Expression of apoptosis-related proteins in peritoneal, ovarian and colorectal endometriosis.

Endometriosis is defined as the presence of endometrial glands and stroma outside the uterus. Apoptosis, a physiological process by which multicellular organisms eliminate superfluous cells, is altered in tumor tissue. Here we studied the expression of the apoptosis-related proteins p53, bcl-2, bax, p21 and fas in proliferative (n=9) and secretory (n=9) endometrium, and in peritoneal (n=11), ovarian (n=20) and colorectal (n=20) endometriosis, by qualitative and semi-quantitative immunohistochemical methods using the percentage of positive cells and HSCORE analysis. In endometrium, p53, p21 and fas expression was low, whereas bax and bcl-2 expression was elevated. Using HSCORE analysis, only bcl-2 expression varied during the menstrual cycle (48.9+/-34.2% in the proliferative phase, 11.5+/-24.7% in the secretory phase, p=0.01). Using HSCORE analysis, p53 expression was higher in ovarian endometriosis than in peritoneal (p<0.0001) and colorectal endometriosis (p=0.03). P21 expression was higher in ovarian endometriosis than in peritoneal (p=0.01) and colorectal endometriosis (p=0.01). Bcl-2 expression was lower in ovarian endometriosis than in peritoneal (p=0.0002) and colorectal endometriosis (p<0.0001). Fas expression was higher in peritoneal endometriosis than in ovarian (p=0.02) and colorectal endometriosis (p=0.008). In conclusion, these results confirm the involvement of apoptosis in the pathogenesis of endometriosis. Moreover, expression of apoptosis-related proteins varies according to the location of endometriosis suggesting the involvement of different apoptotic pathways.

Expression of pro-apoptotic (p53, p21, bax, bak and fas) and anti-apoptotic (bcl-2 and bcl-x) proteins in serous versus mucinous borderline ovarian tumours.

BACKGROUND: We examined the expression of apoptosis-related proteins in serous versus mucinous borderline ovarian tumours, in comparison with benign and malignant ovarian tumours. MATERIALS AND METHODS: Immunohistochemical expression of pro-apoptotic (p53, p21, bax, bak, fas) and anti-apoptotic proteins (bcl-2, bcl-x) was determined in 34 borderline (19 mucinous, 15 serous), 20 benign (10 mucinous, 10 serous) and 28 malignant ovarian tumours (9 mucinous, 19 serous). RESULTS: A difference in semi-quantitative p53 expression was found between benign and borderline tumours (P = 0.01), but not between borderline and malignant tumours. Increased p21 expression was found in borderline versus benign tumours (P = 0.004). Bcl-2 expression was lower in borderline than in benign (P = 0.01) and malignant tumours (P = 0.02). No difference in bax, bak, fas or bcl-x expression was observed among the three tumour types. Higher percentage of p21 positive cells was found in serous than in mucinous borderline tumours (P < 0.001). Bcl-2 expression was higher in serous than in mucinous forms of benign (P < 0.001), borderline (P < 0.001), and malignant tumours (P < 0.003). No difference in p53, bax, bak, fas or bcl-x expression was observed between serous and mucinous borderline ovarian tumours. CONCLUSION: Although p53 overexpression was a common feature of both mucinous and serous borderline tumours, p21 and bcl-2 overexpression appeared specific to serous tumours.

Endometrium from women with and without endometriosis, and peritoneal, ovarian and bowel endometriosis, show different c-kit protein expression.

BACKGROUND: Endometriosis is defined by the presence of endometrium outside the uterus. Changes in the expression of the proto-oncogene c-kit are associated with aggressive behaviour of both benign and malignant tumours, but there are few data on its c-kit expression in endometriosis. Here we examined c-kit expression in endometrium and endometriotic tissue. METHODS: Immunohistochemistry was used for qualitative and semi-quantitative (mean+/-S.D. positive cells) analysis of c-kit expression in endometrium from women with (n=9) and without endometriosis (n=18), and in peritoneal (n=20), ovarian (n=20) and colorectal endometriosis (n=20). RESULTS: Semi-quantitative c-kit expression was higher in endometrial glandular cells from women with endometriosis than from women without endometriosis (15.0+/-14.6% versus 3.9+/-7.4%, p=0.01). No difference in c-kit expression was found in qualitative analysis and according to the phase of the menstrual cycle. C-kit expression values in peritoneal, ovarian and colorectal endometriosis were 2.0+/-3.8%, 2.0+/-4.1% and 21.7+/-18.4%, respectively. Qualitative and semi-quantitative c-kit expression was higher in colorectal endometriosis than in peritoneal and ovarian endometriosis (p<0.001); no difference was found between ovarian and peritoneal endometriosis. No c-kit expression was detected in stromal cells of either endometrium or endometriotic tissue. CONCLUSION: These results suggest that the c-kit/stem cell factor axis is involved in the pathogenesis of endometriosis. Strong c-kit protein expression was associated with invasive endometriotic lesions.

Eutopic endometrium and peritoneal, ovarian and bowel endometriotic tissues express a different profile of matrix metalloproteinases-2, -3 and -11, and of tissue inhibitor metalloproteinases-1 and -2.

Endometriosis is subsequent to the ability of endometrial glands to invade normal tissues. Matrix metalloproteinases (MMPs)--enzymes that mediate normal tissue turnover, including endometrial breakdown during menstruation-appear to be involved in this invasive process. Here, we examined the immunohistochemical expression of MMP-2, MMP-3, MMP-11, tissue inhibitor metalloproteinase (TIMP)-1 and TIMP-2 in endometrium from women with (n=9) or without endometriosis (n=18) in comparison with peritoneal (n=20), ovarian (n=20) and colorectal endometriosis (n=20). Women with endometriosis showed decreased endometrial MMP-2 expression compared with women without endometriosis (mean+/-SD positive cells: 24.3+/-28.3% and 69.3+/-12.1%), together with loss of MMP-3 expression (0 versus 17.5%+/-20.2). MMP-11, TIMP-1 and TIMP-2 expression was similar in the two groups. Endometrial MMP-2, -3 and -11 expression and TIMP-1 and -2 expression were similar in women with endometriosis and in those with peritoneal endometriosis. MMP-2, -3 and -11 expression was higher in colorectal endometriosis than in ovarian and peritoneal endometriosis. TIMP-2 expression was lower in colorectal endometriosis (P=0.0002) and ovarian endometriotic cysts (P=0.003) than in peritoneal endometriosis. TIMP-1 expression did not vary according to the location of endometriotic lesions. These results suggest that MMP-2 and -3 and TIMP-2 may be involved in the pathogenesis of endometriosis. Interestingly, MMP-2 and -3 overexpression was related to the infiltrative nature of endometriotic lesions, with possible sequential expression from peritoneal to colorectal endometriosis.

Restaging surgery for women with borderline ovarian tumors: results of a French multicenter study.

BACKGROUND: The purpose of the current study was to examine the surgical management of women with borderline ovarian tumors and the adequacy of initial staging according to the guidelines of the International Federation of Gynecology and Obstetrics; to evaluate the impact of restaging operations; and to identify risk factors for initial understaging. METHODS: In a retrospective French multicenter study, 54 of 360 women with borderline ovarian tumors underwent a restaging operation. After excluding women with initial complete staging (n = 62), epidemiologic, surgical, and histologic parameters and risk of recurrence were compared between women who underwent restaging (n = 54) and those who did not (n = 244). RESULTS: One hundred fifty (41.6%) of 360 women underwent intraoperative histologic examination, which led to the diagnosis of a borderline tumor in 97 cases (64.7%). Thirty-seven (38.1%) of these 97 women had undergone complete initial staging procedures. A restaging operation was performed for 54 women. A lower median age and a higher rate of conservative treatment were noted in the group that underwent restaging. Eight (14.8%) of the 54 women who underwent restaging had their tumors upstaged: 7 of the 41 cases initially diagnosed as Stage IA tumors were upstaged to Stage IB (n = 3) or to Stage IIA, IIB, IIIA, or IIIC (n = 1 for each); in the eighth case, a Stage IC tumor was upstaged to Stage IIIA. Upstaging tended to be more common in women with serous borderline tumors (P = 0.06) and in women who underwent cystectomy (P = 0.08). There was no difference in recurrence rates according to whether a restaging operation was performed. The recurrence rates after conservative and radical treatment were 15.6% (25 of 160) and 4.5% (9 of 200), respectively (P < 0.001). CONCLUSIONS: Women who initially were diagnosed with Stage IA disease and who had serous borderline tumors or underwent cystectomy appeared to derive the most benefit from restaging surgery. Nonetheless, the indications for restaging surgery remain controversial, as no difference in recurrence rate was observed between women who underwent restaging and those who did not.