Expression of platelet-derived growth factors and their receptors in ovarian clear-cell carcinoma and its putative precursors

Abstract

Recent studies have shown that platelet-derived growth factors and their receptors are frequently co-expressed in ovarian cancers. Herein, we investigated the role of the platelet-derived growth factor pathway in the development of ovarian clear-cell adenocarcinoma, a highly chemoresistant form of ovarian cancer. Immunohistochemical expression of platelet-derived growth factor receptor-a and receptor-b, platelet-derived growth factor A-chain and B-chain was examined in 31 cases of clear-cell adenocarcinoma and 56 coexisting putative precursor lesions: 17 non-atypical and 19 atypical endometrioses, and 10 non-atypical and 10 atypical clear-cell adenofibroma components. Twenty-one solitary endometrioses were also examined. Vascular endothelial cells were always positive for all the markers examined, and were used as positive controls. The frequencies of positivity for platelet-derived growth factor receptor-a and receptor-b, and platelet-derived growth factor A-chain increased in accordance with higher cytologic atypia in the putative precursors: 71, 47, and 59% in the 17 non-atypical endometrioses, 84, 73, and 84% in the 19 atypical endometrioses, 0% each in the 10 non-atypical clear-cell adenofibromas, 100, 90, and 90% in the 10 atypical clear-cell adenofibromas, and 97, 97, and 100% in the 31 clear-cell adenocarcinomas, respectively. Positivity for platelet-derived growth factor B-chain increased in accordance with increased atypia in clear-cell adenofibroma: 0% in non-atypical clear-cell adenofibromas, 30% in atypical clear-cell adenofibromas, and 60% in coexisting carcinomas. However, in contrast, positivity for platelet-derived growth factor B-chain decreased in accordance with increased atypia in endometriosis coexisting with clear-cell adenocarcinomas: 35% in non-atypical endometrioses, 11% in atypical endometrioses, and 5% in coexisting carcinomas. Platelet-derived growth factor receptor-a and receptor-b, and their ligands A-chain and B-chain were positive in 14, 29, 19, and 62% of the solitary endometrioses, respectively. These results indicate activation of the platelet-derived growth factor pathway in ovarian clear-cell adenocarcinomas and suggest biological differences between carcinomas that arise in association with clearcell adenofibroma vs endometriosis.

Accumulative copy number increase of MET drives tumor development and histological progression in a subset of ovarian clear-cell adenocarcinomas

“…From these 21 cases, based on the histopathological criteria described previously, [21][22][23][24] 11 tumors with synchronous endometriotic lesions (endometriosis-associated carcinomas) and 2 tumors with adjacent CCAF components (adenofibromaassociated carcinomas) were identified. These 13 cases were retrieved from the files of the Department of Clinical Laboratory, National Defense Medical College Hospital, Japan; all patients had undergone surgical resection between 1987 and 2006, none had undergone chemotherapy or radiation therapy before surgery, and all specimens were formalin-fixed and paraffin-embedded tissue sections.…”

“…On the basis of previously described histological criteria for 'atypical endometriosis', [21][22][23] endometriotic lesions adjacent to clear-cell adenocarcinoma were classified into non-atypical and atypical forms. Of the 11 endometriosis-associated cases, 9 had both non-atypical and atypical endometriosis, 1 had nonatypical endometriosis only, and 1 had atypical endometriosis only.…”

“…[15][16][17][18][19] Although little is known about the molecular genetic alterations underlying tumor development, a hypothesis of multi-step tumorigenesis of ovarian clear-cell adenocarcinoma, starting with histologically benignappearing precursor lesions (ie, endometriosis and benign clear-cell adenofibroma (CCAF)), progressing to their atypical counterparts (ie, atypical endometriosis and borderline CCAF), and ultimately to clearcell adenocarcinoma has been proposed and widely considered. [20][21][22][23][24][25][26] In this study, to unmask the timing of MET alterations in the development and progression of ovarian clear-cell adenocarcinoma, we selected 13 clear-cell adenocarcinoma cases that were double in situ hybridization-positive cases, as determined by our previous series, 14 and were in a group of carcinomas with adjacent putative precursor lesions. Using double in situ hybridization and immunohistochemistry, the enrolled cases were analyzed for MET gene copy number alterations and MET protein expression in terms of their intratumoral heterogeneity.…”

Loss of ARID1A protein expression occurs as an early event in ovarian clear-cell carcinoma development and frequently coexists with PIK3CA mutations

“…On the basis of the previously described histological criteria for 'atypical endometriosis', 5,7,8 endometriotic lesions adjacent to clear-cell adenocarcinoma were classified into non-atypical and atypical forms. Of the 28 patients with endometriosis-associated carcinoma, 15 had both nonatypical and atypical endometriosis, 6 had only non-atypical endometriosis, and 7 had only atypical endometriosis.…”

“…[1][2][3][4] Although little is known about the molecular genetic alterations underlying tumor development, a hypothesis of multistep tumorigenesis of ovarian clear-cell carcinoma, starting with histologically benign-appearing precursor lesions (ie, endometriosis and benign clear-cell adenofibroma), progressing to their atypical counterparts (ie, atypical endometriosis and borderline clearcell adenofibroma), and ultimately to clear-cell carcinoma, has been proposed and widely considered. [5][6][7][8][9][10][11] To establish novel therapeutic strategies for ovarian clear-cell carcinoma, it is crucial to elucidate the molecular aberrations that are characteristic of this type of carcinoma during tumor development.…”