Endometriosis-associated Ovarian Cancer: A Distinct Clinical Entity?

Discussion

Endometriosis is associated with an increased risk of ovarian cancer (relative risk=1.4-8.95) and the prevalence of endometriosis in ovarian cancer ranges between 3.4 and 52.6% in the literature (5). This wide variability is due to the different definitions of EAOC adopted by authors. EAOC can be strictly defined as the presence of ovarian endometriosis in the same ovary affected by cancer with histological proof of transition from endometriosis to cancer [category A according to Van Gorp classification (1), as considered by Sainz de la Cuesta et al. (10), Ogawa et al. (11), Valenzuela et al. (12), Kumar et al. (13), or according to the less stringent criteria as endometriosis in the same ovary affected by cancer without histological proof of transition from endometriosis to cancer (category B) or even as concurrent extra-gonadal endometriosis (category C).

In our series, the proportion of EAOCs was 22.2%. Most tumors with concurrent endometriosis (82%) were in category C according to Van Gorp classification (1); 15% were in category B and only one patient was in category A. The same definition of EAOC adopted in our study has been used by others (3, 14, 15). The Sampson and Scott criteria to define category A (1, 6, 7) are difficult to meet for different reasons. Sampling techniques cannot be extensive enough to detect all foci of endometriosis adjacent to tumours, especially, if the study is retrospective and sampling was performed with the main goal of studying tumour characteristics and not for identifying concurrent endometriosis. Furthermore, the tumour can be so aggressive that the endometriosic tissue has been destroyed or only a minor residual component, difficult or even impossible to detect, is left.

Many studies have been performed in order to understand whether EAOC is a clinically distinct entity. According to the currently accepted dualistic model of Kurman and Shih for the pathogenesis of epithelial ovarian cancer (9), type I tumours include endometrioid, clear-cell, mucinous and low-grade serous carcinoma, and usually have an indolent clinical behaviour, are often detected in early stage, rarely harbour p53 gene mutations, are genetically stable, carry mutation of Kirsten rat sarcoma virus (KRAS), phosphatase and tensin homolog (PTEN), AT-rich interactive domain 1A (ARID1A) genes (1, 2), and pre-malignant lesion such as borderline tumors and endometriosis can be identified. Type II tumours include high-grade serous and undifferentiated carcinoma, have a very aggressive clinical behaviour, are usually advanced stage at presentation, often harbour p53 gene mutations, and are genetically unstable.

EAOCs frequently exhibit the favourable features of type I tumours, often being diagnosed at an earlier stage and at a younger age, and are associated with nulliparity and infertility (2).

Wang et al. found that concurrent endometriosis was significantly more frequent among those with type I tumours (14). In our series, the same trend was observed: type I tumors were more frequent among those with EAOC; on the contrary, type II tumors were more frequent in the non-EAOC group. However, the difference was not statistically significant.

In our series, EAOCs were significantly more frequently diagnosed at an early stage, consistent with previous findings (2, 13, 16, 17). The earlier diagnosis of EAOC may be due to the symptoms associated with endometriosis (pelvic pain or adnexal mass) or to the concurrent presence of endometrial lesions (polyps, hyperplasia and endometrial carcinoma) (1).

In our study, early-stage EAOCs were 46.7% endometrioid, 26.7% clear-cell, 20% mucinous, 6.7% serous and none was of undifferentiated histotype. The high prevalence among early-stage EAOCs of endometrioid and clear-cell tumours, the absence of undifferentiated tumours and the small number of serous tumours is consistent with the literature (2-4).

In the literature, a younger age at diagnosis is reported for those with EAOC (2, 14, 17-20). In our series, we found no differences in the mean age at diagnosis between those with EAOC and those with non-EAOC.

In our study, only 13.3% of patients with EAOC reported a personal history of endometriosis. Most women did not know they had endometriosis, as also reported in other studies (14). If these data are confirmed, many doubts will be raised as to the feasibility of preventing EAOC with a strict follow-up of women with endometriosis.

We would have expected a higher proportion of nulliparous women among those with EAOC (2, 20) due to the close relationship between endometriosis and infertility; in our series, no significant difference was observed between the two groups as to parity.

As described in the meta-analysis by Kim et al. (2), we also found no significant difference in optimal cytoreduction between the two groups.

In patients with EAOCs, a significantly longer OS was recorded, both in our and in other studies (2, 13, 16). Other authors, instead, saw no benefit in OS, but only a longer disease-free interval (17, 19). Stratifying our series by stage, no significant difference was observed in OS between those with EAOC and those with non-EAOC. Similar findings were reported by others who evaluated the OS of patients with EAOC according to FIGO stage (13, 17, 20). At multivariate analysis, only higher stage of disease was a significant independent predictor of poorer OS (HR=5.7; 95% CI=1.8-18.6; p=0.003).

In conclusion, the association of endometriosis with ovarian cancer is relevant. The advantage in survival associated with EAOC seems more related to its favourable features, disappearing after stratifying by stage, thus suggesting a role of endometriosis as a precursor of cancer and not as a promoter of cancer after its onset (2).