A 2-tier system that classifies ovarian serous carcinoma (OSC) as low grade or high grade is gaining acceptance. Women with low-grade OSC generally have higher 5-year survival rates than do women with high-grade OSC. We examined the expression of various markers to further understand the molecular differences between low-grade and high-grade OSCs: the potential therapeutic targets or prognostic markers Her-2/neu, estrogen receptor, and progesterone receptor (PR); the metastasis-associated markers cyclin D1 (BCL1), E-cadherin, matrix metalloproteinase (MMP) 2, and MMP-9; and the cell proliferation-associated markers BCL1, Ki-67 antigen (Ki-67), and p53. For this immunohistochemical analysis, we used paraffin-embedded specimens from 47 patients with advanced-stage low-grade OSC and from 49 patients with advanced-stage high-grade OSC. Our results showed that low-grade tumors expressed significantly higher levels of estrogen receptor, PR, and E-cadherin than did high-grade tumors, suggesting the involvement of gonadal steroid hormones, especially in the pathogenesis of low-grade OSC; the PR positivity was also observed in the stromal component of these low-grade tumors. On the other hand, high-grade tumors trended toward increased expression of MMP-9, BCL1, p53, and Ki-67, and robust MMP-9 positivity was observed in the stromal component of these high-grade tumors. These differences may lead to the development of different therapeutic strategies for women with either the low-grade or the high-grade form of OSC.

BACKGROUND Tyrosine kinases, such as c‐KIT, c‐ABL, and platelet‐derived growth factor‐beta (PDGFR‐β), are important regulators of cell growth. Highly potent and selective inhibitors of tyrosine kinases are being investigated as alternatives to standard chemotherapy. One such inhibitor, imatinib mesylate, is being used to treat gastrointestinal stromal tumors and chronic myelogenous leukemia. Ovarian carcinomas frequently develop resistance to conventional chemotherapeutic agents. Immunohistochemical expression of c‐ABL, PDGFR‐β, and c‐KIT was evaluated in ovarian carcinomas to determine whether treatment with imatinib mesylate might be feasible. METHODS The expression of c‐ABL, c‐KIT, and PDGFR‐β in tumors was evaluated by immunohistochemical analysis of 52 ovarian serous carcinomas, including 21 low‐grade (well differentiated) and 31 high‐grade (poorly differentiated) tumors. Fourteen normal ovaries were also evaluated. RESULTS In normal ovarian surface epithelium, c‐ABL was expressed universally. PDGFR‐β was expressed in the majority (93%) of samples of normal ovarian epithelium, whereas the c‐KIT protein was undetectable in normal ovarian surface epithelium. Overall, c‐ABL was expressed in 71% of serous carcinomas. c‐ABL was expressed more frequently in the low‐grade serous carcinomas (81%) compared with the high‐grade serous carcinomas (65%). PDGFR‐β expression was observed in 81% of serous carcinomas overall and was observed more frequently in higher‐grade tumors. c‐KIT immunohistochemical staining was absent in low‐grade tumors but was present in 26% of high‐grade serous carcinomas. CONCLUSIONS The majority of ovarian serous carcinomas express one or more of the kinases targeted by the tyrosine kinase inhibitor, imatinib mesylate, suggesting the potential usefulness of this drug in the treatment of ovarian carcinoma. Cancer 2003;98:758–64. © 2003 American Cancer Society. DOI 10.1002/cncr.11561

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