PTK7 protein is decreased in epithelial ovarian carcinomas with poor prognosis

Epithelial ovarian cancer is the most common tumor of ovary. PTK7 plays an important role in tumors. Till now, there is no report about the role of PTK7 in ovarian epithelial neoplasms. This study aims to investigate the expression of PTK7 protein in epithelial ovarian tumors, and its relationship with clinical pathological characteristics. In this study, immunohistochemical staining was used to detect the expression of PTK7 protein in 14 samples of normal fallopian tube epithelium and 204 cases of epithelial ovarian tumor. The relationship between the expression of PTK7 and pathological indicators was statistically analyzed. Kaplan-Meier survival function was used to analyze the prognosis. The expression of PTK7 was found in 92.86% (13/14) of normal fallopian tube epithelium and 45.10% (92/204) of epithelial ovarian tumor tissues. The expression level of PTK7 was significantly decreased from the benign, the intermediate type, to malignant ovarian epithelial tumors (P < 0.001), and decreased from the normal control group to serous carcinomas (P < 0.001). The expression of PTK7 was significantly different in type I and type II epithelial ovarian carcinomas (P < 0.001). PTK7 protein expression was associated with clinical stages (P = 0.038) and metastases (P = 0.038) in ovarian borderline serous tumors. PTK7 protein expression was associated with clinical stages (P = 0.011), WHO grading (P = 0.004), and MDACC grading (P < 0.001) in ovarian serous carcinomas. The survival analysis showed that patients with negative expression of PTK7 protein had a poorer outcome than those with positive expression (P = 0.017). These results indicate that PTK7 protein may be a tumor suppressor and a potential prognostic marker in ovarian serous carcinomas.     

Comparison of c-met Expression in Ovarian Epithelial Tumors and Normal Epithelia of the Female Reproductive Tract by Quantitative Laser Scan Microscopy

The transmembrane tyrosine kinase receptor c-met with its ligand, hepatocyte growth factor/scatter factor (HGF/SF), acts as a mitogen, motogen, and morphogen in many normal epithelia. HGF/SF-met signaling has also been implicated in neoplastic progression and metastasis. In this study, immunofluorescence staining and quantitative laser scanning confocal microscopy were used to measure c-met expression in ovarian surface epithelial tumors from 17 oophorectomy specimens. These specimens were from patients aged 25 to 81 (mean age, 52) and included 10 malignant tumors, 4 borderline tumors, and five benign tumors including a Brenner tumor. For comparison, c-met expression was measured in normal tissues from the same patients, including 4 ovarian surface epithelia, 4 fallopian tube epithelia, 2 endometria, and 3 endocervical epithelia, as well as 3 cases of endometriosis. Relative pixel intensity values of c-met expression ranged from 0.4 in a normal ovarian surface epithelium to 22.3 in a borderline serous tumor. Malignant tumors (mean, 9.6) and borderline tumors (mean, 12.9) had higher average c-met expression levels than normal tissues (mean, 3.6) and endometriosis (mean, 1.8). The expression levels of benign tumors were intermediate (mean, 7.9). Among the normal tissues, c-met expression in fallopian tubes (mean, 8.2; range, 3.4-12.9) was higher than that of the other normal epithelia (mean, 1.6; range, 0.4-4.3). In eight cases where both normal and malignant tissues were sampled, c-met expression was significantly greater in malignant than in normal epithelia (P = 0.01). These findings indicate that c-met plays a role in the biology of the normal tissues examined. They confirm that its expression increases in the malignant progression of ovarian surface epithelial tumors, and suggest that increases comparable to those in frankly malignant carcinomas have already been reached in borderline lesions, ie, early in the neoplastic process.     

叶酸受体α在卵巢上皮性肿瘤中的表达

目的 探讨卵巢上皮性肿瘤中叶酸受体(FR)α的表达及其临床病理学意义.方法 制备包括86例卵巢癌及29例卵巢交界性肿瘤的组织芯片,采用免疫组织化学EnVision法检测上述肿瘤组织中FRα的表达情况,同时采用即时PCR检测40例新鲜冷冻卵巢癌组织以及14例卵巢交界性肿瘤组织中FRα mRNA的表达情况.分析卵巢上皮性肿瘤中FRα表达水平与肿瘤的组织类型、不同发病模式以及临床分期的关系.结果 免疫组织化学染色结果显示,86例卵巢癌中有40例(46.5%)对FRα呈明确阳性反应,其中浆液性癌阳性表达率最高,为62.7%(32/51),高于其他组织类型的癌(P=0.000).按照卵巢癌发病模式区分,Ⅱ型卵巢癌FRα的表达明显高于Ⅰ型卵巢癌,差异具有统计学意义(P=0.001).卵巢癌组FRα表达阳性率高于交界性肿瘤(46.5%∶27.6%),但差异无统计学意义(P=0.074).卵巢癌组FRα的表达与临床分期无相关性(P=0.498).相似的结果也见于采用即时PCR检测FRα mRNA的表达情况:卵巢癌组FRα mRNA表达值高于交界性肿瘤组(P=0.000),在交界性肿瘤中,浆液型mRNA表达值高于黏液型,差异具有统计学意义(P=0.007).结论 卵巢上皮性肿瘤中FRα呈高表达,特别是在恶性肿瘤和浆液性肿瘤中.     

EphB3 protein is associated with histological grade and FIGO stage in ovarian serous carcinomas

Eph (Erythropoietin‐producing human hepatocellular carcinoma cell) is the largest subfamily of receptor tyrosine kinases. Eph receptors and their ephrin ligands are involved in embryonic development and physiological processes. Aberrant expression of Eph/ephrin may contribute to a variety of diseases including cancer. EphB3 is a member of Eph receptors and has been found to play roles in carcinogenesis of some types of human cancer. But, its expression and clinical significance in ovarian serous carcinoma have not been well investigated and are unknown. In this study, a set of ovarian tissues including normal fallopian tube, serous borderline tumor, and serous carcinoma were subjected to immunohistochemistry using a specific polyclonal antibody for EphB3. The relationship between EphB3 expression and clinicopathological parameters was statistically analyzed. EphB3 was strongly expressed in all fallopian tube specimens (19/19, 100%). EphB3 was negatively or weekly expressed in 1 of 17 (5.8%) in borderline tumors and 26 of 50 (52.0%) in serous carcinomas, moderately expressed in 7 of 17 (41.2%) in borderline tumors and 14 of 50 (28%) in serous carcinomas, and strongly expressed in 9 17 (52.9%) in borderline tumors and 10 of 50 (20%) in serous carcinomas. EphB3 expression is significantly reduced in serous carcinomas compared with normal fallopian tubes and borderline tumors (p < 0.001). EphB3 expression is negatively associated with histological grade (p < 0.001, r_s = ?0.613) and FIGO stage (p = 0.001, r_s = ?0.464) of serous carcinomas. Our results show EphB3 protein lost in ovarian serous carcinoma and is associated with tumor grade and FIGO stage, which indicate EphB3 protein may play a role in carcinogenesis of ovarian serous carcinoma and may be used as a molecular marker for prognosis.     

Mucosal carcinoma of the fallopian tube coexists with ovarian cancer of serous subtype only: a study of Japanese cases

Previous studies in Western countries have revealed that mucosal carcinoma of the fallopian tube frequently coexists with pelvic (ovarian, tubal, and peritoneal) serous carcinomas, and early tubal carcinoma is now regarded as a possible origin of these tumors. However, the relationship between early tubal carcinoma and non-serous ovarian cancer, such as clear cell adenocarcinoma, has not been studied in detail. In this study, we sought to examine the coexistence of mucosal carcinoma of the fallopian tube in Japanese ovarian cancer cases. We submitted the fallopian tubes in toto for histological examination in 52 ovarian carcinoma cases and three peritoneal serous carcinoma cases. The ovarian tumors included 12 serous adenocarcinomas, 23 clear cell adenocarcinomas, nine endometrioid adenocarcinomas, three mucinous adenocarcinomas, and four mixed epithelial carcinomas. Mucosal carcinoma of the fallopian tube did not coexist with non-serous adenocarcinoma (n = 40). In contrast, mucosal carcinoma of the fallopian tube was observed in six cases of ovarian serous adenocarcinoma and one case of peritoneal serous adenocarcinoma. In these cases, the p53 immunophenotypes were similar in tubal lesions and invasive ovarian or peritoneal carcinomas. Tumors were negative for p53 in four of seven cases, and one of the p53-negative serous adenocarcinomas showed low-grade morphology. We believe that some ovarian and peritoneal serous adenocarcinomas develop from early tubal carcinomas. However, it should be noted that early tubal carcinomas are not always p53-positive immunohistochemically. Finally, it is unlikely that early tubal lesions are involved in the carcinogenesis of clear cell adenocarcinoma and other non-serous adenocarcinomas.     

K-ras activation occurs frequently in mucinous adenocarcinomas and rarely in other common epithelial tumors of the human ovary.

To explore the role of mutational activation of members of the ras family of cellular protooncogenes in the development of human ovarian neoplasms, a series of 37 ovarian tumors from Japanese patients was studied. These included 30 common epithelial tumors (1 mucinous tumor of borderline malignancy, 7 mucinous adenocarcinomas, and 22 nonmucinous carcinomas: 10 serous, 3 clear cell, 8 endometrioid, and 1 undifferentiated), 5 tumors of germ cell origin, and 2 sex cord/stromal cell tumors. Polymerase chain reaction was performed from selected areas of deparaffinized sections of formalin-fixed paraffin-embedded tissue, and the presence of activating point mutations in codons 12, 13, and 61 of the H-, N-, and K-ras genes was probed by dot-blot hybridization analysis with mutation specific oligonucleotides. Mutations in K-ras were also looked for by direct genomic sequencing. The overall frequency of ras gene mutations was 10/37 (27%). Mutations were detected only in K-ras, and were found in most of the mucinous tumors, including the one such tumor of borderline malignancy (6/8; 75%). In one mucinous adenocarcinoma, two mutations were detected in paraffin-embedded material that had not previously been found in high molecular weight DNA isolated from frozen tissue from the same case. K-ras mutations occurred significantly more frequently in mucinous tumors (6/8, 75%) than in serous carcinomas (2/10, 20%; P = 0.031) or in all nonmucinous types of epithelial ovarian tumors combined (3/22, 14%; P = 0.0031).     

Characterization of the specificity by immunohistology of a monoclonal antibody to a novel epithelial antigen of ovarian carcinomas

An immunohistological study, using the avidin-biotin-peroxidase complex method, was carried out to define the reactivity profile of a murine monoclonal antibody, MOv2, which recognizes a novel glycoprotidic antigen associated with ovarian epithelial tumors. Among the primary ovarian tumors tested, MOv2 immunostained 93% of mucinous and 75% of serous cystadenomas, 100% of mucinous, 81% of serous and 73% of endometrioid carcinomas. Undifferentiated and clear cell tumors revealed more limited reactivity with the antibody, whereas ovarian sex cord-stromal and germinal tumors were immunonegative. Positive reactions were also documented in omental metastases from primary ovarian carcinomas. No immunoreactivity was detected in normal ovarian epithelium, whereas the cells lining Walthard's nests adjacent to the fallopian tubes and a variety of normal epithelia were consistently immunolabeled. These included the lining epithelia of the gastrointestinal tract, bronchi and endocervix, and the epithelium of salivary, biliary and pancreatic ducts and sweat glands. To a lesser extent, positive reactions were detected in other surface epithelia, such as squamous and transitional epithelia. Among tumors other than ovarian, MOv2 consistently reacted with adenocarcinomas and squamous cell carcinomas from different sites, most notably breast, lung and gastrointestinal tract, and with transitional cell carcinomas. In contrast, no staining was demonstrated in non-epithelial malignancies. The antigen defined by MOv2 may be operationally useful as a marker of epithelial lineage in tumor histopathology. Its pattern of immunohistochemical distribution indicates that an antigenic phenotype shared by normal surface epithelia and non-ovarian carcinomas is strongly associated with common epithelial neoplasms of the ovaries.     

Expression and mutational analysis of c-kit in ovarian surface epithelial tumors

Coexpression of Kit ligand and c-kit has been reported in some gynecologic tumors. To determine whether imatinib mesylate is useful in ovarian epithelial tumors, we performed immunohistochemical and mutational analysis. The cases consisted of 33 cases, which included 13 serous cystadenocarcinomas, 1 borderline serous tumor, 8 mucinous cystadenocarcinomas, 6 borderline mucinous tumors and 5 clear cell carcinomas. Five cases of serous cystadenoma and 5 cases of mucinous cystadenoma were also included. In the immunohistochemical study, 3 cases (3/6, 50%) of borderline mucinous cystic tumor and two cases (2/8, 25%) of mucinous cystadenocarcinoma show positive staining for KIT protein. Only one case (1/13, 7.7%) of serous cystadenocarcinoma had positive staining. On mutational analysis, no mutation was identified at exon 11. However, two cases of borderline mucinous tumors and one case of mucinous cystadenocarcinoma had mutations at exon 17. In these cases, the immunohistochemistry also shows focal positive staining at epithelial component. Although, KIT protein expression showed higher incidence in mucinous tumors than serous tumors, they lack KIT-activating mutations in exon 11. Thus, ovarian surface epithelial tumors are unlikely to respond to imatinib mesylate.     

Genomic imbalances in ovarian borderline serous and mucinous tumors

We analyzed 25 ovarian borderline tumors (13 serous and 12 mucinous tumors) by comparative genomic hybridization (CGH). Genomic imbalance was detected in 85% of serous tumors and 75% of mucinous tumors. Different patterns of genomic alterations were identified in serous and mucinous tumors. Gain of the X chromosome was common in both serous (30%) and mucinous (42%) tumors. However, gain of chromosome 8 was detected exclusively in 38% of serous and mixed sero-mucinous tumors, but not in any pure mucinous tumors. According to the present and previous studies, gain of chromosome 8 is the most common abnormality in borderline serous tumors. Gain of the same chromosome is also common in high grade and advanced stage serous carcinomas, but uncommon in early stage serous carcinomas. In addition gain of chromosome X is common in borderline serous and mucinous tumors, while loss of chromosome X is predominant in invasive carcinomas. These findings do not support the multi-step progression theory from borderline tumor to high-grade, advanced stage carcinoma, but indicate that the borderline ovarian tumor is a distinct entity. Genes in chromosome 8 may be critical for the development and the differentiation of borderline serous tumors.     

Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer--shifting the paradigm

Recent morphologic, immunohistochemical, and molecular genetic studies have led to the development of a new paradigm for the pathogenesis and origin of epithelial ovarian cancer based on a dualistic model of carcinogenesis that divides epithelial ovarian cancer into 2 broad categories designated types I and II. Type I tumors comprise low-grade serous, low-grade endometrioid, clear cell and mucinous carcinomas, and Brenner tumors. They are generally indolent, present in stage I (tumor confined to the ovary), and are characterized by specific mutations, including KRAS, BRAF, ERBB2, CTNNB1, PTEN, PIK3CA, ARID1A, and PPP2R1A, which target specific cell signaling pathways. Type I tumors rarely harbor TP53 mutations and are relatively stable genetically. Type II tumors comprise high-grade serous, high-grade endometrioid, malignant mixed mesodermal tumors (carcinosarcomas), and undifferentiated carcinomas. They are aggressive, present in advanced stage, and have a very high frequency of TP53 mutations but rarely harbor the mutations detected in type I tumors. In addition, type II tumors have molecular alterations that perturb expression of BRCA either by mutation of the gene or by promoter methylation. A hallmark of these tumors is that they are genetically highly unstable. Recent studies strongly suggest that fallopian tube epithelium (benign or malignant) that implants on the ovary is the source of low-grade and high-grade serous carcinoma rather than the ovarian surface epithelium as previously believed. Similarly, it is widely accepted that endometriosis is the precursor of endometrioid and clear cell carcinomas and, as endometriosis, is thought to develop from retrograde menstruation; these tumors can also be regarded as involving the ovary secondarily. The origin of mucinous and transitional cell (Brenner) tumors is still not well established, although recent data suggest a possible origin from transitional epithelial nests located in paraovarian locations at the tuboperitoneal junction. Thus, it now appears that type I and type II ovarian tumors develop independently along different molecular pathways and that both types develop outside the ovary and involve it secondarily. If this concept is confirmed, it leads to the conclusion that the only true primary ovarian neoplasms are gonadal stromal and germ cell tumors analogous to testicular tumors. This new paradigm of ovarian carcinogenesis has important clinical implications. By shifting the early events of ovarian carcinogenesis to the fallopian tube and endometrium instead of the ovary, prevention approaches, for example, salpingectomy with ovarian conservation, may play an important role in reducing the burden of ovarian cancer while preserving hormonal function and fertility.     

Nuclear findings of ovarian surface epithelial tumors

While cytoplasmic features of ovarian surface epithelial tumors are well-known, the nuclear findings have received little attention. We reviewed imprint cytology materials of the ovary which were collected at the Kawasaki Medical School Hospital between January 1989-July 1999, and identified 15 mucinous cystadenomas, 3 borderline mucinous tumors, 4 mucinous cystadenocarcinomas, 4 serous cystadenomas, 4 borderline serous tumors, 7 serous cystadenocarcinomas, 6 endometrioid carcinomas, and 2 clear-cell adenocarcinomas. We microscopically observed nuclear findings of the 45 cases. Coffee-bean nuclei were observed in 15.0%, 15.8%, and 10.1% of the tumor cells in mucinous adenomas, borderline mucinous tumors, and borderline serous tumors, respectively. The frequencies of the coffee-bean nuclei in the three tumors were higher than in the remaining tumors (P < 0.001). Intranuclear cytoplasmic inclusions were observed in 2.1% of the tumor cells in mucinous cystadenoma, and their frequency was significantly higher than that in cases of other surface epithelial ovarian tumors (P < 0.001). Semilunar-shaped nuclei were seen in all cases of mucinous cystadenomas and borderline mucinous tumors, and in 3 of 4 mucinous adenocarcinomas. The remaining surface epithelial tumors did not reveal the semilunar-shaped nuclei. In the cytology of the ovary, the semilunar nuclei are characteristic of mucinous tumors, and the intranuclear cytoplasmic inclusion may be a diagnostic clue to mucinous cystadenoma, when it is conspicuous. The coffee-bean nuclei can be seen in mucinous cystadenoma, borderline mucinous tumors, and borderline serous tumors.     

Human papilloma virus (HPV) status, p16INK4a, and p53 overexpression in epithelial malignant and borderline ovarian neoplasms

This investigation is the first to evaluate simultaneously human papilloma virus (HPV) status, p16(INK4a), and p53 immunoreactivity in epithelial ovarian neoplasms. The results were analyzed and correlated with histological type, histological grade, and survival of patients. Subtypes considered are papillary serous and mucinous. Polymerase chain reaction (PCR) analysis, performed in our previous study, had already demonstrated a small number of HPV-positive epithelial ovarian neoplasms. No significant correlation was found between the presence of HPV DNA and subtypes of ovarian neoplasms; thus, HPV cannot be considered responsible for epithelial ovarian neoplasm. Since p16 immunoreactivity was present in many other HPV-negative cases of epithelial ovarian neoplasms, this study suggests that p16 overexpression in some neoplasms of the female genital tract is not related to HPV carcinogenesis. A higher p53 expression rate observed between borderline and malignant serous tumors and between serous and mucinous neoplasms can confirm a recent dualistic model of ovarian carcinogenesis. According to this theory, low-grade serous carcinomas (serous intraepithelial carcinomas, serous borderline neoplasm, and ovarian mucinous neoplasms) (type I tumors) develop from mutations of KAS and BRAF, while high-grade serous carcinomas (type II tumors) develop from mutation of p53. In malignant neoplasms, for univariate analysis, patient survival seems to be related to p53, strong and diffuse p16 overexpression, and the stage of development of neoplasms at the diagnosis. In multinomial logistic regression, used to evaluate the role of staging, grading, p16 and p53 immunopositivity as predictor variables of unfavorable outcome of the disease, only p16 positivity was significantly related to the poor prognosis of the cancer.     

卵巢上皮性肿瘤肠粘液抗原和癌胚抗原的免疫组织化学研究

应用两种肠粘液抗原（ＬａｒｇｅＩｎｔｅｓｔｉｎａｌＭｕｃｉｎｏｕｓＡｎｔｉｇｅｎ，ＬＩＭＡ，ＳｍａｌｌＩｎｔｅｓｄｔｉｎａｌＡｎｔｉ－ｇｅｎ，ＳＩＭＡ）和ＣＥＡ对７８例卵巢上皮性肿瘤石蜡标本进行免疫组化染色。三种抗原在良性和交界性肿瘤中以腔缘型分布为主，可见恶性肿瘤腔缘、胞浆弥漫分布并随组织学分级的增高趋向于胞浆分布；三种抗原的阳性率在浆液性癌和粘液性癌中的差别不显著，但ＣＥＡ在浆液性癌中表达强度低于粘液性癌（Ｐ＜０．０５）；在子宫内膜样癌中三抗原之阳性率和表达强度均较低，故可以辅助鉴别浆液性癌、粘液性癌和官内膜样癌。ＣＥＡ和ＬＩＭＡ大量出现于癌细胞内的肿瘤更具侵袭性，易致肿瘤扩散转移，预后较差。     

S-100 protein in ovarian tumors. A comparative immunohistochemical study of 135 cases

The distribution of S-100 protein in 135 ovarian tumors, of which 127 were epithelial, was investigated using the immunoperoxidase method. S-100 protein has been demonstrated previously in tumors of various origins. The present study further revealed its characteristic distribution in common epithelial tumors of the ovary. S-100 protein was present in 69% of serous tumors (benign, 50%; borderline, 100%; malignant, 71%), as well as in the serous elements of serous & mucinous mixed tumors (30%). S-100 protein was also demonstrated in 25% of clear cell carcinomas and 29% of endometrioid carcinomas. Interestingly, none of the mucinous tumors were positive for S-100 protein. In addition, the expression of S-100 protein by epithelial ovarian tumors was compared with that of CA 125 and carcinoembryonic antigen (CEA). The distribution of S-100 protein was similar to that of CA 125, since both antigens were frequently present in serous tumors, although their expression patterns were different. On the other hand, S-100 protein-positive cases were almost negative for CEA or vice versa. Our observations indicate that demonstration of S-100 protein in common epithelial tumors of the ovary and comparison of S-100 protein distribution with that of CA 125 and CEA may further clarify the characteristics of common epithelial tumors of the ovary.     

Ovarian carcinomas: five distinct diseases with different origins,genetic alterations,and clinicopathological features

Malignant epithelial tumors (carcinomas) are the most common ovarian cancers and also the most lethal gynecological malignancies. Based on histopathology and molecular genetic alterations, ovarian carcinomas are divided into five main types (high-grade serous (70%), endometrioid (10%), clear cell (10%), mucinous (3%), and low-grade serous carcinomas (<5%)) that account for over 95% of cases. These types are essentially distinct diseases, as indicated by differences in epidemiological and genetic risk factors, precursor lesions, patterns of spread, and molecular events during oncogenesis, response to chemotherapy, and prognosis. For a successful specific treatment, reproducible histopathological diagnosis of the tumor cell type is critical. The five tumor types are morphologically diverse and resemble carcinomas of the uterus. Actually, recent investigations have demonstrated that a significant number of cancers, traditionally thought to be primary ovarian tumors (particularly serous, endometrioid, and clear cell carcinomas), originate in the fallopian tube and the endometrium and involve the ovary secondarily. This review summarizes recent advances in the molecular pathology which have greatly improved our understanding of the biology of ovarian carcinoma and are also relevant to patient management.     

S-100 Protein in Ovarian Tumors

The distribution of S 100 protein in 135 ovarian tumors, of which 127 were epithelial, was investigated using the im-munoperoxidase method. S 100 protein has been demonstrated previously in tumors of various origins. The present study further revealed its characteristic distribution in common epithelial tumors of the ovary. S 100 protein was present in 69% of serous tumors (benign, 50%; borderline, 100%; malignant, 71%), as well as in the serous elements of serous & mucinous mixed tumors (30%). S 100 protein was also demonstrated in 25% of clear cell carcinomas and 29% of endometrioid carcinomas. Interestingly, none of the mucinous tumors were positive for S 100 protein. In addition, the expression of S-100 protein by epithelial ovarian tumors was compared with that of CA 125 and carcinoembryonic antigen (CEA). The distribution of S 100 protein was similar to that of CA 125, since both antigens were frequently present in serous tumors, although their expression patterns were different. On the other hand, S 100 protein positive cases were almost negative for CEA or vice versa. Our observations indicate that demonstration of S 100 protein in common epithelial tumors of the ovary and comparison of S-100 protein distribution with that of CA 125 and CEA may further clarify the characteristics of common epithelial tumors of the ovary.     

Fallopian tube precursors of ovarian low‐ and high‐grade serous neoplasms

Traditionally, it was thought that ovarian high‐grade serous carcinoma arises from the ovarian surface epithelium and epithelial inclusion glands and that the pathogenesis is de novo; nonetheless, a convincing precursor in the ovary or peritoneum has not been identified to date. During the last few years, however, there has been a dramatic shift in thinking, and a candidate precursor is now recognized in the fallopian tube, especially within the fimbriated end – serous tubal intra‐epithelial carcinoma (STIC). Accordingly, STIC is probably the earliest histologically recognizable lesion in the pathogenesis of high‐grade serous carcinoma, but steps in this pathway which precede STIC have also been proposed. With subsequent progression, STIC implants onto the ovary and then develops into an invasive high‐grade serous carcinoma with rapid tumour growth. For invasive low‐grade serous carcinoma, it is well‐established that its pathogenesis begins with serous cystadenoma/adenofibroma, which develops sequentially into atypical proliferative serous tumour (typical serous borderline tumour), non‐invasive micropapillary (low‐grade) serous carcinoma (micropapillary serous borderline tumour) and then invasive low‐grade serous carcinoma in a relatively slow stepwise process. It is presumed that cystadenoma/adenofibroma arises from epithelial inclusion glands in the ovary, but recent evidence suggests that epithelial inclusion glands originate in the fallopian tube. Alternatively, it has been proposed that the other early precursors in the low‐grade pathway, including serous borderline tumours, non‐invasive implants and endosalpingiosis, may also arise directly from tubal mucosa. Therefore, the precursor of most ovarian high‐grade serous carcinomas originates in the fallopian tube, and that for low‐grade serous tumours may also be derived from the tube. This review paper provides an overview of the fallopian tube's potential role in the pathogenesis of both types of serous neoplasms of the ovary.     

Aberrant hypermethylation of RASSF1A promoter in ovarian borderline tumors and carcinomas

The newly identified 3p21.3 tumor suppressor gene RASSF1A is inactivated by hypermethylation in variable solid tumors, including those of the lung, breast, prostate, kidney, and ovary. The purpose of this study was to evaluate the methylation status of RASSF1A in various types and stages of ovarian epithelial tumors. We analyzed the DNA methylation status of ovarian tumors using methylation-specific polymerase chain reaction in 54 frozen ovarian tumor tissues and in 97 cases of archival ovarian serous epithelial tumors using a microdissection procedure. Hypermethylation statuses were examined vs clinicopathologic findings. RASSF1A promoter methylation rates in the various types of fresh ovarian tissues were as follows: serous cystadenoma (1/5), serous tumor of borderline malignancy (2/7), serous adenocarcinoma (4/10), mucinous cystadenoma (0/5), mucinous tumor of borderline malignancy (2/7), mucinous adenocarcinoma (3/6), transitional-cell carcinoma (1/3), clear-cell carcinoma (3/3), and malignant müllerian mixed tumor (3/3). In archived serous tumor tissues, RASSF1A promoter hypermethylation was detected in serous cystadenoma (1/6, 16.6%), serous tumor of borderline malignancy (20/41, 48.8%), and in serous adenocarcinoma (25/50, 50%). The status of RASSF1A hypermethylation in borderline tumors was found to correlate statistically with the presence of microinvasion (p=0.002), peritoneal implant (p<0.001), and bilaterality (p=0.019). The RASSF1A promoter hypermethylation was frequently found in borderline tumors and carcinomas, suggesting that RASSF1A promoter hypermethylation may be a useful molecular marker for the early detection of ovarian tumors.     

Expression of Tn and sialyl-Tn antigens in tumor tissues of the ovary.

The expression of sialyl-Tn and Tn antigens in various benign, borderline, and malignant ovarian tumors was examined immunohistochemically using newly developed antibodies specific for sialyl-Tn and Tn antigens. Sialyl-Tn antigen was detected in only one benign tumor, a mucinous adenoma that showed faint cytoplasmic staining in a few cells. However, sialyl-Tn was present in 5 of 12 serous borderline tumors, 10 of 19 mucinous borderline tumors, 10 of 13 serous adenocarcinomas, 15 of 16 mucinous adenocarcinomas, 14 of 15 endometrioid adenocarcinomas, and 7 of 7 clear cell carcinomas of the ovary. The antigen expression was observed throughout the cytoplasm of cancer cells and in the apical cytoplasm and luminal contents of some glands. The incidence and intensity of staining for sialyl-Tn antigen were higher in malignant tumors than in borderline tumors, but these results did not correlate with the histologic classification or differentiation. Coexpression of sialyl-Tn antigen and Tn antigen was observed in two serous adenocarcinomas, six mucinous borderline tumors, five mucinous adenocarcinomas, eight endometrioid, and seven clear cell carcinomas. In no case was Tn antigen expressed without concomitant sialyl-Tn antigen expression. Accumulation of sialyl-Tn antigen seems to be an early event of carcinogenesis of the ovary.     

p73基因在卵巢上皮性肿瘤中的表达及甲基化研究

目的 探讨卵巢上皮性肿瘤中p73蛋白的表达和基因启动子的甲基化情况,并观察其与临床病理学特征的关系.方法 制备包括68例卵巢癌、37例卵巢交界性肿瘤和21例卵巢良性肿瘤的组织芯片,用免疫组织化学EnVision法检测上述组织中p73蛋白表达情况,用亚硫酸氧盐修饰后测序法检测13例新鲜卵巢癌组织及5例新鲜卵巢交界性肿瘤组织的p73基因启动子甲基化情况.结果 92.6％ (63/68)的卵巢癌表达p73,p73蛋白总体表达率均值为32％(p73表达率指p73阳性细胞数所占的百分比),其中浆液性癌( 26/26)的表达率均值为40％,高于其他组织类型的癌(P=0.006).按照卵巢癌发病模式区分,Ⅱ型卵巢癌p73表达率均值(40％)高于Ⅰ型卵巢癌(24％),P=0.010.卵巢癌中p73的表达与临床分期及组织学分级无相关性(均P＞0.05).卵巢交界性肿瘤组(30/37)和良性肿瘤组(12/21)p73的总体表达率均值分别为16％和15％,该两组肿瘤中浆液性肿瘤表达率均值均高于黏液性肿瘤(P-0.003,P=0.026).卵巢癌组的p73阳性表达率均值明显高于交界性肿瘤组和良性肿瘤组(均P ＜0.05),交界性肿瘤组与良性肿瘤组比较差异无统计学意义(P＞0.05).浆液性肿瘤( 49/53)中,卵巢癌组(26/26) p73阳性表达率均值明显高于交界性肿瘤组(12/14)和良性肿瘤组(11/13;P =0.024和P=0.002),而卵巢交界性肿瘤组和良性肿瘤组比较差异无统计学意义(P=0.428).黏液性肿瘤(15/27)中,卵巢癌组(6/7)p73阳性表达率均值高于良性肿瘤组( 1/8;p=0.032),而卵巢癌组与卵巢交界性肿瘤组(8/12)、交界性肿瘤组与良性肿瘤组比较,差异均无统计学意义(P=0.234和P=0.201).p73启动子的甲基化结果显示,13例卵巢癌有8例发生甲基化,但每例样本甲基化频率有所不同,总体甲基化频率均值为8.0％.5例交界性肿瘤有2例发生甲基化,总体甲基化频率均值为9.0％,两组比较差异无统计学意义(P＞0.05).卵巢癌组p73甲基化额率与组织类型、发病模式、组织学分级及临床分期均无相关性(均P＞0.05).结论 卵巢上皮性肿瘤多数表达p73,卵巢癌p73的表达率均值明显高于交界性肿瘤和良性肿瘤,浆液性肿瘤高于其他组织类型;p73蛋白表达率与p73基因甲基化程度不存在简单线性相关关系.