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Epithelial ovarian cancer (EOC) is often a lethal disease because in many cases early symptoms go undetected. Although research proceeds apace, as yet there are few reliable and specific biomarkers for the early stages of the disease. EOC is an umbrella label for a highly heterogeneous collection of cancers, which includes tumours of low malignant potential, serous cystadenomas, mucinous and clear cell carcinomas, all of which are likely to arise from a number of epithelial cell types and a variety of progenitor lesions. Many, but not all types of EOC are thought to arise from the cells lining ovarian inclusion cysts. In this review, we discuss the hypotheses that have driven our ideas on epithelial ovarian carcinogenesis and examine the morphological and genetic evidence for pathways to EOC. The emergence of laser-capture microdissection and expression profiling by microarray technologies offers the promise of defining these pathways more accurately, as well as providing us with the tools for earlier diagnosis.

Benign ovarian cysts are thought to be precursor lesions that differentiate and transform into carcinoma. With the aim of testing the hypothesis that increased ovulation number increases the frequency or number of ovarian cysts, the development and appearance of ovarian cysts was investigated in mice of differing ages and total lifetime ovulation number. High total ovulation number was induced by keeping mice in cages divided by a screen, with a male on one side and two females on the other side. Significantly more cysts were observed in animals subjected to incessant ovulation for 8 months and in 12 month breeding mice than in 3-month virgin mice or 1-month prepubertal animals. These cysts had the appearance of benign serous inclusion cysts. When cystic ovaries were serial sectioned, 47% of cysts had a connection to the ovarian hilus and potentially to the tubules of the rete ovarii, 31% were adjacent to the hilus, and 22% had an intra-ovarian location. A significant increase in intra-ovarian cysts was observed in the 8-month incessant ovulation group, implying that high ovulation number leads to ovarian surface invagination and inclusion cyst formation. In conclusion, ovarian inclusion cysts may be derived from more than one epithelial source, but incessant ovulation may increase the proportion derived from the ovarian surface epithelium. Because the cysts observed resembled human serous inclusion cysts these results have possible implications for epithelial ovarian carcinoma.