The Origin and Pathogenesis of Epithelial Ovarian Cancer: A Proposed Unifying Theory

Abstract

Ovarian cancer is the most lethal gynecologic malignancy. Efforts at early detection and new therapeutic approaches to reduce mortality have been largely unsuccessful because the origin and pathogenesis of epithelial ovarian cancer are poorly understood. Despite numerous studies that have carefully scrutinized the ovaries for precursor lesions, none have been found. This has led to the proposal that ovarian cancer develops de novo. Studies have shown that epithelial ovarian cancer is not a single disease but is composed of a diverse group of tumors that can be classified based on distinctive morphologic and molecular genetic features. One group of tumors, designated type I, is composed of low-grade serous, low-grade endometrioid, clear cell, mucinous and transitional (Brenner) carcinomas. These tumors generally behave in an indolent fashion, are confined to the ovary at presentation and, as a group, are relatively genetically stable. They lack mutations of TP53 but each histologic type exhibits a distinctive molecular genetic profile. Moreover, the carcinomas exhibit a shared lineage with the corresponding benign cystic neoplasm often through an intermediate (borderline tumor) step, supporting the morphologic continuum of tumor progression. In contrast, another group of tumors, designated type II, are highly aggressive, evolve rapidly and almost always present in advanced stage. Type II tumors include conventional high-grade serous carcinoma, undifferentiated carcinoma and malignant mixed mesodermal tumors (carcinosarcoma). They displayTP53 mutations in over 80% of cases and rarely harbor the mutations that are found in the type I tumors. Recent studies have also provided cogent evidence that what have been traditionally thought to be primary ovarian tumors actually originate in other pelvic organs and involve the ovary secondarily. Thus, it has been proposed that serous tumors arise from the implantation of epithelium (benign or malignant) from the fallopian tube. Endometrioid and clear cell tumors have been associated with endometriosis, which is regarded as the precursor of these tumors. Since it is generally accepted that endometriosis develops from endometrial tissue by retrograde menstruation it is reasonable to assume that the endometrium is the source of these ovarian neoplasms. Finally, preliminary data suggest that mucinous and transitional (Brenner) tumors arise from transitional-type epithelial nests at the tubal-mesothelial junction by a process of metaplasia. Appreciation of these new concepts will allow for a more rationale approach to screening, treatment and prevention which potentially can have a significant impact on reducing the mortality of this devastating disease.

Loss of ARID1A/BAF250a-expression in endometriosis: a biomarker for risk of carcinogenic transformation?

“…6 This theory also supports the fact that ovarian clear cell carcinomas and endometrioid ovarian carcinomas represent a different entity and that ovarian endometriotic inclusion cysts (endometriomas) are regarded as precursor of these tumors, originating from retrograde menstruation. 6 There is evidence that eutopic endometrium in women with endometriosis exhibits intrinsic molecular abnormalities such as activation of oncogenic pathways. 1,6 Some epidemiological studies demonstrated a lower risk for ovarian clear cell carcinomas and endometrioid ovarian carcinomas after tubal ligation or hysterectomy.…”

“…In the past years there is growing evidence for the relevance of a pathogenic link between these two diseases. 6 Several studies indicated that in women with ovarian endometriosis there is an increased risk for the development of epithelial ovarian cancer, especially the histological subtypes of ovarian clear cell carcinomas and endometrioid ovarian carcinomas. 4 4 reported 46 cases of ovarian carcinomas in a large prospective population-based Japanese study with an ovarian endometriosis cohort of 6398 women and a follow-up of up to 17 years.…”

“…6 There is evidence that eutopic endometrium in women with endometriosis exhibits intrinsic molecular abnormalities such as activation of oncogenic pathways. 1,6 Some epidemiological studies demonstrated a lower risk for ovarian clear cell carcinomas and endometrioid ovarian carcinomas after tubal ligation or hysterectomy. [30][31][32] A recent proposition for an ovarian cancer risk-assessment tool integrated endometriosis as well as no tubal ligation each as one of totally eight conditions associated with ovarian cancer.…”

“…[3][4][5] There is growing evidence, that endometriosis is linked to ovarian clear cell carcinomas and endometrioid ovarian carcinomas through distinct pathomechanisms. 5,6 One of them is possibly linked to mutations that result in the subsequent loss of the tumorsuppressor gene AT rich interactive domain 1A (ARID1A). Using whole-exome sequencing, recurrent mutations in ARID1A were recently reported in ovarian clear cell carcinomas and endometrioid ovarian carcinomas by two independent groups.…”

Time to diagnosis of Type I or II invasive epithelial ovarian cancers: a multicentre observational study using patient questionnaire and primary care records

“…Type I tumours are thought to develop in a stepwise fashion from benign/borderline ovarian neoplasms,19, 20 whereas accumulating evidence suggests that Type II cancers arise from precursor lesions in the fallopian tubes 18. While type‐specific classification is likely to be an oversimplification of non high‐grade serous histotypes,21, 22 it broadly represents two groups of interest; aggressive, rapidly advancing tumours and slow‐growing tumours.…”