The pathogenesis of ovarian cancer—Developmental aspects and modes of spread

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The ovary gives rise to a multiplicity of neoplasms reflecting the complexity of its embryological origin and the retention in the adult ovary of cells possessing a high degree of pluripotentiality. Ovarian cancer is important as the fifth most common site of fatal malignancies in women and yet little is known of the factors which initiate and promote its growth. Retrospective studies of patients, employed in an attempt to identify risk factors of etiologic significance in the development of epithelial ovarian cancer, have disclosed that the typical patient is nuiliparous or of low parity and has experienced difficulty in conceiving that could not be attributed to anovulatory cycles.‘2 Longterm users of oral contraceptives appear at less risk for the development of ovarian carcinoma. Furthermore, anovulatory patients with polycystic ovary syndrome and children prior to menarche rarely develop epithelial neoplasms. These observations have led to the hypothesis that frequent ovulation is related to the pathogenesis of epithelial tumors, a hypothesis supported by the fact that accelerated ovulation for egg production in the domestic fowl is associated with early development of adenocarcinoma. A link between ovulation and the pathogenesis of ovarian cancer is found in the coelomic-epithelial inclusion cyst. These cysts are significant because of the capacity of their lining cells to undergo metaplasia to form serous, mutinous, endometrial, transitional and clear cell Miillerian cell types.4 Neoplastic proliferation in metaplastic epithelial inclusions predate most ovarian cancers. Coelomic epithelial inclusions are derived through a number of mechanisms, most of which are related to the process of ovulation.‘4 These may arise by the pinching off of surface invaginations created through retraction of corpora lutea and atretic follicles. Alternatively, the coelomic epithelium may grow through the surface tear created at the time of ovulation, thereby trapping portions of epithelium within the cortex. The reorganization of mesothelial cysts in tuboovarian adhesions could also carry portions of epithelium into the ovary. The various Mtillerian-like histological patterns in benign and malignant epithelial ncoplasms of the ovary reflect the retention of embryonic potential by this epithelium. Embryonic potential is also retained by extragonadal mesothelial cells of the peritoneum as shown by the rare occurrence of carcinomas of a typical ovarian type in pelvic or extrapelvic sites, associated with little or no ovarian involvement. The derivation of neoplasms of a “Mtillerian” type directly from peritoneum itself has been termed “Miillerianosis”’ and the peritoneum has been termed a “secondary Miillerian system.“” In extragonadal peritoneal lesions, considerable difficulty is encountered in distinguishing some papillary carcinomas from mesotheliomas.* One group has proposed that papillary lesions of the peritoneum (and their ovarian counterparts) should be regarded as varieties of mesothelioma and have named the process “intraabdominal neoplasia.“‘3.‘8 Intra-abdominal neoplasia is thought to be initiated by unknown irritants acting as carcinogens that have gained access to the peritoneum via patent fallopian tubes. Although th;e nature of the proposed irritants is unknown. the possibility of an environmental carcinogen(s) in pathogenesis of ovarian and peritoneal neoplasms deserves close examination. Woodruff” reviewed reported series of ovariotomies from the 19th and early 20th centuries and found that ovarian malignancies were uncommon then as compared with the present. More recent studies indicate that ovarian malignancies have a greater incidence in industrialized countries (except Japan) than in less developed countries,‘* in keeping with the hypothesis of an environmental carci-