卵巢上皮性包涵体的起源与低级别卵巢浆液性癌的发病机制

目的 探讨卵巢上皮性包涵体的起源与低级别卵巢浆液性癌的发病机制.方法 收集山东大学齐鲁医院和美国亚利桑那大学附属医院病理科自2000年5月至2010年4月间收治的卵巢浆液性肿瘤患者及行预防性附件切除术患者的手术标本共198份.其中,卵巢肿瘤标本138份,包括卵巢浆液性囊腺瘤53份、卵巢交界性浆液性肿瘤44份、低级别卵巢浆液性癌41份;无明显病理学变化的同侧卵巢及输卵管标本116份(卵巢及输卵管分别为60、56份),取自60例行预防性附件切除术患者的一侧附件.HE染色后镜下观察所有标本的病理学形态特点;并采用免疫组化单染色法检测其免疫表型配对盒基因8抗原( PAX8)、钙结合蛋白(calretinin)、微管蛋白(tubulin)、核增殖相关抗原(Ki-67)的表达,免疫组化双染色法检测其免疫表型PAX8/calretinin的表达.结果 免疫组化PAX8、calretinin单染色法检测显示,90％( 54/60)的卵巢表面生发上皮细胞的免疫表型为PAX8阴性(-)、calretinin阳性(+),HE染色后镜下观察符合间皮组织的形态特点,为间皮型上皮;但有10％(6/60)的卵巢表面生发上皮细胞的免疫表型为PAX8(+)、calretinin(-),HE染色后镜下观察其与输卵管上皮组织的形态相似,为输卵管型上皮.60份正常卵巢中共有921个卵巢上皮性包涵体,表现出两种免疫表型,79％( 728/921)为PAX8(+)、calretinin(-),HE染色后镜下观察其与输卵管上皮组织的形态相似,为输卵管型包涵体;21％(193/921)为PAX8(-)、calretinin(+),HE染色后镜下观察其与间皮组织的形态相似,为间皮型包涵体.免疫组化PAX8/calretinin双染色法进一步验证了卵巢上皮性包涵体的这两种免疫表型.免疫组化PAX8、calretinin、tubulin单染色法检测显示,免疫表型为PAX8(+)、calretinin(-)、tubulin(+)的卵巢表面生发上皮和卵巢上皮性包涵体均包含纤毛型细胞和分泌型细胞2种柱状细胞,形态上接近输卵管黏膜上皮;而免疫表型为PAX8(-)、calretinin(+)、tubulin(+)的卵巢表面生发上皮和卵巢上皮性包涵体则为单层扁平或立方形细胞,与间皮组织的细胞形态类似.免疫组化tubulin、Ki-67单染色法检测显示,分泌型细胞与纤毛型细胞数的比值和细胞增殖指数在卵巢上皮性包涵体及卵巢浆液性囊腺瘤、卵巢交界性浆液性肿瘤、低级别卵巢浆液性癌中呈明显递增趋势(P＜0.05).结论 免疫表型为PAX8(+)、calretinin(-)的卵巢上皮性包涵体可能起源于输卵管,低级别卵巢浆液性癌的发生可能与分泌型细胞的克隆扩增有关.     

Unusual cystadenofibromas: endometrioid, mucinous, and clear cell types

Cystadenofibromas are benign ovarian neoplasms containing both epithelial and stromal components. The epithelial component is usually of simple serous type resembling fallopian tube epithelium. Occasionally, tumors with unusual epithelial pattenrs are encountered. In this study, 16 cystadenofibromas with unusual epithelium are described. Twelve are examples of an endometrioid type, 3 of a clear cell (mesonephroid) type, and 1 of a mucinous-type epithelium. The stromal component in all tumors is identical to that of ordinary cystadenofibromas. One of the patients with a tumor containing endometrioid epithelium developed recurrence in the vagina after surgical removal of the ovarian tumor. The rest of the clinical features of these tumors are similar to those of ordinary cystadenofibromas with the exception that the median age is 10--20 years greater in the unusual-epithelium group.     

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.     

Lectin histochemistry in mucinous and serous ovarian neoplasms.

The lectin-binding properties of 44 cases of serous and mucinous ovarian cystadenoma, tumor of low malignant potential (LMP), and invasive carcinoma were examined histochemically. Wheat germ agglutinin (WGA), concanavalin A (con A), Ulex europaeus agglutinin I (UEA-I), peanut agglutinin (PNA), Ricinus communis agglutinin I (RCA-I), soybean agglutinin (SBA), and Robina pseudoaccacia (RPA) were employed. All the lectins examined were bound to neoplastic epithelial cells of benign and malignant tumors, but none bound exclusively to ovarian tumor cells. Different lectin-binding patterns between serous and mucinous neoplasms were observed, with the exception of RPA. UEA-I, con A, RPA, and PNA in serous neoplasms and UEA-I, RPA, and WGA in mucinous neoplasms demonstrated lectin-binding properties of LMP tumors intermediate between those of cystadenoma and invasive carcinoma. These findings indicate that serous and mucinous ovarian neoplasms contain different glycoconjugates, that malignant transformation of the neoplasms is associated with alteration of these glycoconjugates, and especially that LMP tumors have a different composition of cellular glycoconjugates from that of invasive ovarian carcinoma.     

Epithelial ovarian tumors in adolescents: a retrospective pathologic study and a critical review of the literature

Objectives

The aim of this study was to further evaluate the pathologic features of epithelial ovarian neoplasms and their relative frequency among all ovarian tumors in the adolescent population.

Design

We conducted a retrospective pathologic study of all cases of epithelial ovarian neoplasms in adolescents (aged 11-19 years) diagnosed in the pathology laboratory of our hospital over the past 25 years.

Results

A total of 86 ovarian tumors were identified, including 23 epithelium-derived ovarian neoplasms (26.7%), 53 germ cell tumors (61.6%), 9 sex-cord stromal tumors (10.5%) and 1 benign Brenner tumor (1.2%). Most cases of epithelial tumors were found in patients 17 years of age or older (14/23 cases, 60.9%). All tumors were unilateral, and their size ranged from 2.5-21 cm (mean 11.7 cm). Epithelial tumors were further histologically subtyped into 21 benign cystadenomas (14 serous and 7 mucinous) and 2 mucinous borderline tumors.

Conclusions

A relatively high frequency of epithelial ovarian neoplasms among all ovarian tumors in a purely adolescent population was found in our study. Age-related selection bias may account at least in part for the discrepancy between our data and most previous reports. The most common subtype of epithelial ovarian tumor in our series was the benign serous cystadenoma.     

Prostate-derived Ets factor is overexpressed in serous epithelial ovarian tumors.

The frequent overexpression of prostate-derived Ets factor (PDEF) mRNA in ovarian cancer has been previously reported. The aim of this study was to evaluate PDEF protein expression in ovarian cancer and how this expression might vary at different stages of epithelial ovarian tumors in comparison to normal ovary. A new rabbit polyclonal antibody to PDEF was prepared, and immunohistochemistry was performed on tissue sections from 12 normal ovaries, 10 cases of benign serous cystadenoma, 17 cases of low malignant potential tumor, 19 cases of stage 1, and 15 cases of advanced stage primary epithelial (serous) ovarian carcinomas and their peritoneal metastases. Expression levels were assessed based on the percentage of positively staining cells and the intensity of staining. All 12 normal ovary and 10 benign serous cystadenoma cases were negative for PDEF expression. In contrast, 6 of 17 (35%) low malignant potential tumors, 5 of 19 (27%) stage 1, and 5 of 15 (33%) advanced stage ovarian tumors stained positive for PDEF expression. Together, these results show frequent overexpression of PDEF protein in epithelial ovarian tumors and its lack of expression in normal ovary and cystadenomas, and this supports a role for PDEF in ovarian tumorigenesis. Furthermore, these results suggest that PDEF is a potential marker and target in ovarian cancer.     

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.     

Oviductal glycoprotein, a new differentiation-based indicator present in early ovarian epithelial neoplasia and cortical inclusion cysts

OBJECTIVE: With neoplastic progression, the precursor of epithelial ovarian cancers, the ovarian surface epithelium (OSE), undergoes Mullerian differentiation, usually of the oviductal type. The aim of this study was to examine the expression of oviduct-specific glycoprotein (OGP), a marker of normal oviductal epithelium, for use as a diagnostic or prognostic marker for ovarian cancer. METHODS AND MATERIALS: Immunohistochemical analysis for OGP was performed on 389 ovarian tumors and 19 normal ovaries, as well as 433 cases representing 45 normal tissues and 51 benign and malignant tumor types from 37 different tissues. RESULTS: OGP was absent in OSE but present in 28 of 31 epithelial inclusion cysts, 13 of 14 (93%) serous cystadenomas, and 46 of 65 (71%) serous borderline tumors. Of 183 serous adenocarcinomas, 26 (14%) were positive for OGP, including 5 of 8 (63%) grade I, 7 of 41 (17%) grade II, and 14 of 134 (10%) grade III carcinomas. OGP was found in 7 of 14 (50%) borderline and 9 of 15 (60%) malignant mucinous ovarian tumors and in 10 of 39 (26%) endometrioid adenocarcinomas. The localization of OGP in the lumen of glandular structures suggested that it was secreted. OGP was absent in 41 of 45 normal tissues and positive in oviduct and, weakly, in salivary gland, duodenum, and ileum. Forty-six types of nongynecologic tumors were negative, as were gynecologic neoplasms except for 2 of 47 cervical and 3 of 56 endometrial carcinomas. CONCLUSION: OGP is a new tubal differentiation marker which characterizes benign and borderline serous neoplasms and may indicate early events in ovarian carcinogenesis.     

Periodic acid-Schiff stain as a prognostic indicator in serous and mucinous ovarian tumors

The prognostic significance of periodic acid-Schiff (PAS) stain in 112 serous: 43 benign, 25 borderline and 44 malignant cystadenomas: and in 106 mucinous: 60 benign, 32 borderline and 14 malignant cystadenomas of the ovary were investigated. The amount of positively stained mucin was estimated morphometrically. The outcome of most patients with benign or borderline lesion was good. One patient with benign mucinous cystadenoma died, however, of pseudomyxoma peritonei and another patient with borderline mucinous cystadenoma died of peritoneal carcinosis. Other patients were alive and free of the disease after a follow-up of 1-14 years, or had died of causes unrelated to the ovarian disease. Abundant PAS positive mucin predicted a longer survival both in serous and in mucinous malignant tumors. The 5-year survivals for the serous cystadenocarcinomas with and without PAS positive mucin were 21% and 13%, respectively (not statistically significant). For mucinous cystadenocarcinomas with mucin value over and below the median, the 5-year survival rates were 57% and 14%, respectively (P less than 0.10). High PAS positivity in both serous and mucinous cystadenocarcinomas clearly indicated better prognosis, although statistical significance was not achieved. Thus, further studies are needed for final evaluation of the prognostic significance of the PAS stain in these ovarian tumors.     

Transition from benign to malignant epithelium in mucinous and serous ovarian cystadenocarcinoma.

The slides of all patients with ovarian cystadenocarcinoma treated at the University of Kentucky Medical Center from 1966-1990 were reviewed. Fifty-four serous tumors and 42 mucinous neoplasms were identified for further study. Benign epithelium adjacent to an area of borderline or malignant epithelium was observed in 74 tumors (79%) and a site of epithelial transition was noted in 38 cases (40%). The presence of associated benign epithelium was more common in borderline or well-differentiated lesions and in patients with early-stage disease. These findings are consistent with epidemiologic and molecular genetic data and suggest that certain benign serous or mucinous ovarian tumors have the potential for malignant transformation. Removal of these tumors, particularly in postmenopausal women, should result in a subsequent reduction in the frequency of ovarian cancer.     

The cytokeratin profiles of ovarian common "epithelial" tumors

An improved immunohistochemical determination of the cytokeratin profiles of epithelia and their neoplasms is possible using monoclonal antibodies that will either identify all 19 cytokeratins (AE1/3) or delineate specific subsets (35 beta H11, 34 beta E12, 34 beta B4 and Cam 5.2). Ovarian common "epithelial" tumors (CET) contain cytokeratin filaments. To determine the nature and differences in the cytokeratin profiles of ovarian CET, eight benign Brenner tumors, four serous cystadenofibromas, 28 mucinous tumors, 27 serous tumors and six endometrioid, five clear cell and five undifferentiated carcinomas, as well as nine normal ovaries were immunostained with the above five antibodies. AE1/3 staining was predominant, while Cam 5.2 and 35 beta H11 displayed the most frequent staining thereafter. Statistically significant staining differences were found between a number of tumor groups using the antibodies 35 beta H11, 34 beta E12 and Cam 5.2. In this study, all ovarian CET, except the benign Brenner tumors, displayed a predominantly low molecular weight cytokeratin profile. The same profile in the normal surface epithelium lends credence to the belief that these tumors are derived from this epithelium. A significant staining difference between some of the tumor types using some of the antibodies suggests a possible ancillary, diagnostic role of cytokeratin profiling in situations where exact tumor typing is difficult.     

Risk factors for benign serous and mucinous epithelial ovarian tumors

OBJECTIVE: To investigate the risk factors for benign serous and mucinous epithelial ovarian tumors. METHODS: Cases were women newly diagnosed with benign serous ovarian tumors (n=230) or benign mucinous tumors (n=133) between 2002 and 2005. Control women were selected at random from the general population (n=752). All participants completed a comprehensive reproductive and lifestyle questionnaire. Multivariable logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) and to simultaneously adjust for potential confounding factors. RESULTS: Current smoking was associated with a three-fold increase in risk of benign mucinous tumors (OR 3.25, 95% CI 1.97-5.34), and there was a trend of increasing risk with increasing amount smoked (P<.001). Both recent obesity (OR 1.93, 95% CI 1.30-2.88) and obesity at age 20 (OR 4.38, 95% CI 1.88-10.20) were associated with increased risk of benign serous ovarian tumors, and having had a hysterectomy was also related to increased risk of serous (OR 2.75, 95% CI 1.90-3.96), but not mucinous tumors. Ever having had a term pregnancy was inversely associated with both tumor types (combined OR 0.65, 95% CI 0.43-0.97), although greater numbers of pregnancies did not decrease risk further. Use of hormonal contraceptives was unrelated to risk. CONCLUSION: Our results suggest some differences in risk factors between benign serous and mucinous epithelial ovarian tumors and that risk factors for benign serous tumors differ from those well established for ovarian cancer. The results also suggest that there is potential for prevention of these common conditions through avoidance of smoking and obesity. LEVEL OF EVIDENCE: II.     

Ovarian cancer metastatic to the breast

The breast is an uncommon site for metastasis from epithelial ovarian cancer. Such lesions are purportedly secondary to blood-borne metastases. The accurate classification of ovarian epithelial neoplasms is the cornerstone of decisions regarding therapy and prognosis. Taylor, in 1929, reported a hyperplastic variety of papillary cystadenoma which, on occasion, produced multiple implants on the peritoneum but usually behaved in a benign fashion. The International Federation of Gynecologists and Obstetricians adopted a classification of benign cystadenomas, cystadenocarcinomas of low malignant potential (LMP), and cystadenocarcinomas. The serous tumors of LMP rarely metastasize outside of the abdominopelvic cavity. This case, of a serous tumor of LMP with breast metastasis, permits an analysis of metastatic breast lesions secondary to epithelial ovarian cancer.     

Neutral endopeptidase/CD10 expression in the stroma of epithelial ovarian carcinoma.

This study investigated the immunohistochemical expression and localization of neutral endopeptidase (NEP) (CD10), which plays a functional role by degrading bioactive peptides, in ovarian tumors. In normal ovaries and benign cystadenomas, NEP was not detected in any epithelial or stromal cells. In borderline tumors, NEP was detected in the stromal cells in 6 of 7 serous tumors, but not in those from mucinous tumors. In ovarian carcinomas, NEP in the stromal cells was observed in 13 of 20 serous, 8 of 10 endometrioid, and 7 of 10 clear-cell adenocarcinomas. NEP was weakly detected in only 1 of 9 mucinous adenocarcinomas. The staining intensity of stromal NEP was decreased in grades 2 and 3 serous carcinomas compared with that in grade 1 serous carcinomas. In conclusion, NEP was specifically expressed in the stroma of borderline and malignant ovarian tumors, but not in adenomas. Furthermore, stromal NEP was downregulated as the histological grade advanced. These results suggest that NEP may play a role in the regulation of neoplastic transformation and tumor differentiation in epithelial ovarian carcinomas.     

Expression P53 protein and chromosome aberrations in benign tumors and ovarian carcinoma

OBJECTIVES: The epithelial ovarian tumors arise from the single layer of epithelial cells that line the ovarian surface or from underlying inclusion cysts. One from many theories of oncogenesis has been proposed that benign, borderline and invasive tumors represent sequential stages in the growth of an ovarian cancer, and p53 tumor suppressor gene mutation is the most common molecular genetic alteration. Because locus of p53 gene is located on 17 chromosome we performed the cytogenic analysis of tumor tissues. DESIGN: Analysis of mutated p53 protein expression and chromosomal aberrations in tissues of benign tumors and epithelial ovarian carcinomas. MATERIAL AND METHODS: Tissue samples from 19 women with benign and 17 women with invasive epithelial ovarian cancers were obtained for the study at the time of surgical procedures. From among benign tumors 12 were serous cystadenomas, 5 were endometrial cysts and 2 adult teratomas. All cases of invasive epithelial ovarian carcinomas were histologically recognized as serous adenocarcinomas, and were staged on I (9 cases), II (5 cases) and III (3 cases), according to the FIGO guidelines for ovarian cancers. Frozen tissue samples were stained immunohistochemically for mutated p53 protein using commercial monoclonal antibodies and standard detecting system. The fresh tumor samples were prepared for cytogenic analysis according to standard protocol. RESULTS: Among the all benign ovarian tumors overexpression of mutated form of p53 protein was not seen in any cases, but was noted in 6 cases in I stage and in all cases in II and III stages of advanced ovarian cancers. In 1 case of benign ovarian tumor deletion of X chromosome was observed. Most common numerical changes were observed in ovarian carcinomas e.g. loss of 8, 13, 17, and 22 chromosomes. Other chromosomes were involved at least once in structural rearrangements and several breakpoint cluster regions were identified: 19p13, 11p13-15, 1q21-23, 1p36, 19q13, and 6q21-23. CONCLUSIONS: The mutated form of p53 protein is often expressed in ovarian epithelial carcinoma tissues. This protein are unable to function effectively to inhibit proliferation and accumulate in the cells because is resistant to degradation. In tissues of ovarian carcinomas many chromosomal nondisjunctions (monosomics) and multiple structural rearrangements were observed, what means of genetically nonstable cell lines of neoplasms and probably it heterogenous origin.     

Poly(adenosine diphosphate-ribose) polymerase expression in serous ovarian carcinoma: correlation with p53, MIB-1, and outcome.

This study investigated the expression of poly(adenosine diphosphate-ribose) polymerase (PARP) in a cohort of ovarian serous carcinomas by immunohistochemistry with regard to outcome, clinicopathologic parameters, proliferation as assessed by MIB-1 labeling indices (LIs), and p53 immunoexpression. Formalin-fixed, paraffin-embedded archival tissues of 50 ovarian serous carcinomas were immunostained with antibodies to PARP, MIB-1, and p53. In addition, 10 benign serous cystadenomas and 10 typical serous borderline ovarian tumors were included in the PARP immunostudy. Immunostaining for PARP was scored with regard to quantity and intensity of positively stained nuclei as negative, low, or strong. The MIB-1 LIs were quantitated as the percentage of positively stained nuclei in 1000 nuclei. For p53, at least 10% of tumor cells had to display nuclear staining. The expression of PARP was scored negative in all serous cystadenomas and low in serous borderline ovarian tumors. Strong PARP expression was determined in 38 cases (76%), and low expression in 12 cases (12%) of ovarian serous carcinomas; MIB-1 staining was noted in all cases (mean, 44.2; range, 10.8-66.5), positivity for p53 in 39 cases (78%). The PARP immunoreactivity increased with the International Federation of Gynecology and Obstetrics stage (P = 0.0075), as well as p53 positivity (P = 0.0141) and MIB-1 LIs (P = 0.0102), with grade determined after Malpica et al. (P = 0.0445) but not with grade assessed after Shimizu et al. (P = 0.1495). A trend for poor outcome was observed in patients whose tumors displayed high levels of PARP immunoexpression (P = 0.0196, log-rank test). This study indicates that PARP expression is frequently upregulated in ovarian serous carcinomas, related with MIB-1 LIs and p53 expression, and may serve as a marker of aggressive behavior with prognostic value.     

The role of actin bundling protein fascin in the progression of ovarian neoplasms

PURPOSE OF INVESTIGATION: The aim of the study was to investigate the role of fascin in tumor progression and to investigate the role of fascin on endothelial cell migration and angiogenesis in ovarian neoplasms. METHODS: In the study, 94 malign epithelial ovarian neoplasms, 13 borderline epithelial ovarian neoplasms, 25 serous and mucinous cystadenomas and four normal ovarian tissues were examined by means of immunohistochemistry, using monoclonal antihuman fascin antibody, clone IM20. RESULTS: Total stromal fascin score in cases of borderline and malign epithelial ovarian tumors was significantly higher compared to normal ovaries and benign epithelial ovarian tumors (.000, p < 0.001). There was no statistically significant difference in terms of total epithelial fascin scores of samples between groups (.080, p > 0.05). Presence of vascular invasion (.000, p < 0.001), psammomatous calcifications (.001, p = 0.001), and lymphocytic infiltration (.000, p < 0.001) were significantly higher in malign neoplasms. There was no significant difference in terms of mean microvessel count and homogeneous or heterogeneous fascin expression of microvessels between the benign and malign groups (respectively p = .228 and p = .143). CONCLUSIONS: This study suggests that up-regulation of fascin in tumoral tissue may promote invasion of ovarian carcinoma by cell-matrix adhesion.