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On the Origin of Ovarian Cancer … Is It the Ovary?
By Robert L. Coleman, MD, Professor, University of Texas; M.D. Anderson Cancer Center, Houston, is Associate Editor for OB/GYN Clinical Alert.
Dr. Coleman reports that he is a consultant to GlaxoSmithKline, Eli Lilly Co., Abbot Laboratories, Sanofi-Aventis, and Pfizer; and serves on the speakers bureau of OrthoBiotech.
One of the most common and poignant questions an ovarian cancer patient asks upon learning of her diagnosis is, "How did I get this? … Where did it come from?" The answer, unsatisfactory to both, is usually of the form, "… it's not exactly clear … but it likely comes from disregulated growth at the surface of the ovary." The pacifying (maybe just temporizing) statement of fact is supported by epidemiological data focusing on the ovulatory axis, where risk association is highest in nulliparous women and women with early menarche and late menopause, and lowest in those with multiple live births and those with a history of prolonged oral contraceptive use.1 The observational data support a contention that functional mutations arise in the repetitive breaking and repairing of the ovarian coelomic surface, leading over time and under the influence of various molecular promoters, to development of cancer.2 Evidence of surface epithelia-lined inclusion cysts are usually pointed to as the germinal culprit, where, in the event of malignant transformation, access to the surface and peritoneal cavity is the principal pathway to metastatic spread.3 This "incessant ovulation" theory is presented in nearly every contemporary textbook on the subject and data from interventional studies, such as the documented risk reduction by hormonal contraception or bilateral salpingo-oophorectomy in high-risk women (because of either family history or BRCA mutation), support the contention.4,5 Yet what is undeveloped in most accounts is the controversy that lies at the true core of the question posed by our patient — the origin of disease.
Ovarian cancer is a rare condition diagnosed in fewer than 25,000 patients annually. The constellation of disease termed "ovarian" frequently includes morphologically similar processes arising in the peritoneal cavity (so called primary peritoneal cancer) or fallopian tubes (fallopian tube cancer). Molecular studies have demonstrated the similarity of these conditions6 and investigational treatment studies frequently allow all three, although criteria to separate their origin are available. For instance, a peritoneal malignancy can only be classified as primary if: 1) both ovaries are normal in size or enlarged by a benign process, 2) the involvement in the extra-ovarian sites is greater than the involvement on the surface of either ovary, or 3) the ovarian tumor involvement is either nonexistent, confined to the ovarian surface epithelium without stromal invasion, or involving the cortical stroma with tumor size less than 5 × 5 mm.7 Nevertheless, it is troublesome that the histological spectrum that makes up "ovarian" cancer in the ovary consists of cells that are not native to this organ. Serous cancer, the most common type, is composed of cells morphologically resembling the epithelial lining of the fallopian tube; mucinous cancer, resembling those of the endocervix; and endometrioid cancer, resembling those of the uterine glandular lining. According to the coelomic origin theory, the development of these cell types comes from the metaplastic differentiation of the ovarian (or peritoneal) mesothelium, which then de-differentiate in inclusion cysts to become cancer. The differentiation and de-differentiation process, while explicative, is counterintuitive to our current understanding of malignant progression. Further, the elusive intermediary step, in situ or pre-cancer, has yet to be described, and represents a problematic distraction of this theory.
An alternative hypothesis on the origins of "ovarian" cancer has resurfaced, and now armed with provocative molecular findings, deserves closer examination.8-10 Binding the histological elements of cancers called "ovarian" is their origin, the Müllerian system. Embryological development of the upper vagina, cervix, uterus, and fallopian tube comes from the paramesonephric ducts, which in the absence of Müllerian inhibiting substance (MIS), fuse distally to make the midline structures, and remain unfused proximately to form the fallopian tubes. The undifferentiated gonad that becomes the ovary (in the absence of MIS) is unrelated to this tract, yet malignancy attributed to the ovary comes from cells that describe the Müllerian system, namely fallopian tube, uterus, and endocervix. Beyond morphology though, evidence has recently surfaced that molecularly links ovarian cancer histology and cells of the Müllerian tract.11 The HOX family of homeobox genes controls the normal developmental pattern along the anterior-posterior axis. These genes uniquely appear to specify morphological identity through their spatially and temporally restricted expression. The discovery that specific HOX genes responsible for the formation cells of the fallopian tube, endometrial glands, and endocervix could produce ovarian cancers of serous, endometrioid, and mucinous variety, respectively, lends credence to the hypothesis that ovarian cancers could arise from cells of the Müllerian tract. Mixed tumors may be explained in the differential expression of more than one of these genes.
Further support comes from the identification of an in situ lesion in the fallopian tube, first discovered through serial sectioning in specimens retrieved from women with BRCA germline mutations undergoing risk-reducing prophylactic bilateral salpingo-oophorectomy.12 The so-called "serous tubal intraepithelial carcinoma," or STIC, was also identified in nearly one-half of tumors designated as primary peritoneal (based on the definition presented above), which was typically fimbrial and unifocal.13-17 However, in cases where primary and distant STIC was found, the p53 signature was identical in all, harboring the same p53 mutation.18
The data are clearly provocative, but don't explain the origin of disease in women in whom the uterus, tubes, and ovaries are removed. Proponents of the theory point to the existence of a secondary Müllerian system, which includes vestigial remnants of the oviducts and cystic inclusions lined with Müllerian epithelium along the paratubal and paraovarian tissues.8 These extra-Müllerian lesions, termed endosalpingiosis, endometriosis, and endocervicosis, reflect their source organ histologically. They are found throughout the peritoneal cavity and extraperitoneally, and have been documented with benign, low malignant potential (borderline), low-grade serous, and carcinomatous elements. Given the high prevalence of these types of cystic inclusions, it is not surprising that multifocal (peritoneal) disease is commonly described when cancer is diagnosed. More study of this phenomenon is indicated.
The principal and ultimate impact of understanding the origin and biology of disease is to develop effective and acceptable prevention strategies. It is well documented that more than three-quarters of women presenting with ovarian cancer have advanced disease, and while many will enjoy a good response to surgery and chemotherapy, recurrence is both common and deadly. Describing the molecular events leading to a precursor lesion (e.g., STIC) or identification of its presence is an initial step forward. The recent discovery of circulating nucleic acids, circulating tumor cells, and microRNA (miRNA) cells offer new opportunities to meet this challenge.19-21