is endometriosis a prenoplastic condition ? prof. dr. fuat demirkıran i.u cerrahpaşa school of...
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Is endometriosis a prenoplastic condition ?
Prof. Dr. Fuat DemirkıranI.U Cerrahpaşa School of Medicine.
Department of OB&GYN Division Of Gynocol Oncol
Asian Con. on EndometriosisNowember Istanbul
Endometriosis…to be present
10–15% of women in the reproductive age group..
2–5% of postmenopausal women..
25–30% of infertile women ..
40–70% of women with chronic pelvic pain..
starting with ectopic tissue implantation
bleeding in this ectopic tisue
Inflamation
fibrin deposition,
adhesion and scar formation
distortion of peritoneal surfaces
The natural course of endometriosis
The points of discussion here are to
clarify
whether endometriosis should be
considered a precursor lesion of cancer
such as, ovarian uterine and breast and if
transformation to the cancer occurs
frequently.
The relationships between endometriosis and cancer
Malignant transformation of endometriosis occurs generally in 1.7-3.6% of cases.
Ovarian cancer develops in 1–5% of cases with ovarian endometriosis and in a lower percentage of cases with extra-ovarian endometriosis.
Endometriosis is present in 10 to 15% of patients with ovarian cancer.
The course of endometriosis
Jian-Jun Wei and et al Int J Gyncol Patho 2011
Similar factors effect the incidence of ovarian cancer and endometriosis.
Decreased risks
tubal ligationhysterectomy
oral contraceptives pregnancy
Increased risks
infertilityearly menarche, Late menopause
Ovarian Cancer and Endometriosis
The relationship between endometriosis and ovarian cancer
RR was 4 in primary infertil patients with endometriosis.
The relationship between endometriosis and ovarian cancer
In this study, dataset consisted of data from 23 144 women. (7911 with invasive ovarian cancer, 1907 with borderline ovarian cancer, and 13 326 controls)
* No association was noted between a history of endometriosis and borderline ovarian cancer.
* History of endometriosis was associated with an increased risk of invasive epithelial ovarian cancer.
* 2-3 fold increase in the risk of clear-cell, low-grade serous, and endometrioid invasive ovariancancer in patients with endometriosis.
Clinico-pathologic characteristics of ovarian cancer seen in patients having endometriosis
…….tended
to be younger
to be diagnosed in earlier stages to be tumor with lower grade lesions to be better survival to be endometrioid and clear cell subtypes
The relation between endometriosis and other cancers
such as breast, cervical and endometrial cancer
The relationship between endometriosis and breast cancer
The relationship between endometriosis and cervical cancer
The relationship between endometriosis and endometrial cancer
There is a relation between endometriosis and ovarian cancer,
so.
endometriosis increases the risk of ovarian cancer !!!
The weaknesses of the these studies
Most of the cohorts consisted only of patients hospitalized for endometriosis. This could result in the inclusion of women with mainly moderate or severe disease and thereby lead to an overestimation of the risk of cancer among women with endometriosis.
Limitation of the studies was the lack of information on possible confounding factors that might have influenced the results.
In most of studies, there is no imformation about drug / hormon use, origin of endometriosis, fertility, parity and histologic verification of endometriosis.
It is often suggested that a relative risk of at least 2 is required before the conclusion that a risk estimate can be considered strong and, in particular, to be free of the influence of confounders and other sources of bias and selectivity. Relative risks of less than 2.0 may also be consistent with causality.
Overall, the reported strength of association between endometriosis and ovarian cancer ranged between 1.3 and 4. Despite the weak association, majority of studies documented statistically significant association between endometriosis and ovarian cancer.
Some studies found that the cancer risk markedly increased in women having a long-standing history of the disease. This finding suports the causal association.
Causality between endometriosis and ovarian cancer - I
Causality between endometriosis and ovarian cancer - II
endometroid or clear cell ovarian carcinoma
Histological, Genetic and Molecular Alterations in Endometriosis
Histological Alterations
Atypical endometriosis as a precursor of malignancy
Of the 127 patients with ovarian ca, 37(29%) had histologic evidence of endometriosis. And 70% of clear cell ca. 43% of endometrioid ca, 7% of serous ca., and 0% of mucinous ca. had endometriozis
In 37 cases with endometriosis, 78% showed atypical
endometriosis
The mean Ki-67 indices were as follows: ovarian carcinoma, 23.1; atypical endometriosis, 9.9; typical endometriosis, 2.7.
Atypical endometriosis shows proliferation activity, suggesting it is a precancerous status.
Gynecologic Oncology 77, 298–304 (2000)
Metaplasia 41 12.1 (8.8–16.0)
Hyperplasia 32 9,4 (6.5–13.1)Atypia 20 5,9(3.6–9.0) Endometrioid adenoca 14 4.11(2.3–6.9)
Conclusions. Epithelial abnormalities are a common finding in cystic ovarian endometriosis.
Fukunaga M, Nomura K, Ishikawa E, Ushigome S. Ovarian atypical endometriosis: its close association with malignant epithelial tumours. Histopathology 1997;30:249–55.
They reported that atypical endometriotic region were observed in 61% of 54 endometriosis associated ovarian
cancers,but these changes (atypical glandular) were seen in only 1.7% of 255
endometriosis cases without cancers.
Retrospective analysis of 160 malignant and 23 borderline ovarian tumours during the period 1995–
2001.
7.7% of the ovarian ca tumours contained endometriosis.
The incidence of ovarian endometriosis in borderline tumours was 13% compared to in ovarian cancer 6.9%.
57% of cases were classified as atypical endometriosis and 43% cases were typical endometriosis.
Endometriosis observed in 22% of the endometrioid, 9% of clear cell ca and 10.8% of the mixed adeno adenoca
Atypical endometriosis are considered to be precancerous
lesion.
With these findings, it is considered thatAtypical endometriosis may represent a transition
from benign endometriosis to carcinoma.
Genetic alterations in endometriotic tissue I
monoclonality of endometriosis…….. 60-100 % (in 7 studies)
monoclonality of endometriosis…….. 6 % (in 1 study)
loss of heterozygosity (LOH) in endometriosis
Genetic alterations in endometriotic tissue II
commonly involving chromosomes 9p, 11q, and 22q.
P53 mutations
PTEN mutations
K-Ras mutations
There are conflicting results
Genetic alterations in endometriotic tissue III
in 30% of endometriosiscoexisting with Ovarian CCC
in 10-20% of endometrioticassociated ovarian Ca.
in 20% of endometrioticcyst, in 20% of ECand in 8% of CCC
ARID1A mutations in endometriosis
Genetic alterations in endometriotic tissue V
ARID1A mutations were seen in
46% of endometriosis associated-ovarian clear-cell ca. 30% of endometriosis associated- ovarian endometrioid ca. 0% of endometriosis associated-high-grade serous ovarian ca.
Wiegand et al. NEMJ 2010
Epigenetic variations in endometriosis
Heme and free iron induced oxidative stress
Inflammation
Steroid hormones
The repetition of hemorrhage in the endometriotic cysts result in excess accumulation of heme and free iron in endometriotic lesions. Heme and free iron are pro-oxidant and can induce oxidative stress and DNA damage, possibly increasing the risk of some cancer.Inflammatory cells and cytokines in endometriosis may promote angiogenesis, cell proliferation, inhibition of apoptosis, and production of reactive oxygen species that may induce DNA damage and mutations. Thus, inflammation may contribute to tumor growth and progression.
Some studies have demonstrated a local increase in estradiol concentration in endometriotic lesions. Estradiol stimulates cyclooxygenase-2 (COX-2). This can induce DNA damage.
Jian-Jun Wei and et al Int J Gyncol Patho 2011
Finaly, endometriosis-associated tumor progression may be related to many independent factors
In conclusion, the exact molecular mechanisms that may lead to malignant transformation of endometriosis are not completely understood. The potential etiology regarding the association between
endometriosis and ovarian cancer seems to be multifactorial.
Given the high prevalence of endometriosis and the high mortality of ovarian cancer, the potential association has important public health implications
and
So, OB&GYNs should be aware of the apparently increased risk of ovarian cancer
among endometriosis patients, and increased attention should particularly be
paid to patients with early diagnosis, a long-
standing history of disease and/or associated infertility,
Thank you