There is evidence that endometriosis as well as drugs used in the process of in vitro fertilisation appear to associate with increased risk for gynaecological cancer. In this review, we attempt to describe this relationship according to the most recent epidemiologic data and to present the possible mechanisms on the molecular level that could potentially explain this correlation.  There are data to support that ovarian endometriosis could have the potential for malignant transformation. Epidemiologic and genetic studies support this notion. It seems that endometriosis is associated with specific types of ovarian cancer (endometrioid and clear cell). There is no clear association between endometriosis and breast or endometrial cancer. More studies are needed to establish the risk factors that may lead to malignant transformation of this condition and to identify predisposed individuals who may require closer surveillance. Currently, there is no proven relationship between any type of gynaecological cancer and drugs used for infertility treatment. In principle, infertile women have increased risk for gynaecologic malignancies. Nulligravidas who received treatment are at increased risk for malignancy compared with women who had conceived after treatment. There is limited evidence that clomiphene citrate use for more than six cycles or 900 mg or treatment of women over the age of 40 could increase their risk for ovarian and breast cancer. More studies with the .......

Introduction

Endometriosis is a disorder of the reproductive age defined as the presence of endometrial-like
tissue (e.g., glands and stroma) outside of the endometrial cavity. Endometriosis is uncommon before
menarche and it frequently regresses after menopause. The prevalence of endometriosis reaches 7–15%
among women of reproductive age, but can increase up to 25–30% in women with infertility and to 40–
70% in women with pelvic pain.1,2 Although endometriosis is considered to be a benign condition, it
shares characteristics often encountered in malignancy, such as development of local and distant
metastases, attachment, invasion and subsequent damage of adjacent tissues. Endometriosis, however,
does not cause metabolic disturbance, does not have catabolic consequences and does not lead to
death.
Studies that have investigated the overall risk of cancer in women with endometriosis have failed to
demonstrate an increased risk for cancer in those women compared with population controls. In
a study involving 64 492 Swedish patients hospitalised with the diagnosis of endometriosis, with an
average follow-up of 12.7 years, the overall risk of cancer was similar to the general population
(standardised incidence ratio (SIR) 1.04, 95% confidence interval (CI): 1.00–1.07).3 Similarly, no overall
increased risk of cancer (age-adjusted relative risk (RR) 0.9, 95% CI: 0.7–1.2) was found after 13 years of
follow-up in an epidemiological study of 1392 postmenopausal women with a self-reported history of
endometriosis.4
Although endometriosis does not appear to be associated with an increased risk of cancer in
general, evidence is accumulating suggesting a relation between endometriosis and specific types of
cancer. To date, the main scientific interest has been focussed on the relationship between endometriosis and gynaecological cancer, with special emphasis on ovarian cancer.
Endometriosis and ovarian cancer
Sampson was the first to describe, back in 1925, a malignancy (ovarian carcinoma) derived by an
endometriotic lesion.5 Since then, several studies have indicated a relation between endometriosis and
ovarian cancer.3,6–16
In a Swedish study involving 20 686 patients with endometriosis with an average follow-up of 11.4
years, the risk for developing ovarian cancer was about 2 times higher than in the general population
(standardised incidence ratio (SIR) 1.9, 95% confidence interval (CI): 1.3–2.8). Furthermore, for women
with long-standing endometriosis involving the ovaries, the risk was even higher (SIR 4.2, 95% CI 2.0–
7.7).6 A more recent study from Scandinavia, which included 28 163 women with endometriosis, had
also showed that these women had a 30% increase in the possibility of developing ovarian cancer.17
In the study by Melin et al.,3 with an average follow-up period of 12.7 years, an increased risk for
ovarian cancer was documented in women with endometriosis compared with the general population
(SIR 1.43, 95% CI: 1.19–1.71). Women with early diagnosed and long-standing endometriosis had
a higher risk of ovarian cancer, with SIR of 2.01 and 2.23, respectively. Women who had a hysterectomy
before or at the time of the endometriosis diagnosis did not show an increased risk of ovarian cancer,
suggesting that hysterectomy or possibly tubal occlusion (ligation) may offer some protection. Both
these studies,3,6 however, have been criticised that they have overestimated the risk of ovarian cancer
in women with endometriosis, due to the fact that the cohorts were hospitalised patients with more
advanced stages of endometriosis.
There is sufficient evidence to support that endometriosis is related to specific histological types of
ovarian cancer. In a pathology review of 1000 consecutive cases, there was a strong correlation
between endometriosis and endometrioid and clear cell ovarian carcinomas, whereas extraovarian 

endometriosis was associated with adenocarcinomas and adenosarcomas.18 In a review of 556 patients
with ovarian cancer, the frequency of endometriosis was significantly higher in patients with endometrioid, clear-cell and mixed-types tumours (26.3%, 21.1% and 22.2% respectively) compared with
those with mucous or serous carcinomas.9
In another study,8 pathology slides from 79 patients with stage I epithelial cancer of the ovary were
evaluated. Endometriosis was evident in 22 out of the 79 cases (28%). Ovarian tumours of endometriod,
clear cell and mixed type were associated with endometriosis in 39%, 41% and 50%, respectively. Thirtytwo percent of the ovarian tumours developed in areas of endometriosis, with evidence of progression
from benign to atypical endometriosis (characterised by cytologic atypia and architectural proliferation) to cancer.
These findings were confirmed by Ogawa et al.,19 who in 127 patients with primary ovarian
carcinoma documented 37 patients with endometriosis. Out of 43 patients with clear-cell carcinoma 30
had endometriosis (70%), and out of seven patients with endometrioid carcinoma three had endometriosis (43%). By contrast, endometriosis was documented in only four out of 60 (7%) patients with
serous carcinoma and in none out of 17 with mucinous carcinoma. Twenty-nine cases had atypical
endometriosis and the transition from atypical endometriosis to carcinoma was evident in 23 cases.
The authors concluded that atypical endometriosis could be a precancerous condition for ovarian
carcinoma.19
Others, however, do not support this notion. Olson et al., in a group of 37434 postmenopausal
women, which included a cohort of 1392 patients with a self-reported diagnosis of endometriosis,4
failed to document any increased risk of ovarian carcinoma (RR 0.8, 95% CI: 0.2–2.4). This study had an
acceptable follow-up period of 13 years, but has been criticised by the fact that the cohort was small
and included only three ovarian cancer cases. Other limitations of this study were the inclusion of only
postmenopausal women and the fact that the diagnosis of endometriosis was not surgically confirmed.
The relationship between endometriosis and ovarian cancer was further explored in terms of
causality by Vigano et al. by employing the nine criteria proposed by Austin Bradford Hill, which still
stand as fundamental of causal inference.20 The criterion of strength was not fulfilled, and there were
mixed or insufficient data for four criteria (i.e., biological gradient, biological plausibility, analogy and
coherence). The other four criteria (i.e., consistency, temporality, specificity and experimental evidence
in animal model) were fulfilled, and the authors concluded that a causal relationship between endometriosis and ovarian cancer should be recognised, but that the low magnitude of the risk observed
could be associated with the fact that ectopic and eutopic endometrium undergo malignant transformation with the same frequency.
Molecular and genetic aspects linking endometriosis to ovarian cancer
During the past several years, a significant amount of research on molecular and genetic factors that
may connect endometriosis to ovarian cancer has been conducted. There is significant evidence to
support the presence of common molecular pathways for the development of both conditions. On the
other hand, the existing data highlight the possibility of endometriosis being a benign disease that may
transform into a malignant one.
Both endometriosis and ovarian cancer share common pathogenetic factors such as familiar
predisposition, genetic instability and a similar reaction to immunologic, angiogenetic and hormonal
factors. Similar alterations in the immune response cascade and in the mechanism of inflammation
have been observed in women with ovarian cancer and endometriosis.13
Mechanisms that lead to both ovarian cancer and endometriosis due to genetic instability include
deactivation of one or two alleles of tumour-suppressive genes, changes of the enzymes that act in DNA
repair and higher oncogenic activity. The most commonly affected chromosome loci include 9p, 11q
and 22q.21
Mutations in the genes that encode metabolic and detoxification enzymes, like GALT and GSTM,
have been implicated in the pathogenesis of endometriosis as well as in development of ovarian
cancer.22 Mutations in PTEN, a tumour-suppressive gene, have been documented in endometriosis as
well as in certain histologic types of ovarian carcinomas.23,24 PTEN mutations as well as loss of
heterozygosity (LOH) at locus 10q23.3 are quite common in ovarian endometriomas, in atypical 

endometriosis as well as in endometrioid and clear-cell ovarian cancers.15,24,25 K-ras is an oncogene
that has been related to endometriosis and ovarian cancer. Mutations of K-ras are found in clear-cell
ovarian carcinomas in women with endometriosis. K-ras mutations were found in cancerous cells, but
not in the neighbouring cells with endometriosis or atypical endometriosis.26 According to the
investigators, K-ras mutations are associated with malignant transformation of benign endometriosis
to clear-cell carcinoma of the ovaries.26 In a rodent model, activation of the oncogenic K-ras or
conditional PTEN deletion within the ovarian surface epithelium gave rise to pre-neoplastic ovarian
lesions with an endometrioid glandular morphology.27 The authors were able to demonstrate that
a combination of the two mutations in the ovary leads to the induction of invasive and widely
metastatic endometrioid ovarian adenocarcinomas.27
The p-53 and c-erbB-2 genes have also been found to associate with endometriosis-related ovarian
cancer.28 The expression of these two oncogenes was significantly higher in the endometriosis-associated clear-cell tumours compared with those patients without endometriosis. These findings were in
agreement with the report by Sainz de la Cuesta et al.29 In their study, 17 out of 410 (4.1%) women with
epithelial ovarian cancer had endometriosis, whereas six out of 521 (1.2%) women with endometriosis
had atypical lesions. Of the 17 patients, 14 (82.4%) with endometriosis-associated ovarian cancer and
six out of six (100%) women with atypical endometriosis had an over-expression of the p-53 gene. Only
two out of 17 (11.8%) women with endometriosis had a mutation of the p-53 gene, and this difference
was statistically significant.29

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