarian cancer.

Table is n0t clear on mobile, please use tablet or computer!

A summarizing table of the reviews’ findings
was modified from the Glasgow appraisal tool (Table 1) [6].
In our review, 11 studies were identified, which addressed
the association between endometriosis and ovarian cancer
[14–24]. To remove the selection bias, studies on the subfertility
patients with endometriosis [14, 15] and studies on
endometriomas instead of endometriosis [16] were excluded.
Eight studies were included in the list [17–24]. Seven out of
the eight studies have shown an increased risk of ovarian
cancer. However, the effect size is modest (odd ratio OR,
relative risk RR, and standardized incidence ratio SIR),
ranging between 1.32 and 1.9 (95% CI) Figure 1.
In epidemiological terms, when the RR is less than 2, a
careful assessment of the confounding factors must be conducted
before any conclusion of causality can be made [25,
26]. The previous epidemiologic definition was considered
when we selected the studies. Table 2 summarises the types,
sample size, followup time, confounding factors, and limitation
of each one of the eight studies included in our review.

Discussion

Despite the studies presented, the risk of ovarian cancer
among patients with endometriosis has always been contentious.
Endometriosis is usually confirmed by laparoscopic
or histological examination, and many patients are unaware
of having the disorder. Therefore, identifying endometriosis
as a preceding factor of ovarian cancer is not possible in
many cases. On the other hand, the natural history of ovarian
cancer is not well understood and the origin of the precursor
cell, especially for endometrioid and clear-cell variants, is
questionable. For these reasons, all studies in the literature
would struggle to establish a causal relationship between the
two entities. In this updated review we have tried to assess
the epidemiologic evidence in the literature and to discuss
our findings in view of the other genetic, immunological, and
biological relevant studies.
In our review we have found another group of eight
epidemiologic studies that correlated endometriosis with
endometrioid and/or clear-cell ovarian carcinoma as a specific
histological subtype [27–34].

They all reported a specific
link between endometriosis and endometrioid and/or clearcell
ovarian carcinoma, with an OR ranging between 3.7 and
35.4 (CI 95%). We have excluded these case series studies
from our meta-analysis as there were not case-control or
cohort studies.
In a previous review, Somigliana et al. included two
other studies which assessed the risk of endometriosis on
ovarian cancer in infertile patients [4]. In the first study,
infertile patients with endometriosis had the highest risk
with an SIR of 2.5 (95% CI, 1.3–4.2) compared to the general
population and an SIR of 4.2 (95% CI, 2.0–7.7) for the
group with primary infertility [15]. In the second study,
endometriosis and unknown cause of infertility resulted in
an independently associated elevation in ovarian cancer risk
after adjustment for standard confounding factors (odds
ratios (OR) 1.7 (95% CI, 1.1–2.7) and 1.2 (95% CI, 1.0–
1.4), resp.,) [14]. As infertility involvesmultiple confounding
factors, and to remove the selection bias in our review, these
two studies were excluded from our review.
Additionally, we have excluded another study conducted
by Kobayashi et al.’s in Japan. They documented only endometriomas
and evaluated the risk of ovarian cancer based on
varying time periods from time of diagnosis of endometrioma
[16]. Kobayashi et al. study did not account for patients
with extraovarian endometriosis and only approximately
one-third of these patients had surgically confirmed endometriomas,
with the remaining diagnoses made based on
ultrasonographic findings and physical exam only [16].

Figure 1: A Forest pilot summarises the eight studies’ effect size. Effect size was measured in odd ratio (OR), standardized incidence
ratio (SIR), or relative risk (RR). The 95% confidence interval is represented by the horizontal line, and the dimensions of the boxes are
proportional to the sample size.

During followup of up to 17 years, 46 incidental ovarian cancers
were identified, translating into a standardized incidence
ratio of 8.95. This risk increased with age, with an incidence
ratio of 13.2 in women over age 50 [16].
Many genetic, biological, and immunological studies
have tried to address the causal relationship between endometriosis
and ovarian cancer. Different types of genomic instability
and mutations have been shown to occur in endometriosis
and ovarian cancer [35, 36]. Moreover, microsatellite
analysis has demonstrated that loss of heterozygosity on p16
(Ink4), GALT (galactose-1-phosphate uridylyltransferase)
and p53, as well as on APOA2 (apolipoprotein A), a region
frequently lost in ovarian cancer, occurs in endometriosis
[37]. Another study by Baxter et al. has found the GSTM1
(glutathione S-transferase M1) null allele not to be an
endometriosis susceptibility allele [38]. However, it may predispose
endometriotic lesions to malignant transformation
to endometrioid and clear-cell ovarian cancer [38]. Overexpression
of p53, oncogenic K-ras Pten deletion, and loss
of heterozygosity may also be involved in the endometriosis
transformation to ovarian cancer [39–41].
A vital factor in the development of both endometriosis
and malignancy is considered to be angiogenesis. In a study
by Hayrabedyan et al., the expression of several angiogenic
factors (interleukin-1 alpha (IL-1 alpha), Fibroblast growth
factor FGF-1, and S100A13) and a common pan-ovarian
carcinoma antigen were investigated, in several cases of
adenomyosis and ovarian endometriosis [42]. They have
shown that the common ovarian carcinoma marker, as well
as these angiogenic factors, was expressed in most of
the studied cases, implying possible common pathological
mechanisms shared between endometriosis and malignancy
[42]. In another study, Chou et al. illustrated that the
cyclooxygenase-2 (COX-2) overexpression rate was higher
in ovarian carcinoma associated with endometriosis than in
isolated ovarian carcinoma (27.8% versus 5.6%, P = 0.083)
[43]. They suggested that COX-2 over-expression may be
a result of the malignant transformation of endometriosis
to endometrioid type ovarian cancer or may represent an
interaction between the two cellular components [43]. By
contrast, Keita et al. suggested alteration in the expression
of interleukin-1 receptor antagonist IL-1RA, a key protector
against tumorigenic effects of IL-1, as a possible link between
the endometrium, endometriosis, and endometrioid ovarian
cancer [44].
Recently, Wiegand et al. published new data implicating
ARID1A (AT-rich interactive domain-containing protein 1A)
as a tumor-suppressor gene frequently disrupted in ovarian
clear-cell and endometrioid carcinomas [45]. They have found
ARID1A mutations in 55 of 119 ovarian clear-cell carcinomas
(46%), 10 of 33 endometrioid carcinomas (30%), and
none of the 76 high-grade serous ovarian carcinomas [45].
They demonstrated that the loss of the BAF250a protein was
correlated strongly with the ovarian clear-cell carcinoma
and endometrioid carcinoma subtypes and the presence of
ARID1A mutations [45]. By comparing ovarian clear-cell
carcinomas to their contiguous atypical endometriotic lesions
in two patients, they have shown that the samemutations
ISRN Obstetrics and Gynecology 5
may be present in the putative precursor lesions and in the
tumors. In contrast, the distant endometriotic lesions do not
have ARID1A mutations [45].
It seems, from the previous discussion, that there is insufficient
evidence to suggest a specific gene mutation or a
specific biological pathway that predisposes endometriosis
patients to ovarian cancer. There is good evidence, however,
to demonstrate the potential transformation from
endometriosis to ovarian endometriosis cell and clear-cell
carcinoma. The association between the two entities with
an effect size of 1.32–1.9 may be due to sharing similar risk
factors, rather than a causal relation.

Conclusion

There is increased risk of ovarian cancers, specifically endometrioid

and clear-cell carcinoma, in women with endometriosis.

The estimated effect size, however, is modest

varying between 1.32 and 1.9. A causative relationship between

the two incidences cannot be confirmed. However,

there is increasing evidence on the role of genetic mutations

in ovarian clear-cell and endometrioid carcinoma developing

from endometriosis. There are few gene mutations

involved, and yetmore evidence is needed before generalising

any mutation screening test or changing the treatment of

endometriosis to include radical excision in case of a positive

genetic mutation.

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