Quantitative biochemical analysis of lactate dehydrogenase in human ovarian tissues: correlation with tumor grade

Abstract.   Šimaga Š, Osmak M, Babič D, Šprem M, Vukelič B, Abramič M. Quantitative biochemical analysis of lactate dehydrogenase in human ovarian tissues: correlation with tumor grade. Int J Gynecol Cancer 2005; 15: 438–444.
In an attempt to identify glycolytic capacity of normal and neoplastic human ovary, total lactate dehydrogenase (LDH) activity was measured in tissue cytosol originating from 69 patients (18 with benign ovarian tumor, 34 with ovarian carcinoma, six with nonepithelial ovarian malignant tumors, and 11 with tumor metastatic to ovary) and compared to the LDH activity of normal ovarian tissues ( n = 19). Median value of total LDH-specific activity expressed as U/mg protein was 0.546 in normal tissues, 0.584 in benign tumors, 1.071 in malignancies metastatic to ovaries, 0.872 in nonepithelial primary ovarian tumors, and 0.818 in primary carcinomas. A significant rise in LDH-specific activity was found in malignant primary and secondary tumors of epithelial and nonepithelial origin, but not in benign neoplasms, compared to the activity in normal tissue. Ovarian carcinomas of serous histologic type did not differ in LDH activity from mucinous tumors. However, poorly differentiated carcinomas (grade 3) showed significantly enhanced activity of this glycolytic enzyme when compared to its grade 1 counterpart. The subgroup of grade 1 tumors did not differ in LDH activity from normal and benign ovarian tissue. Obtained results suggest that direct correlation might exist between ovarian epithelial tumor grade and lactate dehydrogenase activity.     

Analysis of Telomerase Activity in Ovarian Cystadenomas, Low-Malignant-Potential Tumors, and Invasive Carcinomas

OBJECTIVE: Inappropriate telomerase expression has been reported to be associated with the development and/or progression of malignancies. Therefore, the purpose of the study was to determine and evaluate the levels of telomerase activity in normal ovary, cystadenomas, low-malignant-potential tumors, and carcinomas of the ovary. METHODS: In the present study, telomerase activity was examined in frozen tissue specimens of normal ovary (n = 6), ovarian cystadenomas (n = 13), ovarian low-malignant-potential (LMP) tumors (n = 12), and ovarian invasive carcinomas (n = 81). Clinicopathological information including age at diagnosis, histological grade, FIGO stage, presence of distant metastasis at diagnosis, and residual disease was available for all patients with ovarian carcinomas (n = 81). Telomerase activity was assessed by the telomeric repeat amplification protocol (TRAP). Arbitrary values were assigned to processivity of telomerase activities based on the molecular weights of the telomeric repeat DNA ladders, and were graded as "negative," "moderate" (< or =99 bp), or "high" (>100 bp) activities. The specificity of telomerase activity was determined by the pretreatment of telomerase-positive control or tumor samples with RNase that led to the abolition of the activity. In addition, to determine the possibility of false negativity due to the presence of telomerase inhibitors, TRAP assay was performed on each of the telomerase-negative specimens by mixing them individually with the telomerase-positive control. RESULTS: Telomerase activity in the progression of ovarian carcinogenesis was evaluated. In comparison with normal ovary/cystadenoma (32%), a much higher frequency of the moderate activity was observed in LMP tumors (67%) or invasive carcinomas (57%), suggesting a close association between the latter two categories. The results reflect a subpopulation of telomerase-positive LMP tumor cells with the potential to develop invasive carcinomas. None of the specimens of the benign or LMP tumors exhibited high activity. In contrast, 18% of ovarian invasive carcinomas showed high telomerase activity (P = 0.013, Fisher exact test) and further 57%, moderate activity (75% in all). A statistically significant difference was observed in the expression of telomerase activity between normal ovary/benign cystadenomas and ovarian invasive carcinomas (P = 0.001, chi(2) test). CONCLUSIONS: The study showed a high prevalence of telomerase activity in LMP tumors or invasive carcinomas, the high levels of telomerase activity being associated exclusively with the invasive ovarian carcinomas. Therefore, the levels of processivity of telomerase activity and evidence of its statistically significant association with ovarian carcinoma suggest its role in the progression of ovarian carcinogenesis.     

Type IV collagen and CD44v6 expression in benign, malignant primary and metastatic ovarian tumors: correlation with Ki-67 and p53 immunoreactivity

OBJECTIVE: Loss of basement membrane (BM) components, such as type IV collagen has been demonstrated in ovarian cancer, but the associations with other molecules like CD44v6, involved in metastatic process of ovarian carcinoma, have not been fully analyzed. This study investigates the expression of type IV collagen, CD44v6 molecule in correlation with p53 and Ki-67 presence in primary and metastatic lesion of ovarian carcinoma to define their role in metastases of ovarian carcinoma. METHODS: The expression of type IV collagen, CD44v6, p53, and Ki-67 was evaluated on frozen tissue sections from primary ovarian tumors (malignant n = 37, benign n = 16), metastatic lesions (n = 29) and ascitic fluid cells (n = 28). Protein expression of all studied biomarkers was evaluated in a subset of specimens using immunohistochemistry (IHC). RESULTS: Type IV collagen expression in the primary ovarian carcinoma was positively correlated with International Federation of Gynecology and Obstetrics (FIGO) stage and tumor grade. Significant difference was observed for type IV collagen immunoreactivity in carcinoma cells in effusions when compared to corresponding primary tumors (P < 0.001) and metastatic lesions (P < 0.001). Likewise down-regulation of type IV collagen expression was seen in primary ovarian carcinomas (P = 0.01), ascitic fluid cells (P < 0.001), and metastases (P = 0.003) when compared to benign ovarian neoplasms. CD44v6 expression was detected in a comparable percentage of primary carcinomas (51%) and metastatic lesions (52%). In cells isolated from ascitic fluid, CD44v6 immunopositivity was observed in 43% of cases. A comparative analysis of primary and metastatic tumors and carcinoma cells in effusion did not reveal differences in expression of CD44v6. Positivity of CD44v6 was found in 2/16 (12%) of benign ovarian neoplasms. There were no significant differences between CD44v6 expression in benign neoplasms compared to primary malignant tumors and metastases (P > 0.05). CD44v6 expression in primary ovarian carcinomas was associated with higher tumor grade (P = 0.01) and histological type of tumors (P = 0.01). An inverse relationship of type IV collagen expression with p53 and CD44v6 positivity in benign and malignant ovarian tumors was found (P > 0.01). Type IV collagen expression was inversely correlated with p53 status (P = 0.03) in metastatic lesions. A slight trend toward an inverse correlation between Ki-67 and type IV collagen expression was observed in both benign and malignant ovarian tumors and metastases. CONCLUSIONS: Our data suggest that observed inverse correlation of type IV collagen expression with p53, CD44v6, and slight with Ki-67 positivity in primary benign and malignant tumors indicates that these molecules may cooperate in the invasion and progression of ovarian carcinomas.     

DNA flow cytometry of ovarian tumors with correlation to histopathology

Tissue samples from 49 women with seven benign and 42 malignant ovarian tumors were examined by means of DNA flow cytometry (FCM). The FCM data (DNA-ploidy and the number of S-phase fractions) were compared with the International Federation of Gynecology and Obstetrics (FIGO) stage, the histologic grade of differentiation and in some cases with the clinical outcome. The benign ovarian tumors were all diploid with a mean of 2.1% (+/- 1.66) S-phase fractions. Adenocarcinomas with the histologic grade 1 were diploid and had a mean of 2.1% (+/- 1.17) S-phase fractions. Grade 2 adenocarcinomas were aneuploid in eight of nine cases and revealed an increased proliferative activity (7.7% +/- 2.67 S-phase fractions). A high number of aneuploid cases (nine of 13) and an increased DNA synthesis were found in grade 3 adenocarcinomas (12.0% +/- 5.72 S-phase fractions). Four of six malignant nonepithelial tumors also had high numbers of S-phase fractions (9.7-14.5%). A significant correlation between the histologic grade and the DNA synthesis, FIGO stage, and DNA-ploidy was found. DNA-FCM may be used as an additional diagnostic tool supplementing routine histopathologic examination of ovarian tumors for better biological characterization, especially for those with uncertain grading, for grade 2 neoplasms, and for malignant nonepithelial tumors.     

L1 (CAM) (CD171) in ovarian serous neoplasms

PURPOSE OF THE INVESTIGATION: The evaluation of L1 (CAM) as a tumor progression marker and as a prognostic factor in serous ovarian tumors. METHODS: L1 (CAM) protein expression was assessed by immunohistochemistry and Western blot in serous ovarian tumors [cystadenomas (n = 20), borderline tumors (n = 14) and carcinomas (n = 47)], and was correlated with stage,grade, progression-free survival time (PFS) and overall survival. RESULTS: L1 (CAM) immunoreactivity correlated significantly with stage and grade. It increased from benign tumors to early carcinomas and to advanced stage carcinomas progressively and significantly. In Stage III G3 carcinoma patients, low L1 (CAM) expressing tumors exhibited better response to chemotherapy and were associated with statistically significantly longer PFS (p = 0.002). CONCLUSION: L1 (CAM) expression represents a novel diagnostic marker in serous ovarian neoplasms that shows characteristics of tumor progression. L1 expression was associated with chemotherapy response.     

NAD dependent 11beta-hydroxysteroid dehydrogenase activity in human endometrium and endometrial tumors

BACKGROUND: The isoforms of 11beta-hydroxysteroid dehydrogenase (11beta-HSD) types 1 and 2, regulated by ovarian steroids, catalyze the interconversion of glucocorticoids and their 11-keto metabolites. The role of these enzymes in malignancies of human endometrium is unknown. We compare NAD dependent 11beta-HSD (type 2) activity levels among normal human endometrium and endometrial carcinomas of differing grades and histologies. METHODS: NAD dependent 11beta-HSD activity was determined in endometrial tissue obtained from patients undergoing hysterectomy for benign or malignant disease (endometroid, serous and carcinosarcomas). Student's t test was utilized with p < 0.05 considered significant. Data are presented as mean +/- SD. RESULTS: NAD dependent 11beta-HSD activity was present in all endometrial samples. The activities were 0.61+/- 0.27 in normal (n = 9), 0.43 +/- 0.29 in endometrioid endometrial carcinoma (n = 14), 0.50 +/- 0.26 in uterine serous carcinoma (n = 6) and 0.25 +/- 0.37 in carcinosarcomas (n = 9). NAD dependent 11beta-HSD activity was lower in the carcinosarcoma group as compared to normal endometrial tissue (p = 0.03). CONCLUSIONS: NAD dependent type 2 11beta-HSD activity was demonstrated in all normal and endometrial tumors. Enzyme activity in endometroid and uterine serious carcinoma tumors was similar to enzyme activity in normal endometrium. In contrast, carcinosarcomas show significantly lower enzyme activity compared to normal tissue.     

RNA expression of MDR1/P-glycoprotein, DNA-topoisomerase I, and MRP2 in ovarian carcinoma patients: correlation with chemotherapeutic response

OBJECTIVE: Clinical drug resistance is the major obstacle in the successful treatment of ovarian cancer. Besides elevated expression of adenosine triphosphate binding cassette (ABC) transporters, such as MDR1/P-gp or MRP2/cMOAT/ABCC2, alterations in the expression of DNA topoisomerase I (TOP1) are associated with drug-resistant phenotypes in various model systems. METHODS: In ovarian specimens of 61 patients, the mRNA expression levels of MDR1/P-gp, MRP2, and TOP1 were determined using a competitive quantitative RT-PCR protocol with internal standards. The mRNA expression levels were correlated with the clinical outcome and histopathological criteria. The tumor specimens included 11/61 (18%) benign ovarian tumors, including 2 LMP tumors, and 50/61 (82%) ovarian carcinomas, including 34 primary and 16 recurrent cancers. Moreover, 20/61 (33%) ovarian specimens showed low or no MDR1/P-gp expression. RESULTS: None of the benign tumors showed MRP2 expression, whereas 15/50 (30%) ovarian carcinomas expressed MRP2. In 61/61 (100%) of the samples, expression of TOP1 could be measured. In patients with recurrent ovarian cancer, no differences in expression of any of the factors could be observed. In patients with primary FIGO III carcinomas (n = 18), the overall-survival time (OST) was significantly prolonged with low MDR1/P-gp expression level (P = 0.015). Expression levels of MRP2 and TOP1 did not correlate with OST. Moreover, the progression-free survival (PFS) in FIGO III patients showed a clear tendency to be associated with low MDR1/P-gp (P = 0.218) and TOP1 expression (P = 0.466), and negativity for MRP2 (P = 0.244). CONCLUSION: MDR1/P-gp and MRP2 might have some additional predictive value for the clinical outcome of patients with advanced ovarian carcinoma.     

Diagnostic value of telomerase activity in gynecologic malignancies

Nagai N, Murakami J, Oshita T, Ohama K, Tahara H. Diagnostic value of telomerase activity in gynecologic malignancies. Int J Gynecol Cancer 1998; 8 : 481–488.
We investigated the diagnostic significance of telomerase activity in gynecological malignancies. Tissue samples were obtained from 24 cervical cancers, 27 uterine cancers (22 endometrial cancers and five sarcomas), 33 ovarian cancers (31 epithelial tumors and 2 germ cell tumors), and 11 benign ovarian tumors. In addition, cervical cytology specimens were obtained from 30 squamous intraepithelial lesions (13 low grade and 17 high grade), and from 22 normal females. Telomerase activity was detected using the TRAP assay, and the relative telomerase activity was obtained using the BioMax DNA image analysis system. Telomerase activity was detected in 22/24 (91.7 %) cervical cancers, 23/27 (85.2%) uterine tumors and 30/33 (90.9%) ovarian cancers. Weak telomerase activity was detected in two mature cystic teratomas and also found in 9/17 (52.9%) high grade SIL and 2/13 (15.4%) low grade lesions. Telomerase activity showed no relationship with tumor histology or clinical stage, and there was no statistically significant difference between patients with uterine cancer and ovarian cancer. Relative telomerase activity showed a correlation with the dilution assay, and significantly higher telomerase activity was found in uterine cervical cancer compared with precancerous lesions and in ovarian cancer compared with benign ovarian tumors. After establishment of an assay for telomerase, it may be useful for cancer diagnosis and identification of high-risk groups.     

Prognostic value of histologic grading of ovarian carcinomas.

Histologic grading of ovarian carcinomas has prognostic and therapeutic relevance, but although several grading systems have been proposed, no universal grading system has been established. Silverberg's group has recently proposed a simple histologic grading system of ovarian carcinomas. We studied its prognostic value in 70 patients with invasive ovarian carcinomas and compared it with that of histologic typing and clinical staging. Kaplan-Meier survival curves showed the following 5-year survival rate using the Silverberg grading system: grade I (n=21) 91%, grade II (n=20) 64%, grade III (n=29) 38% (p<0.001). Multivariate analysis indicated that the histologic grade, the clinical stage, and clear cell histologic type were significant prognostic factors. The Silverberg histologic grade correlated well with prognosis for all histologic types of ovarian carcinomas except for clear cell carcinoma. It is simple, reproducible, and provides useful prognostic information.     

抗细胞凋零基因bcl-2和bax与卵巢上皮性肿瘤的关系

目的:研究抗凋零基因bcl-2和bax与卵巢上皮性肿瘤发生及预后的关系。方法:通过免疫组化方法,用抗bcl-2及抗bax抗体检测卵巢上皮肿瘤76份(良性27份、交界性24份、恶性25份)中bcl-2和bax的表达产物,并以正常卵巢12份做对照。结果:正常卵巢组织12份中bcl-2和bax阳性检出率为0,在良性、交界性及恶性肿瘤组织中bcl-2和bax的阳性检出率分别为7.4%(2/27)、16.7%(4/24)、36.0%(9/25),22.2%(6/27)、45.8%(11/24)、56.0%(14/25),良性与恶性肿瘤之间差异有显著性(P<0.05),而且bax的表达率比bcl-2高(P<0.05),bax在恶性肿瘤组Ⅰ级与Ⅲ级间差异有显著性(P<0.05)。结论:抗细胞凋零基因bcl-2和bax过度表达可能与卵巢上皮性肿瘤发生有关,推测bax不仅参与细胞凋零的调控,而且可能与肿瘤分化及预后有关。     

B7-H4 overexpression in ovarian tumors

OBJECTIVES: Despite great advances in therapeutic management, the mortality rate for ovarian cancer has remained relatively stable over the past 50 years. This study was designed to evaluate the expression of B7-H4 protein, recently identified as a potential molecular marker of breast and ovarian cancer by quantitative PCR analysis, in benign tumors, tumors of low malignant potential and malignant tumors of the ovary. METHODS: Archival formalin-fixed tissue blocks from serous, mucinous, endometrioid and clear cell ovarian tumors were evaluated by immunohistochemistry for the distribution of B7-H4 expression, and staining intensity was measured by automated image analysis. Univariate analyses were used to test for statistically significant relationships. RESULTS: B7-H4 cytoplasmic and membranous expression was detected in all primary serous (n = 32), endometrioid (n = 12), and clear cell carcinomas (n = 15), and in all metastatic serous (n = 23) and endometrioid (n = 7) ovarian carcinomas. By contrast, focal B7-H4 expression was detected in only 1/11 mucinous carcinomas. The proportion of positive cells and median staining intensity was greater in serous carcinomas than in serous cystadenomas or serous tumors of low malignant potential, and the differences were statistically significant (P < 0.0001 and P = 0.034, respectively). The median staining intensity was also significantly greater in endometrioid carcinomas than in endometriosis (P = 0.005). CONCLUSIONS: The consistent overexpression of B7-H4 in serous, endometrioid and clear cell ovarian carcinomas and the relative absence of expression in most normal somatic tissues indicates that B7-H4 should be further investigated as a potential diagnostic marker or therapeutic target for ovarian cancer.     

Grading of ovarian carcinomas.

Grading of ovarian carcinomas can have important implications for therapeutic decisions, in particular in International Federation of Gynecology and Obstetrics (FIGO) stage I. However, there are no universally accepted grading guidelines for this type of cancer. We applied the grading system suggested by Shimizu et al. (1) to a series of ovarian carcinomas from a single institution to evaluate its prognostic significance in relation to other predictive factors. One hundred ninety-two cases of ovarian carcinomas were studied, including all major histologic types. The histologic slides were evaluated with regard to architecture (glandular = 1 point, papillary = 2 points, solid = 3 points), nuclear pleomorphism (nuclear variability < or = 2:1 = 1 point, intermediate nuclei = 2 points, nuclear variability > or = 4:1 = 3 points), and mitotic activity per 10 high-power fields using objective 40x, ocular 10x/20 (0-7 mitoses = 1 point, 8-18 mitoses = 2 points, > or = 9 mitoses = 3 points). Carcinomas with a total score of 3-5 points were designated as grade I, 6-7 points were designated as grade II, and 8-9 points were designated as grade III. Kaplan-Meier curves showed the following 5-year survival rates: grade I (n = 42) 88%, grade II (n = 98) 60%, grade III (n = 52) 38% (p < 0.0001); stage I 90%, stage II 60%, stage III 38%, stage IV 10% (p < 0.0001); residual disease < or = 2 cm 67% and > or = 2 cm 27% (p < 0.0001). Multivariate Cox analysis revealed that grade (p < 0.0002), as well as nuclear pleomorphism alone (p < 0.0001), both provided statistically significant independent prognostic information. Our observations showed that the grading system used can be easily applied to all histologic types of ovarian carcinomas yielding prognostically relevant information and can be incorporated into routine diagnostic practice.     

Immunohistochemical localization of metallothionein in benign and malignant epithelial ovarian tumors

Abstract. McCluggage WG, Strand K, Abdulkadir A. Immunohistochemical localization of metallothionein in benign and malignant epithelial ovarian tumors.
Metallothioneins (MTs) are a group of low-molecular-weight proteins that are overexpressed in a variety of human neoplasms and are related to differentiation and prognosis in some tumor types. This study investigated immunohistochemically detectable metallothionein expression in benign and malignant ovarian surface epithelial tumors of serous, mucinous, and endometrioid types. MT expression was observed in 56% of carcinomas ( n = 139) and in 2% of benign neoplasms ( n = 81). Of the malignant tumors, MT expression was found in 68% of endometrioid, 56% of mucinous, and 52% of serous neoplasms. There was increased MT expression in grade 3 carcinomas (64%) as compared with grade 2 (60%) and grade 1 (23%). The overexpression of MT in malignant as opposed to benign ovarian surface epithelial tumors may suggest a role in tumorigenesis. Analogous to the situation in endometrial carcinomas, there is a tendency toward higher expression in poorly differentiated tumors. Whether high MT expression is an independent prognostic factor and increased expression indicates chemotherapy resistance in ovarian cancer, as has been previously suggested, should be determined by further studies.     

Histopathologic features of genetically determined ovarian cancer.

Inheritance of germline mutations of BRCA1 or BRCA2 genes account for approximately 10% of ovarian carcinomas, but the characterization of these genetically determined cancers is incomplete. The objective of our study was to characterize the histologic features of ovarian carcinomas associated with germline mutations of BRCA1 and BRCA2. Thirty-two ovarian carcinomas associated with germline BRCA1 or BRCA2 mutations and 40 ovarian carcinomas from patients screened as negative for germline mutations were obtained from three centers. A gynecologic pathologist, blinded to mutation status, reviewed each case, with documentation of the histologic type, Gynecologic Oncology Group (GOG) grade, architectural and nuclear grade, Silverberg grade, and mitotic activity. All BRCA1 and BRCA2 mutation-associated cases were invasive serous carcinomas, and of these 50% were GOG grade 3, 41% had an architectural grade of 3 (predominant solid architecture), 84% a nuclear grade of 3, 72% a mitotic score of 3 (>25 mitoses per 10 HPF), and 75% a Silverberg grade of 3. The differences in histologic type (p = 0.001) and Silverberg grade (p = 0.002) between these tumors and the control group were statistically significant and remained so when comparisons between BRCA carriers and noncarriers were restricted to carcinomas of serous histology alone. Ovarian carcinomas associated with germline mutations of BRCA1/BRCA2 are, in this study, invasive serous carcinomas, with a statistically significant higher histologic grade than ovarian carcinomas without BRCA mutations when using the recently proposed Silverberg grading system.     

Characterization of human ovarian epithelial tumors (ex vivo) by proton magnetic resonance spectroscopy

Proton magnetic resonance spectroscopy (¹H MRS) offers an alternative investigational modality that will assist current pathologic techniques in the diagnosis of human ovarian epithelial tumors. Histologically normal human ovarian tissue ( n = 12) was compared with ovarian benign fibromas ( n = 3) and surface epithelial-stromal tumors (benign, n = 18; proliferating, n = 9; frankly malignant, n = 30) ex vivo by ¹H MRS. The distinction between carcinomatous and benign or normal tissue ( P <0.0001; Student's t -test) was made on one-dimensional (1-D) ¹H MR spectra utilizing differences in resonance intensities of cellular lipid, creatine/phosphocreatine and lysine. The sensitivity and specificity of the test were 87% and 91%, respectively. Two-dimensional (2-D) MRS of carcinomatous biopsies showed multiple crosspeaks attributable to cell-surface fucosylation that correlated with tumor grade and loss of cellular differentiation. The multiple fucose crosspeaks were absent in spectra from normal ovary and benign tumors. The distinction between carcinomatous and normal or benign tissue based on MR-visible fucosylation gave a sensitivity and specificity of 88% and 97%, respectively. Proliferating tumors exhibited a range of cell-surface fucosylation patterns indicative of malignant potential.     

卵巢上皮性肿瘤组织中KiSS-1、基质金属蛋白酶9和核因子κBp65蛋白的表达及其相关性

目的 探讨KiSS-1、基质金属蛋白酶9（MMP-9）、核因子κB（NF-κB）p65蛋白3者在卵巢上皮性肿瘤组织中的表达及其相关性。方法 采用免疫组化方法检测50份卵巢上皮性癌（卵巢癌）、20份卵巢交界性肿瘤、20份卵巢良性肿瘤和10份正常卵巢组织中KiSS-1、MMP-9、NF-κBp65蛋白的表达,并分析其临床意义及3者间的相关性。结果 KiSS-1蛋白在卵巢癌组织中的阳性表达率（80％）明显高于良性肿瘤组织及正常卵巢组织（分别为35％、10％;P〈0．05）;在卵巢交界性肿瘤组织中阳性表达率（65％）明显高于正常卵巢组织（P〈0．05）。在卵巢癌组织中,KiSS-1蛋白阳性表达率与淋巴结转移有关（P〈0．05）,与手术病理分期、病理类型及病理分级均无关（P〉0．05）;MMP-9蛋白阳性表达率与手术病理分期及淋巴结转移有关（P〈0．05）,而与病理类型及病理分级均无关（P〉0．05）;NF-KBp65蛋白阳性表达率与手术病理分期、病理分级及淋巴结转移有关（P〈0．05）,而与病理类型无关（P〉0．05）。在卵巢癌组织中,KiSS-1与MMP-9、NF．KBp65蛋白表达呈显著负相关关系（rs=-0．547,P〈0．05;rs=-0．414,P〈0．05）;MMP-9与NF-κBp65蛋白表达呈显著正相关关系（rs=0．695,P〈0．05）。结论 KiSS-1基因可能对卵巢癌的转移起一定的抑制作用;KiSS-1基因可能通过抑制MMP-9、NF-κB基因,从而发挥抑制卵巢癌转移的作用。     

k-ras mutation may be an early event in mucinous ovarian tumorigenesis.

We explored the possible pathogenetic pathway for mucinous ovarian tumorigenesis by examining the k-ras mutational patterns in ovarian mucinous tumors (OMTs) with benign, borderline, and invasive epithelium in which the different types of mucinous epithelium are in close proximity. Sixteen patients with ovarian mucinous borderline tumors (OMBTs) and 4 patients with grade 1 ovarian mucinous adenocarcinomas (OMCs) were selected for the presence of a single histologic section which contained a clear "transition" zone from benign mucinous epithelium to borderline mucinous epithelium, and in four cases, to invasive epithelium. A PixCell II Laser Capture Microscope was used to microdissect and retrieve benign, borderline, and invasive epithelium separately from the 20 OMTs. Normal ovarian stroma from the same histologic section in each case was also microdissected and retrieved for use as a control. k-ras mutations were detected in these samples by PCR-SSCP analysis followed by direct PCR cycle sequencing. k-ras mutations were found in 8/16 (50%) of the OMBTs and 2/4 (50%) of the grade 1 OMCs. In 6 of these 10 cases (4 in OMBTs, 2 in grade 1 OMCs), the same k-ras mutation was found in both the benign and borderline (and invasive) regions. In 3 cases in which k-ras mutations were identified, the mutation was found in either the benign or borderline tissue samples alone, and in one case, two distinct mutations were found. No k-ras mutations were identified in the normal ovarian stroma. The presence of a k-ras mutation in adjacent benign and borderline regions of a single OMT may suggest a progression in the development of OMTs from benign to borderline and grade 1 OMCs. k-ras mutations, when they occur, are likely early genetic changes but may not alone be sufficient for malignant transformation of ovarian epithelium.     

卵巢上皮性肿瘤中环氧合酶-2的表达及相关性研究

目的　探讨环氧合酶 - 2在卵巢上皮性癌发病中的作用。方法　应用SABC免疫组化技术 ,检测 4 2例卵巢上皮性癌、 1 6例卵巢交界性上皮性肿瘤、 2 0例卵巢良性上皮性肿瘤和 2 0例正常卵巢组织中环氧合酶 - 2的表达 ,并对其在卵巢上皮性癌临床分期、组织学分级和有无淋巴结转移之关系进行探讨。结果　环氧合酶 - 2阳性表达率在卵巢上皮性癌、卵巢交界性上皮性肿瘤中明显高于卵巢良性上皮性肿瘤及正常卵巢组织 (P<0 0 5 ) ;在G3 级卵巢上皮性癌组织中明显高于G1 级 ,差异有显著性 (P <0 0 5 ) ;环氧合酶 - 2阳性表达率在卵巢上皮性癌临床分期及有无淋巴结转移之间无显著性差异 (P >0 0 5 )。结论　环氧合酶 - 2过度表达可能在卵巢上皮性癌的发生中起一定作用