**2. Risk of cancer development in endometriosis**

Endometriosis is a common disease affecting 10 to 15% of women of reproductive age (Irving, 2011). An association between endometriosis and cancer was reported as early as the 1920s in English publications. Sampson (Sampson, 1925) proposed that endometrial carcinoma of the ovary develops from endometrial tissue, based on classic microscopic observation using several strict criteria (i.e., the coexistence of benign and malignant tissue with a shared histologic relationship in the same organ and evidence against invasion from other sites or sources). Further studies were interrupted by World War II; however, in the late 1940s and 1950s, several groups published case reports that met Sampson's criteria (Scott, 1953; Postoloff & Rodenberg, 1955). Although none of the studies demonstrated any direct evidence, the consensus of the major researchers in the field at that time was that malignant transformation or transition occurred in ovarian endometriosis.

In 1990, Heaps et al. analyzed 195 cases that mostly fulfilled Sampson's criteria (Heaps, 1990). They found that the primary endometriosis site was most frequently the ovary (78.7%), followed by various other sites such as the pelvis, rectovaginal septum, colon or rectum, or the vagina. The most frequent histologic subtype was endometrioid adenocarcinoma in either of the primary sites, ovarian (69%) or extragonadal (66%), followed by clear cell carcinoma and sarcoma in 13.5% and 11.6% of ovarian tumors, respectively, and sarcomas in 25% of extragonadal tumors. More recently, an elevated risk of ovarian cancer development in endometriosis has been shown by statistical analyses. A

Endometriosis-Associated Ovarian Cancer: The Role of Oxidative Stress 313

process is thought to have a causative role in endometriosis development and progression, leading to carcinogenesis (Murphy, 1998; Ness & Cottreau, 1999; Ngo, 2009). Alternatively, the high concentration of free iron in endometrial cysts may directly provide oxidative stress that induces genomic mutation in epithelial cells (Yamaguchi, 2008), and whether the direct pathway or the indirect pathway involving macrophages has a major role in carcinogenesis remains to be resolved. Iron overload in experimental animals enhances epithelial cell proliferation (Defrere, 2006) and causes malignant tumors with genomic abnormalities (Hu, 2010), which suggests a similar mechanism leading to carcinogenesis in human endometriosis (Fig. 1). However, further studies are awaited to elucidate the precise role of iron-deposition induced oxidative stress in carcinogenesis of endometriosis-associated

Fig. 1. A proposed mechanism of carcinogenesis in endometriotic (chocolate) cysts

Endometriosis itself is generally considered a benign disease; however, endometriosis shares certain features with cancer, including the ability of cells from different lineages (i.e., epithelial cells, stromal cells, and the vasculature) to proliferate in ectopic sites. Thus, earlier studies have focused on the clonal or malignant potential of endometriosis by analyzing the loss of heterozygosity (LOH) at several candidate tumor suppressor gene loci. Positive results, such as the detection of LOH at the p53, p16 or PTEN gene, were observed in the majority of the endometriosis samples ((Jiang, 1996; Jiang, 1998; Sato, 2000), for review of other studies with similar results, see (Prowse, 2005)). Another approach, which assesses the clonality of endometriosis samples by analyzing methylation-related marker genes, also demonstrated the clonal nature of endometriosis (Jimbo, 1997). The findings, together with the LOH analysis, led to the conclusion that endometriosis was a neoplasm that may even have malignant potential. However, recent studies deny the malignant or neoplastic potential of endometriosis, demonstrating that most endometriosis tissues are not monoclonal (Mayr, 2003). Furthermore, neither LOH of

**4. Precancerous lesions in endometriosis** 

cancer.

direct prospective study of 20,686 Swedish patients hospitalized with endometriosis between 1969 and 1983 with a mean follow-up period of 11.4 years demonstrated a standardized incidence ratio (SIR) of 1.9 and a 95% confidence interval [CI] of 1.3 to 2.8 (Brinton, 1997). Similar results were reported in a case-control study analyzing patients from the United States, in which the relative risk for ovarian cancer development in endometriosis patients was 1.7 (Ness, 2000). A nationwide case-control study of Australian patients with ovarian cancer revealed that endometriosis increased the risks of both endometrioid adenocarcinoma and clear cell carcinoma, with odds ratios of 3.0 and 2.2, respectively (Nagle, 2008). A recent retrospective study from Canada also showed a significant increase in the relative risk (rate ratio [RR], 1.6; 95% CI, 1.12 to 2.09) of ovarian cancer in patients with endometriosis (Aris, 2010). In line with these reports, a recent prospective study from Japan showed a significant and much greater elevation in the relative risk (SIR, 8.95; CI, 4.12 to 115.3) of cancer development in Japanese patients with endometrioma, or endometrial cyst of the ovary (Kobayashi, 2007). The reason for this discrepancy is unclear, but one possibility is that the endometriosis patients in the Japanese study included only those with clinically detectable ovarian endometrial cysts. It is also important to note that Danazol (17-α-ethinltestosterone), a synthetic androgen that has been used to treat endometriosis, has been revealed to be an independent risk factor for the development of ovarian cancer. A negative correlation between oral contraceptive use and ovarian cancer, regardless of histologic type other than mucinous tumors, was recently shown by a collaboration of various groups worldwide (Cottreau, 2003). These factors may also influence the relative risk of ovarian cancer development.

In addition to an epidemiologic approach, the retrospective pathological analysis of samples from ovarian cancer patients is also useful to confirm the presence of endometriosis associated with ovarian cancers of various histological types. A comprehensive review of 2,807 ovarian cancer patients from 15 independent publications from western countries from the 1970s to 1990s, including 3 articles from Japan, revealed that endometriosis was incidentally found in 14.1% of ovarian cancer patients (39.2%, 21.2%, 3.3% and 3.0% of clear cell, endometrioid, serous and mucinous carcinoma patients, respectively), with a tendency toward a higher incidence of endometriosis in Japanese patients with clear cell carcinoma (Yoshikawa, 2000).
