Published and unpublished data for this review were identified by searches of Medline and PubMed. Keywords used to identify papers were “ovarian”, “cancer”, “metastasis”, “peritoneum”, “dissemination”, “anoikis”, “ascites”, “adhesion”, “detachment”, “migration”, “motility”, “invasion”, “immunology”. We did not restrict the year of publication, but only articles published in English were selected.
ReviewMechanisms of transcoelomic metastasis in ovarian cancer
Introduction
Epithelial ovarian cancer comprises 90% of all ovarian cancers. Most patients with this disease have advanced stage disease (ie, stage III–IV) at the time of diagnosis, which is associated with a substantially poorer prognosis than its early-stage counterparts. Consequently, ovarian cancer is the most lethal gynaecological malignant disease in the UK.
Like most other epithelial tumours, epithelial ovarian cancer spreads initially by direct extension into adjacent organs, especially the fallopian tubes, uterus, and contralateral adnexa, and, occasionally, the rectum, bladder, and pelvic sidewall are also invaded.1 However, its metastatic pattern differs from those of most other epithelial malignant diseases. After direct extension, epithelial ovarian cancer most frequently disseminates via the transcoelomic route, with about 70% of patients having peritoneal metastases at staging laparotomy (figure 1). In addition, many of these cancers have pelvic lymph-node involvement with a strong correlation between intraperitoneal and lymph-node spread.2 Haematogenous metastases are almost never present at diagnosis.1 Transcoelomic metastases contribute substantially to the morbidity associated with this cancer because they occur so frequently and have the capacity to affect multiple vital organs within the abdomen, including the gastrointestinal and genitourinary systems. In addition, transcoelomic metastases are often associated with the formation of malignant ascites, resulting in raised intra-abdominal pressure and consequent abdominal distention and discomfort, early satiety leading to dietary deficiency, impaired circulation of blood and lymphatic vessels, and respiratory embarrassment secondary to diaphragmatic splinting. Hence, therapeutic advantages could be gained from understanding the process of transcoelomic metastasis.
Section snippets
Pathogenesis: a blueprint for metastasis?
Although the cause of ovarian cancer remains mostly unknown, most epithelial ovarian carcinomas have been suggested to arise from the ovarian surface epithelium, which has its embryonic origins in the coelomic mesothelium.3 The coelomic mesothelium can evolve into serous (tubal), endometrioid (endometrium), and mucinous (cervix) epithelia of the female genital tract, and the ovarian surface epithelium is a specialised coelomic mesothelial layer of flat to cuboidal cells that covers and protects
Models of metastasis
Two models have been proposed for the genetic origins of tumour metastases. The first model, often referred to as the seed-and-soil hypothesis,8 is that tumours are genetically heterogeneous and that metastases arise from clones with a genetically acquired metastatic phenotype, and that the clonal genotype determines the final site of metastasis. The second hypothesis is that metastatic cells are not a genetically selected clone distinct from the primary tumour. Instead, they arise as a
The transcoelomic journey: adaptive or passive metastasis?
Although omental metastases have been well documented in many other cancers, they do not occur as frequently as in epithelial ovarian cancer. The reasons for this discrepancy are unknown, but are most probably related to the close proximity of the ovaries to the peritoneal cavity. In view of the common lineage of the omental surface mesothelium and ovarian epithelium, we could speculate that if the transcoelomic metastatic process is indeed akin to the seed-and-soil hypothesis, then the omental
From peritoneum to circulation
The transcoelomic route provides direct access to the circulatory system (figure 2). Ascitic fluid carrying epithelial ovarian cancer cells enters the subperitoneal lymphatic lacunae between the muscle fibres of the diaphragm. To reach the lacunae, the fluid passes through stomata located between cuboidal mesothelial cells of the lacunar roof.84 These stomata seem to be exclusive to the diaphragm and are the main drainage channels for fluid absorption from the peritoneal cavity. From the
Conclusions
Although very little is understood about the metastatic process in ovarian cancer, transcoelomic metastasis is clearly the most common route of metastasis in epithelial ovarian cancer, and is associated with substantial morbidity and mortality. Clinical studies38, 39 suggest a transcoelomic metastatic route that involves tumour shedding followed by dissemination via the peritoneal or ascitic fluid current. However, this is a complex process, which, although facilitated by the circulation of
Search strategy and selection criteria
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