Ovarian cancer development and metastasis

Abstract

The biology of ovarian carcinoma differs from that of hematogenously metastasizing tumors because ovarian cancer cells primarily disseminate within the peritoneal cavity and are only superficially invasive. However, since the rapidly proliferating tumors compress visceral organs and are only temporarily chemosensitive, ovarian carcinoma is a deadly disease, with a cure rate of only 30%. There are a number of genetic and epigenetic changes that lead to ovarian carcinoma cell transformation. Ovarian carcinoma could originate from any of three potential sites: the surfaces of the ovary, the fallopian tube, or the mesothelium-lined peritoneal cavity. Ovarian cacinoma tumorigenesis then either progresses along a stepwise mutation process from a slow growing borderline tumor to a well-differentiated carcinoma (type I) or involves a genetically unstable high-grade serous carcinoma that metastasizes rapidly (type II). During initial tumorigenesis, ovarian carcinoma cells undergo an epithelial-to-mesenchymal transition, which involves a change in cadherin and integrin expression and up-regulation of proteolytic pathways. Carried by the peritoneal fluid, cancer cell spheroids overcome anoikis and attach preferentially on the abdominal peritoneum or omentum, where the cancer cells revert to their epithelial phenotype. The initial steps of metastasis are regulated by a controlled interaction of adhesion receptors and proteases, and late metastasis is characterized by the oncogene-driven fast growth of tumor nodules on mesothelium covered surfaces, causing ascites, bowel obstruction, and tumor cachexia.

Figure 1

Major histological subtypes of borderline tumors, epithelial ovarian carcinoma, and the normal tissue they resemble. A and B: Normal fallopian tube at ×100 (A) and ×400 (B) magnification; C: serous borderline ovarian tumor at ×100. D: Micropapillary, well-differentiated ovarian carcinoma (×400). E: Low-grade serous ovarian carcinoma (×100). F: Low-grade serous ovarian carcinoma (×400). G: High-grade serous ovarian carcinoma (×100). H: High-grade serous ovarian carcinoma (×400). High-grade serous carcinoma stained for cytokeratin 7 (×400) (I) and in cytokeratin 20 (×400) (J). K: Proliferative endometrium (×400). L: Endometrioid endometrial carcinoma, Grade I (×400). M: Invasive endometrioid ovarian carcinoma (×200). N: Benign endocervical glands (×200). O: Normal colon (×200) P: mucinous borderline tumor (×400). Q and R: Low-grade mucinous ovarian carcinoma at ×40 (Q) and ×200 (R) magnification. S and T: Clear cell carcinoma at ×40 (S) and ×200 (T) magnification. U and V: Fallopian tube with areas of dysplasia at ×100 (U) and ×400 (V) magnification. W: Fallopian tube with dysplastic epithelium that is p53 positive (×400). X: Fallopian tube with dysplastic epithelium that is Ki-67 positive (×400). Y: In situ fallopian tube carcinoma (×400). Z: Dysplastic fallopian tube transitioning into an invasive fallopian tube carcinoma (×200).

Figure 2

Serous ovarian carcinoma metastasis. Normal human peritoneum (×200). A: H&E staining. MC (mesothelial cells), Fib (fibroblasts). B: Trichrome staining to detect collagen. C: Photograph of peritoneal surface; implants (white patches) in a patient with disseminated ovarian carcinoma on a background of normal peritoneum (laparotomy). D: Implant in C. E: Peritoneal implant with neoangiogenesis. Other smaller implants in the background (laparoscopy). F: H&E picture of normal omentum. G: Very early serous ovarian carcinoma (OvCa) metastasis on the omentum. Cancer cells proliferating on the surface of f the omentum without invading. H: Later phase: cancer cells invading into the omentum.