at an advanced stage at an average age of 48 years, which is younger than in non-hereditary ovarian cancer. Identification of these gene ­mutations, which are related to 10–13% of high-grade serous ovarian cancers, is important, as these patients have a better prognosis, and new therapeutic options can be offered (Jayson et al. 2014; Neto and Cunha 2015).

inal US and CA-125 testing for women with BRCA1 or BRCA2 gene mutations beginning at age 30–35 years (NCCN 2016). Prophylactic sal- pingo-oophorectomy should also be considered to reduce the cancer risk in these women. It may be delayed until childbearing is completed, or at the ages of 35–40 years (Clarke-Pearson 2009).

3\ Screening for Ovarian Cancer

Successful screening for ovarian cancer, by definition, is able to decrease mortality and morbidity from the disease (Ozols et al. 2001). Large randomized trials have assessed transvaginal sonography and serum CA-125, or both, or included complex algorithms as screening tests for ovarian cancer (Clarke-Pearson 2009; Jayson et al. 2014; Buys et al. 2011; Moyer 2012). Due to lack of evidence that screening improves survival, screening for ovarian cancer is currently not recommended in the general population (Clarke-Pearson 2009; Jayson et al. 2014; Moyer 2012). This is based upon the fact that prevalence of ovarian cancer is very low and the issue of false-positive screening tests (Moyer 2012). In the randomized controlled PLCO (prostate, lung, colorectal, ovarian) cancer screening trial, no difference was found in stage at diagnosis and the ovarian cancer death rate, but approximately 10% of participants had a false-positive result. False-­ positive findings during screening may even lead to adverse effects with an increased morbidity due to unnecessary surgeries. The PLCO trial reported a ratio of surgeries to cancer of approximately 20:1 and considerable complication rates after surgery (Buys et al. 2011).

However, women at an increased personal risk, with relatives with BRCA1 and BRCA2 gene mutations, with Lynch syndrome or a strong familiar risk for ovarian cancer should be referred to formal genetic counseling, and multigene testing may be offered (Clarke-Pearson 2009; Moyer 2012; NCCN 2016). Because of their markedly increased lifetime risk of ovarian cancer, the National Comprehensive Cancer Network ­recommends screening with semiannual transvag-

4\ Tumorigenesis of Ovarian

Cancer

On the basis of distinct histological features, primary ovarian malignancies can be separated into three major entities: epithelial carcinomas, germ cell, and sex-cord stromal malignancies (Lengyel 2010). Rare malignancies include sarcomas and lymphomas. 5–15% of ovarian malignancies account for metastases. Primary tumors with a propensity to metastasize to the ovaries include colorectal, gastric, breast, and endometrial cancer. Epithelial ovarian cancer constitutes the vast majority (85–95%) of all ovarian malignancies (Koonings et al. 1989). A dualistic model of carcinogenesis of epithelial ovarian cancer that differentiates between cancer types I and II has been introduced (Kurman and Shih 2011). These two major cancer types not only develop along different pathways but differ considerably in terms of tumor biology, aggressiveness, precursors, and prognosis (Kurman and Shih 2011;). Cancer types I include low-­grade serous cancers, endometrioid cancer, and clear cell, transitional, and mucinous cancers (Kurman and Shih 2011). They are characterized by specific gene mutations including KRAS, BRAF, ERBB2, etc. They exhibit a slow growth, mutate stepwisely from precursor lesions, and are less aggressive in their clinical course. In contrast, type II cancers are composed of highgrade serous cancers. They are clinically aggressive and usually present in an advanced stage. Often TP53 mutations and high cellular proliferations are found, and genetically, these tumors are typically instable (Kurman and Shih 2011). It is now accepted that the origin of high-grade serous, primary peritoneal cancer and most fallopian tube cancers is not the ovaries but that these tumors derive from the fallopian tube (STIC theory) (Lengyel 2010; Kurman and Shih 2011).