Is endometriosis a prenoplastic condition ? Prof. Dr. Fuat Demirkıran I.U Cerrahpaşa School of Medicine. Department of OB&GYN Division Of Gynocol Oncol Asian Con. on Endometriosis Nowember 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 % 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 ligation hysterectomy oral contraceptives pregnancy Increased risks infertility early 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 women. (7911 with invasive ovarian cancer, 1907 with borderline ovarian cancer, and 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 ovarian cancer 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 (8.8–16.0) Hyperplasia 32 9,4 (6.5–13.1) Atypia 20 5,9(3.6–9.0) Endometrioid adenoca (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– % 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 that Atypical endometriosis may represent a transition from benign endometriosis to carcinoma.

Genetic alterations in endometriotic tissue I monoclonality of endometriosis…… % (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 endometriosis coexisting with Ovarian CCC in 10-20% of endometriotic associated ovarian Ca. in 20% of endometriotic cyst, in 20% of EC and 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 I nflammation 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,

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