Ovarian cancer stroma: pathophysiology and the roles in cancer development

Abstract

Ovarian cancer represents one of the cancers with the worst prognostic in adult women. More than half of the patients who present with clinical signs such as abdominal bloating and a feeling of fullness already show advanced stages. The majority of ovarian cancers grow as cystic masses, and cancer cells easily spread into the pelvic cavity once the cysts rupture or leak. When the ovarian cancer cells disseminate into the peritoneal cavity, metastatic nests may grow in the cul-de-sac, and in more advanced stages, the peritoneal surfaces of the upper abdomen become the next largest soil for cancer progression. Ascites is also produced frequently in ovarian cancers, which facilitates distant metastasis. Clinicopathologic, epidemiologic and molecular studies on ovarian cancers have improved our understanding and therapeutic approaches, but still further efforts are required to reduce the risks in the patients who are predisposed to this lethal disease and the mortality of the patients in advanced stages. Among various molecules involved in ovarian carcinogenesis, special genes such as TP53, BRCA1 and BRCA2 have been well investigated. These genes are widely accepted as the predisposing factors that trigger malignant transformation of the epithelial cells of the ovary. In addition, adnexal inflammatory conditions such as chronic salpingitis and ovarian endometriosis have been great research interests in the context of carcinogenic background of ovarian cancers. In this review, I discuss the roles of stromal cells and inflammatory factors in the carcinogenesis and progression of ovarian cancers.

Figure 1

Macroscopic and microscopic features of the ovary. (A) Cut surface of the ovary. Cortex, medulla and hilus are distinguishable; (B) Intermediate magnification of cortex area; Rectangle (C) contains an inclusion cyst; (C) High magnification of cortex area indicated by rectangle in (B); Inclusion cysts are surrounded by dense fibrotic stroma; (D) High magnification of ovarian surface. Thin columnar surface epithelial cells are lined; (E) High magnification of an inclusion cyst. Tall columnar epithelial cells are lined; (F) High magnification of hilus area. Numerous vessels are accumulated.

Figure 2

Histologic types of ovarian cancers. (A) Serous adenocarcinoma. The tumor shows papillary structure, and the cells do not contain intracytoplasmic mucin; (B) Mucinous adenocarcinoma. Irregular glands are composed of cell with atypical nuclei and intracytoplasmic mucin; (C) Endometrioid adenocarcinoma. The histology closely resembles endometrioid adenocarcinoma of the uterine corpus; (D) Clear cell adenocarcinoma. The cells have clear or eosinohpilic cytoplasm, protruding into glandular lumen; (E) Macroscopic feature of peritonitis carcinomatosa. The omental fat is completely replaced by metastatic cancer; (F) Macroscopic feature of EAOC in a chocolate cyst. Circle indicates cancer lesion.

Figure 3

Cancer stroma. (A) Endometriosis. The ovarian stroma is infiltrated by numerous hemosiderine-laden macrophages, lymphocytes and plasma cells; (B) CD68 immunostaining is shown. Macrophages are highlighted; (C) Transitional lesion between endometriosis and EAOC; (D) High magnification of the rectangle indicated in (E). Lining epithelial cells show cytologic atypia; (E) Carcinosarcoma. Stromal component surrounding cancer nests demonstrates highly atypical nuclei, irregular morphology and often multi-nucleated appearance; (F) Functioning stroma. Stroma cells with clear cytoplasm are noted in the vicinity of epithelial glands. Inset: Functioning stroma cells are immunostained for Inhibin-α.