WT1 is differentially expressed in serous, endometrioid, clear cell, and mucinous carcinomas of the peritoneum, fallopian tube, ovary, and endometrium.

The Wilms' tumor gene WT1 plays complex roles in the development of the organs of the genitourinary tract and mesothelium, as well as Wilms' tumors. Although its biologic role is still unclear, most serous carcinomas of the ovary and peritoneum, mesotheliomas, and Wilms' tumor have been shown to express WT1. A recent study, however, found no WT1 expression in serous carcinomas of the endometrium, suggesting that WT1 could be useful in identifying the primary site of serous carcinomas. We examined the expression of WT1 and p53 by immunohistochemistry in 69 cases of endometrial carcinoma (35 endometrioid, 18 clear cell, 16 serous), 68 cases of ovarian carcinoma (28 serous, 11 endometrioid, 18 clear cell, and 11 mucinous), 14 fallopian tube carcinomas (12 serous, 2 endometrioid), and 20 primary peritoneal serous carcinomas. WT1 nuclear reactivity of any extent and intensity was considered positive. Immunohistochemical stains were evaluated semiquantitatively using a four-tiered scale. Among endometrial carcinomas, WT1 immunoreactivity was seen in 10 of 16 serous, but in none of 35 endometrioid or 18 clear cell carcinomas. Among ovarian tumors, WT1 expression was seen in 24 of 28 serous and 4 of 18 clear cell carcinomas, but in none of 11 endometrioid and 11 mucinous tumors. All 12 serous carcinomas but none of 2 endometrioid carcinomas of the fallopian tube were positive for WT1. WT1 expression was seen in 19 of 20 serous primary peritoneal carcinomas. The difference in WT1 expression was highly significant between serous and other types of tumors in all sites (p<0.0001, chi-square test), although the level of WT1 expression was significantly different among serous carcinomas arising at different sites (p<0.0001, Kruskal-Wallis test). A significant positive correlation was found between the level of p53 and WT1 expression in all carcinomas combined (r = 0.3935, p<0.0001, Spearman test), but when only serous carcinomas were analyzed, the correlation between p53 and WT1 expression levels did not reach statistical significance. Our results suggest that WT1 expression in epithelial tumors of the female genital tract may be related to cell differentiation and histologic subtypes of carcinomas, rather than to primary site of origin.     

p63 expression in epithelial ovarian tumors

Ovarian cancer is a highly lethal disease and its underlying biology is poorly understood. The p63 is a homologue gene of the tumor suppressor p53. p63 appears to be important for the development and differentiation of reproductive epithelium and interacts with p53 in human tumorigenesis. This study presents the immunoexpression of the p63 in benign and malignant epithelial ovarian tumors. We evaluated the p63 immunoexpression in 91 ovarian benign cystadenomas (29 mucinous and 62 serous) and in 29 ovarian malignant tumors (3 mucinous borderline, 3 serous borderline, 17 serous carcinomas, 2 endometrioid, 2 undifferentiated, 1 mucinous, and 1 clear-cell carcinoma) using a monoclonal antibody clone 4A4 (1:200), which recognizes all p63 variants. The tumors were considered p63 positive if 5% or more cells presented nuclear immunostaining. We observed 85.7% of positivity in benign tumors, 50% in borderline tumors, and 8.7% in invasive ovarian cancer (P < .0001). The benign serous cystadenomas were positive in 91.9% of cases and benign mucinous cystadenomas in 72.4% (P= .02). These data suggests an important role of p63 in the control of ovarian epithelium behavior. The p63 may be involved in the development of benign and malignant epithelial ovarian tumors.     

Immunohistochemical study of amylase in common epithelial tumors of the ovary

Cellular localization of amylase in various ovarian tumors was studied by the immunoperoxidase method using an antibody to human pancreatic amylase. Amylase was present in eight of 34 serous carcinomas and eight of 27 endometrioid carcinomas. However, only in one poorly differentiated serous carcinoma and two well-differentiated endometrioid carcinomas were a large number of amylase-reactive cells found. Five benign and three borderline serous tumors contained no amylase. Also, amylase was not detected in any of 34 mucinous tumors or five malignant clear cell tumors. The results obtained suggest that amylase will be a useful tumor marker, when present, for follow-up of endometrioid and serous carcinomas of the ovary.     

E-cadherin expression in endometrioid,papillary serous,and clear cell carcinoma of the endometrium

OBJECTIVE: To compare the frequency and pattern of E-cadherin expression in endometrioid, papillary serous, and clear cell carcinomas of the endometrium. METHODS: E-cadherin expression was examined in 76 endometrial carcinomas by immunohistochemistry using a monoclonal antibody to E-cadherin and was correlated with poor prognostic indicators such as depth of myometrial invasion, lymph node status, and intraperitoneal spread. The frequency of expression was compared between endometrioid, papillary serous, and clear cell carcinomas by the Fisher exact test. Logistic regression was used to examine the simultaneous effect of histological type and tumor grade on E-cadherin expression. RESULTS: Sixty-three endometrioid, nine papillary serous, two clear cell, and two carcinomas of mixed histology were examined. E-cadherin negative tumors were more likely to be poorly differentiated (P <.01), have cervical extension (P =.02), have positive peritoneal cytology (P <.01), and have adnexal spread (P =.01) when compared with E-cadherin positive tumors. Papillary serous and clear cell carcinomas were significantly less likely to express E-cadherin than endometrioid carcinoma (38% versus 95%, P <.001). Tumor grade and histological type were identified as significant predictors of E-cadherin expression in univariable analysis; however, only histological type remained significant in multivariable analysis (P =.01). When grade was controlled, endometrioid carcinoma remained 23 times more likely to express E-cadherin than papillary serous and clear cell carcinomas. CONCLUSION: Papillary serous and clear cell carcinomas are significantly less likely to express E-cadherin than endometrioid tumors. This difference may account for the more aggressive behavior of papillary serous and clear cell carcinomas.     

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.     

卵巢浆液性癌B7-H4的表达及临床病理意义

目的:探讨B7-H4在卵巢上皮性肿瘤浆液性癌中的表达及其临床病理意义。方法:用逆转录聚合酶链反应(RT-PCR)技术及免疫组织化学染色的方法检测6例良性卵巢上皮性肿瘤、10例交界性卵巢上皮性肿瘤、41例卵巢浆液性癌、5例内膜样癌、2例透明细胞癌和10例粘液性癌标本中B7-H4 mRNA及蛋白表达,并结合临床病理资料对其中41例卵巢浆液性癌中B7-H4蛋白的表达进行分析。结果:B7-H4 mRNA在74例卵巢上皮性肿瘤中均有表达,B7-H4蛋白在良性卵巢上皮性肿瘤、交界性卵巢上皮性肿瘤、恶性卵巢上皮性肿瘤中的表达阳性比例分别为2/6、6/10、52/58,恶性标本阳性率明显高于非恶性标本,差异有统计学意义(P<0.05);58例恶性卵巢上皮性癌标本中浆液性癌、内膜样癌、透明细胞癌、黏液性癌的B7-H4蛋白阳性比例分别为41/41、5/5、2/2、4/10,前三种病理类型B7-H4蛋白阳性率明显高于最后一种,且差异有统计学意义(P<0.05);41例卵巢浆液性癌标本中B7-H4蛋白阳性细胞比例在<10%,>10%~50%,>50~80%,>80~100%4组中的分布差异无显著性(P>0.05),且其蛋白表达与临床分期及病理分级有关(P<0.05),而与患者年龄、腹水细胞学、淋巴结转移无关(P>0.05)。结论:B7-H4在卵巢浆液性癌的高表达及其与临床分级分期的关系,提示其可能与肿瘤发生发展有关,可为卵巢恶性肿瘤诊断及治疗提供靶位点。     

Toward understanding the natural history of ovarian carcinoma development: a clinicopathological approach

OBJECTIVE: The natural history of the development of ovarian carcinoma is not known. It also remains undetermined whether ovarian carcinomas develop from benign and/or borderline malignant tumors or arise de novo from the ovarian surface epithelium. METHODS: To address these issues clinicopathologically, we reviewed the clinical charts of 543 patients with epithelial ovarian carcinoma and 252 patients with borderline tumors who underwent laparotomy at seven hospitals and collected patients whose clinical and transvaginal ultrasonography (USG) findings for adnexal regions 12 months or fewer prior to the surgery were available. Histological slides of the resected specimens were reexamined concerning the diagnosis and histological grade, as well as the presence or absence of benign- or borderline-like lesions adjacent to the carcinoma. RESULTS: Forty-nine patients had had gynecological examination with transvaginal USG 12 months or fewer prior to laparotomy. Among them, 35 had carcinomas (11 serous, 6 mucinous, 8 clear cell, 10 endometrioid) and 14 had borderline tumors (8 serous, 6 mucinous). Of the 35 patients with carcinoma, 19 (54%) had been followed up for benign-appearing cysts or endometriotic cysts. In these cases, serial USG examinations revealed an increase in size and/or appearance of the solid part of the cyst. In the remaining 16 (46%), however, there had been no apparent abnormalities in USG, and such cases occurred most frequently for serous carcinomas. CONCLUSIONS: Our findings suggest that approximately half of ovarian carcinomas develop secondarily from preexisting, benign-appearing cysts or endometriotic cysts, whereas the remaining half seem to develop suddenly from a normal-appearing ovary. This appears to be consistent with two possible pathways of ovarian carcinoma development; adenoma-carcinoma sequence and de novo carcinogenesis.     

Molecular pathology of epithelial ovarian cancer

Ovarian cancer is the most lethal gynaecological malignancy and it most commonly occurs in postmenopausal women. Ninety per cent of ovarian cancers are derived from the ovarian surface epithelium and these neoplasms are classified into serous, mucinous, endometrioid, clear-cell and transitional-cell types. The molecular pathology of ovarian carcinomas is heterogeneous and involves various putative precursor lesions and multiple pathways of development. The most common subtype, high-grade serous carcinoma, is characterized by p53 mutations, and BRCA1 and/or BRCA2 dysfunction. It most likely arises from epithelium within inclusion cysts or from the surface of the ovary. In contrast, low-grade serous carcinomas are characterized by KRAS or BRAF mutations and appear to arise via an adenoma-borderline-carcinoma sequence. Similarly, mucinous carcinomas have KRAS mutations and probably develop via an adenoma-borderline-carcinoma sequence. Low-grade endometrioid carcinomas, however, are characterized by mutations in PTEN and CTNNB1, and microsatellite instability, and may arise from ovarian endometriosis or borderline endometrioid tumours. High-grade endometrioid carcinomas have similar changes to high-grade serous carcinomas. Clear-cell carcinomas are characterized by mutations of TGFbetaR2 and over-expression of HNF-1beta, and probably arise from ovarian endometriosis. The molecular changes in transitional-cell carcinomas of the ovary remain largely unknown. The identified molecular changes and pathways of development in epithelial ovarian cancer will facilitate the rationalized development of new diagnostic modalities and tailored therapies for this malignancy.     

Wnt信号通路成分β-catenin和APC在卵巢肿瘤中的表达及意义

目的:探讨Wnt信号通路成分β-catenin和APC基因在上皮性卵巢癌的表达及意义。方法:应用免疫组织化学染色SABC法检测49例卵巢癌(24例浆液性囊腺癌、15例黏液性囊腺癌、10例子宫内膜样癌),10例交界性卵巢肿瘤及16例良性卵巢肿瘤中β-catenin、APC基因的表达,分析其相关性。结果:卵巢癌中β-catenin的异常表达率明显高于卵巢交界性肿瘤和卵巢良性肿瘤,差异有统计学意义(P0.05)。卵巢癌中APC基因的阴性表达率明显高于卵巢良性肿瘤,差异有统计学意义(P0.05),而与卵巢交界性肿瘤无显著差异(P0.05)。卵巢癌中APC基因的阴性表达与β-catenin的异常表达无相关性(r=0.0429,P0.05)。2例卵巢子宫内膜样癌中可见β-catenin胞核表达,但不伴有APC基因的阴性表达。结论:卵巢癌中Wnt信号通路中的成分发生变化,但其激活机制可能有别于Wnt信号通路的传统激活机制,可能在卵巢子宫内膜癌的发生中发挥作用。     

Multifocal tumorigenesis in the upper female genital tract--implications for staging and management

A review of 128 cases of "primary" ovarian müllerian carcinoma treated at the King George V Memorial Hospital was undertaken to determine the relative frequency with which such tumors were associated with evidence of multifocal primary neoplasia. Of the 128 cases studied, 115 were invasive carcinomas and 13 were noninvasive or borderline ovarian tumors ("tumors of low malignant potential"). Eight of 10 borderline serous ovarian tumors (80%) and 37 of 75 invasive serous carcinomas (49%) exhibited evidence of independent primary neoplasia at more than one anatomical site in the biopsy material available for review. Many of these cases represented bilateral primary ovarian tumors, but autochthonous extraovarian neoplasia was also commonly encountered. A single borderline endometrioid ovarian tumor and six of 15 endometrioid carcinomas (40%) were associated with biopsy-proven multifocal primary tumorigenesis. These were predominantly neoplasms in one or both ovaries plus adenocarcinoma in the uterine corpus. Other histological types of malignant common epithelial tumors of the ovaries did not demonstrate any such tendency, highlighting major differences in pathogenesis between members of this loosely associated group of ovarian cancers. Our study suggests that gynecological endometrioid and serous malignancies are commonly multifocal and we feel this has significant implications for the way these neoplasms are staged and therefore treated.     

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.     

Cyclooxygenase 2 expression in serous tumors of the ovary.

This study was designed to investigate the expression of cyclooxygenase (COX)-2 in ovarian serous tumors (benign, borderline tumors, and carcinomas) and primary peritoneal serous carcinomas. Cases diagnosed between 1995 and 2001 were reviewed; 47 benign tumors, 6 borderline tumors, and 39 carcinomas were examined, as well as 12 normal ovaries that served as controls. Blocks were stained with anti COX-2 polyclonal antibody and staining was graded qualitatively. The staining intensity was assessed as weak (score of 1), moderate (score of 2), or strong (score of 3). Normal ovarian and tubal epithelium, inclusion cysts, benign serous tumors, and borderline tumors had a uniform score 3 staining pattern. Serous ovarian carcinomas had variable staining scores, tending to correlate with the level of tumor differentiation. Well-differentiated carcinomas had more intense COX-2 staining than poorly differentiated carcinomas, which had only weak COX-2 staining. The degree of COX-2 staining was not significantly related to overall survival. In conclusion, COX-2 expression is present in serous tumors, including benign tumors, borderline tumors, and carcinomas. Similar to the findings in other neoplasms, COX-2 expression is strongest in well-differentiated tumors and is much less evident in those that are poorly differentiated. The clinical utility of these findings is related to the potential role of nonsteroidal anti-inflammatory drugs, which are COX-2 inhibitors, in treating and/or preventing some forms of ovarian carcinoma.     

Serous tumors of the ovary: ultrastructural observations.

One borderline primary serous ovarian tumor and six carcinomas were studied by means of electron microscopy. Borderline malignant tumor evidenced concomitant presence of both benign and malign serous epithelium. Ultrastructural observations revealed differentiation characteristics which involved complex architecture of cell arrangement and polarity in the distribution of the organelle and intercellular junctions. The cilia believed to be more frequent in benign tumors were also reported in poorly differentiated carcinomas and so may not be considered as reliable prognostic markers.     

Current issues in the pathology of ovarian cancer

The majority of primary ovarian tumors are histologically classified as surface epithelial-stromal neoplasms. The malignant potential of such neoplasms may be categorized, on the basis of the extent of epithelial proliferation and stromal invasion, as benign, borderline or malignant. Recent efforts to further classify the malignant potential of such neoplasms have produced a new system for the histologic grading of ovarian carcinoma as well as new potential histologic predictors of behavior, including micropapillary morphology and stromal microinvasion in serous tumors. Among mucinous ovarian neoplasms, new criteria have been proposed to distinguish primary ovarian from metastatic carcinomas; the distinction may be difficult but has great clinical significance. The origin of ovarian mucinous tumors associated with pseudomyxoma peritonei has been reassessed. Finally, recent pathologic findings from prophylactic salpingo-oophorectomy specimens in patients with hereditary risks for ovarian carcinoma have highlighted the additional risk for fallopian tube carcinoma and primary peritoneal carcinoma. Special processing of the pathologic specimens is required to detect early and minimal neoplasia in this setting. These current issues in the pathology of ovarian carcinoma and their clinical significance form the basis of this review.     

Placental leucine aminopeptidase (P-LAP) and glucose transporter 4 (GLUT4) expression in benign, borderline, and malignant ovarian epithelia

OBJECTIVE: Increased glucose consumption is a characteristic of malignant cells. Glucose is transported into the cell via facilitative glucose transporters, which are known to be members of a supergene family. The insulin-responsive GLUT4 isoform is expressed almost exclusively in insulin target tissues. P-LAP is a cell surface aminopeptidase, and is a synonym for oxytocinase. P-LAP is also referred to as insulin-regulated membrane aminopeptidase (IRAP) associated with GLUT4-containing vesicle. The authors evaluated P-LAP and GLUT4 expression in benign, borderline, and malignant ovarian epithelia. METHODS: Histologic sections of formalin-fixed, paraffin-embedded specimens from 11 patients with benign serous or mucinous cystadenomas, 14 patients with serous or mucinous borderline tumors, and 80 patients with epithelial-ovarian adenocarcinomas (29 serous, 17 endometrioid, 14 mucinous, and 20 clear cell adenocarcinomas) were stained for P-LAP and GLUT4 using each polyclonal antibody. Expressions of P-LAP and GLUT-4 in ovarian cancer cells were detected by Western blotting. RESULTS: P-LAP immunoreactivity was detected in 2 of 11 benign cystadenomas. None of the 11 benign ovarian tumors showed any immunoreactivity for GLUT4. Seven of 14 borderline tumors demonstrated P-LAP immunoreactivity, while 5 of 14 borderline tumors demonstrated GLUT4 immunoreactivity. P-LAP was expressed in 23 of 29 in serous, 15 of 17 endometrioid, 13 of 14 mucinous, and all clear-cell adenocarcinomas. The tendency toward increased P-LAP expression with advancing grade was observed in serous adenocarcinomas. GLUT4 was expressed in 13 of 29 serous, 13 of 17 endometrioid, 13 of 14 mucinous, and 18 of 20 clear-cell adenocarcinomas. In invasive carcinomas, there was a direct correlation between P-LAP immunoreactivity and GLUT4 immunoreactivity (correlation coefficient [r] = 0.58; P < 0.01). Furthermore, P-LAP overexpression in SKOV3 cells induced the GLUT4 expression. CONCLUSIONS: P-LAP and GLUT4 are available not only for the evaluation of ovarian epithelial malignancy, but also as targets for molecular therapy. Further study to investigate the roles of P-LAP and GLUT4 in ovarian carcinoma is needed.     

Differential expression of WT1 and p53 in serous and endometrioid carcinomas of the endometrium.

Wilms' tumor antibody (WT1) has recently been reported to be reactive in most ovarian and peritoneal serous carcinomas, but few studies have looked at WT1 reactivity in endometrial carcinomas. p53, like WT1, is a tumor suppressor gene and in its mutated form is frequently present in endometrial serous carcinoma. Routine immunohistochemical staining for p53 and WT1 was performed in 70 endometrial carcinomas (39 endometrioid and 31 serous) of varying differentiation using tissue microarrays. Only 2 (7.5%) serous carcinomas and none of the endometrioid carcinomas (0%) were reactive for WT1. p53 immunoreactivity was found in 26 (83.9%) serous carcinomas and in 2 (5.1%) endometrioid carcinomas. We conclude that WT1 and p53 expression are not related and that WT1 expression in endometrial serous carcinoma differs from that of its extrauterine counterparts.     

Carcinoembryonic antigen (CEA) and carbohydrate determinant 19-9 (CA 19-9) localization in 121 primary and metastatic ovarian tumors: an immunohistochemical study with the use of monoclonal antibodies

An immunoperoxidase study, using the Avidin-Biotin-Peroxidase complex method and the monoclonal antibodies, anti-carcinoembryonic antigen (CEA) and anti-carbohydrate determinant 19-9 (CA 19-9), was carried out on 108 common epithelial tumors of the ovary and 13 epithelial tumors metastatic to the ovary. Primary mucinous tumors were positive in 62% of the cases (benign, 15%; borderline, 80%; and carcinomatous, 100%) with anti-CEA. None of the serous tumors were positive with anti-CEA, but 27% (benign, 23%; borderline, 40%; and carcinomatous, 20%) were positive with anti-CA 19-9. With anti-CEA, 30% of the endometrioid carcinomas, 50% of the malignant mesodermal mixed tumors, 14% of the clear cell carcinomas, 36% of the Brenner tumors, and 83% of the metastatic carcinomas from the large intestine were positive. With anti-CA 19-9, 76% of the mucinous, 40% of the endometrioid, 25% of the malignant mesodermal mixed tumors, 57% of the clear cell carcinomas, 45% of the Brenner tumors, and all the metastatic carcinomas from the large intestine were positive. All the undifferentiated carcinomas were unreactive with both antibodies. Although neither CEA nor CA 19-9 is a specific marker for any type of ovarian tumor or for malignancy per se, the presence of the former antigen can be useful in differentiating serous from mucinous tumors. Moreover, demonstration of either antigen in a variety of tumors may indicate its potential value as a serum marker in monitoring the course of the patient.