Ovarian serous borderline tumors: a critical review of the literature with emphasis on prognostic indicators

BACKGROUND: The behavior of ovarian serous borderline tumors (SBTs) and significance of various prognostic factors are unclear and difficult to evaluate because of inconsistencies and confusion in the literature. Recent studies have suggested that the morphological features of the primary tumor (presence or absence of micropapillary features) and the peritoneal "implants" (presence or absence of invasive features) can reliably subclassify SBTs into benign and malignant types. The aim of the current review was to test two hypotheses. First, that the alleged malignant behavior of SBTs is poorly documented, and second, that the morphological features of the primary ovarian tumors and the associated peritoneal implants are sufficient to separate SBTs into benign and malignant types, thereby obviating the need for the category. METHODS: 245 studies reporting approximately 18,000 patients with borderline ovarian tumors were reviewed. After excluding series that lacked clinical follow-up or were not analyzable for other reasons, there remained 97 reports that included 4,129 patients. In addition to recurrences and survival, we evaluated the type of peritoneal implants, microinvasion, lymph node involvement, late recurrences, and progression to carcinoma, as these features have served as the underpinning of the concept of "borderline malignancy" or "low malignant potential." RESULTS: Among 4,129 patients with SBTs reviewed, the recurrence rate after a mean follow-up of 6.7 years was 0.27% per year for stage I tumors, the disease-free survival was 98.2%, and the overall disease-specific survival rate was 99.5%. For patients with advanced-stage tumors, the recurrence rate was 2.4% per year. However, the majority (69%) of reported recurrences were not pathologically documented, and only 26 cases (8.4% of all recurrences) were documented to have recurred from an adequately sampled ovarian tumor. The most reliable prognostic indicator for advanced stage tumors was the type of peritoneal implant. After 7.4 years of follow-up, the survival of patients with noninvasive peritoneal inplants was 95.3%, as compared with 66% for invasive implants (P < .0001). Microinvasion in the primary ovarian tumor was associated with a 100% survival rate at 6.7 years, and lymph node involvement was associated with a 98% survival rate at 6.5 years. The few reported cases of stage IV disease, progression to invasive carcinoma, and very late (>20 years) recurrences were poorly documented. The survival for all stages among approximately 373 patients in 6 prospective randomized trials followed for a mean of 6.7 years was 100%. CONCLUSION: Surgical pathological stage and subclassification of extraovarian disease into invasive and noninvasive implants are the most important prognostic indicators for SBTs. Survival for stage I tumors is virtually 100%. Survival for advanced stage tumors with noninvasive implants is 95.3%, whereas survival for tumors with invasive implants is 66%. Invasive implants behave as carcinomas and are most likely metastatic. The precise nature of so-called noninvasive implants is not clear, but they behave in a benign fashion. The presence of a micropapillary architecture in the primary ovarian tumor is a strong predictor of invasive implants. These data support the recommendation that ovarian tumors with a micropapillary architecture be designated "micropapillary serous carcinomas," and those lacking these features, "atypical proliferative serous tumors."     

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.     

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.     

Uncommon ovarian epithelial tumours

Epithelial ovarian tumours represent the most common type of ovarian tumour. Most of malignant cases represent high-grade serous, clear cell and endometrioid carcinomas; borderline serous and mucinous tumours of intestinal type are less common. This review focuses on the uncommon or rare epithelial tumours of the ovary which include borderline and malignant Brenner tumours, the recently-described mesonephric-like carcinoma of the ovary, and primary ovarian neuroendocrine tumours, with emphasis on helpful and diagnostic features.     

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.     

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.     

Ovarian serous cystadenofibromas associated with a low-grade serous carcinoma of the peritoneum

Ovarian serous cystadenofibromas are benign neoplasms that sometimes have focal areas of borderline serous tumor and rarely have been associated with epithelial proliferations in the peritoneum, resembling implants. We are reporting 2 cases of ovarian serous cystadenofibromas with serous peritoneal lesions of higher grade than the ovarian tumor: 1 case had a serous carcinoma and another 1 a serous borderline tumor.     

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.     

Inhibitory role of prohibitin in human ovarian epithelial cancer

Objectives: To characterize the exact individual roles of gonadotropins on ovarian epithelial carcinogenesis, an earlier study showed that prohibitin was significantly up-regulated by luteinizing hormone (LH). To further clarify the role of prohibitin in ovarian carcinogenesis and its association with LH, herein we studied the expression of prohibitin in various ovarian tissues including different developmental stages of ovarian epithelial tumors. Methods: A total of 135 samples were studied by immunohistochemistry. These included benign ovarian cases with follicles, ovarian surface epithelia and ovarian epithelial inclusions (OEI) (n=30), serous cystadenoma (n=14), serous borderline tumor (n=12), serous carcinoma (n=20), mucinous cystadenoma (n=10), mucinous borderline tumor (n=10), mucinous carcinomas (n=10), endometrioid carcinomas (n=12), poorly/undifferentiated carcinomas (n=5), and fallopian tube (n=12). Results: Strong and diffuse staining of prohibitin was detected in luteinized ovarian stromal cells, follicular cells, fallopian tube, and OEI with serous differentiation. A significantly higher prohibitin expression in luteinized stromal cells than in non-luteinized stromal cells was observed (P<.01). Within the ovarian epithelium, the level of prohibitin expression was basically negative in ovarian surface epithelia, but highly expressed in OEI. However, compared to the level of prohibitin expression in OEI, it showed a trend of gradual loss from benign ovarian tumors, to borderline tumors and to carcinomas (P<.0001). Compared to the serous tumors, epithelial tumors with mucinous differentiation showed a significant lower level of prohibitin (P<.0001). An inverse correlation was noted between prohibitin expression and cancer grade. It is interesting to note that a high prohibitin expression level was seen in the fallopian tube, which is similar to OEI. Conclusions: These data further suggest that prohibitin plays a tumor suppressing role, which is probably associated with LH mediated protection role against ovarian epithelial carcinoma. In addition to the tumor suppressive role of prohibitin, it also plays a role in cellular differentiation, which may be helpful to differentiate ovarian mucinous tumors from the tumors with serous differentiation in clinical settings. More importantly, our findings are supportive that the ovarian epithelial cancers, particularly the serous cancers including those precursors with serous differentiation are likely to be derived from fallopian tube instead of ovarian surface epithelia.     

Expression of Fas and FasL in human serous ovarian epithelial tumors

The expression of Fas and FasL was studied in 86 patients with benign, borderline, and malignant serous ovarian lesions. Four normal ovaries, and monolayer epithelial cultures from a human fetal ovary, a borderline, and a serous adenocarcinoma were used for comparison. Expression of Fas and FasL was studied immunohistochemically and flowcytometrically. Fas was expressed in all 90 lesions; FasL in 57 lesions, including 2 normal ovaries. Fas expression was significantly increased in borderline tumors compared with benign (P = 0.005, t = -2.94) or malignant serous tumors (P = 0.0001, t = 4.15). FasL expression was significantly increased in malignant tumors compared with benign (P = 0.039, t = -2.10) and borderline tumors (P = 0.0016, t = -3.33). Flow cytometry showed a range of Fas expression in short-term cultures isolated from normal, borderline, and malignant ovarian serous tissue; in the few samples studied, FasL was not expressed. Expression in three serous ovarian cell lines was similar. Fas and FasL expression differed throughout the spectrum of ovarian lesions. FasL expression was increased in malignant tumors, and Fas expression was increased in borderline tumors. Changes in Fas/FasL expression in ovarian surface epithelium might play a functional role in the biology of ovarian tumors.     

K-RAS mutations in ovarian and extraovarian lesions of serous tumors of borderline malignancy

K-RAS mutations are the most frequent molecular genetic alteration in serous ovarian tumors of borderline malignancy (SBOT). The pathogenesis of associated contralateral tumors and extraovarian implants and Müllerian inclusion cysts is obscure. We hypothesized that the comparison of K-RAS mutations in these lesions might help to distinguish multifocal from metastatic foci. Eight cases of SBOT with known K-RAS mutation (RAS+) and two cases without mutation (RAS-) were analyzed for comparison. DNA was extracted from multiple samples of 58 paraffin-embedded and laser-microdissected ovarian and extraovarian lesions (10 ovarian borderline tumors, 8 contralateral tumors, 25 implants, 15 inclusion cysts; total: 97 samples). K-RAS exon 1 was amplified by PCR and analyzed by denaturing gradient gel electrophoresis and cycle sequencing. In 12 of 14 SBOT and in 2 of 2 extraovarian implants, the K-RAS mutation could be found in different areas of the same lesion, indicating monoclonality. All RAS+ ovarian borderline tumors with contralateral tumors (six of six) harbored an identical mutation in both ovaries (in one case, a separate surface borderline tumor component contained a different mutation in addition). In 4 of 5 RAS+ ovarian tumors with extraovarian lesions, RAS mutations were also found in implants (15/21 implants [71%]) and more rarely in inclusion cysts (3 of 12 lesions [25%]). These extraovarian mutations were always identical to the one in the ovary (18 of 18 [100%]). Regarding the contralateral and extraovarian lesions of the two RAS- SBOT, only one extraovarian implant contained a RAS mutation. The demonstration of K-RAS mutations in Müllerian inclusion cysts and implants of SBOT suggests that K-RAS mutations represent a pivotal event during neoplastic transformation of ovarian and extraovarian serous epithelium. Considering our observations, the two putative pathogenetic mechanisms for the development of implants and endosalpingiosis-multifocal tumorigenesis and spread from the ovarian primary tumor-seem to coexist.     

卵巢浆液性和粘液性交界瘤的临床病理分析

目的：观察卵巢交界瘤的临床病理学特点,探索肿瘤不同组织学改变的意义。方法：对45例卵巢浆液性和粘液性交界瘤进行回顾性分析,肿瘤分期按国际妇产科联合会（FIGO）标准,Ⅰ期34例,Ⅱ期4例,Ⅲ期7例。结果：45例卵巢浆液性和粘液性交界瘤占同期卵巢上皮恶性肿瘤的25．4％,浆液性同粘液性交界瘤的比为1：1．3,11例生长于卵巢表面的浆液性交界瘤中,9例出现腹膜种植,2例为浸润性种植,7例为非浸润性种植。2例浆液性交界瘤和1例粘液性交界瘤分别于术后5、4和1年复发。33例交界瘤经2－9年随访,按Kaplan-Meier法5年生存率为100％。结论：卵巢浆液性交界瘤预后较好,卵巢表面生长的浆液性交界瘤常伴有腹膜种植。     

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.     

Ovarian tumors of borderline malignancy (tumors of low malignant potential): a critical appraisal.

Before the designations borderline malignancy and low malignant potential were used, the surface epithelial-stromal tumors of the ovary were simply classified into benign and malignant categories. The introduction of the borderline category of tumors has been a great advancement in classification, because it has set apart from the general group of surface epithelial cancers a subgroup with a much better prognosis, stage-for-stage, than that of conventional ovarian carcinomas. Over the last 20 years, pathologists have learned to recognize the distinctive clinicopathologic features of serous borderline tumors as well as the adverse prognostic significance of the associated invasive peritoneal lesions, whether they may represent true implants or independent primary tumors. We have urged our surgical colleagues to search for the peritoneal lesions, and sample them meticulously, and advised our fellow oncologists not to administer adjuvant therapy to patients with noninvasive implants lacking malignant epithelial cells. There is now convincing evidence in the literature that the only fatal cases of serous borderline tumors are those associated with invasive implants, and chemotherapy is indicated only for these rare tumors. It has also been demonstrated that Stage I intestinal mucinous borderline tumors and noninvasive well-differentiated mucinous carcinomas both have an almost equally good prognosis. The current treatment for pseudomyxoma peritonei is still unsatisfactory, but we have recently learned that most of the mucinous ovarian tumors associated with pseudomyxoma peritonei are secondary to similar tumors of the appendix. In the remaining cases, however, the ovarian tumor appears to be responsible for the pseudomyxoma peritonei. Borderline tumors also exist in the endometrioid, clear cell, and Brenner surface epithelial categories, but these tumors have been too rare for clear delineation of their clinical and pathologic features. Recently, some investigators have proposed to abandon the borderline category and to return to the old benign-malignant classification system by dividing unevenly the borderline tumors into a larger group of atypical proliferative epithelial cystadenomas and a smaller category of recently described but still not well-characterized noninvasive carcinomas. In the author's opinion, such a recommendation is misleading because it ignores the possibility of rare but significant behavioral exceptions on each of these two groups of tumors. Furthermore, careful tumor staging is mandatory in both instances regardless of the type of terminology used. It is hoped that by keeping the borderline designation, knowledge on this group of ovarian tumors will continue to expand as it has been until now.     

Evolution of the concept and termiology of borderline ovarian tumours

The borderline category of ovarian tumours was established in the early 1970s because of the observation that a group of proliferative epithelial ovarian tumours lacking invasion that generally behaved in a benign fashion occasionally pursued an indolent malignant course. Over the last 25 years, a large database on these tumours has been accrued. Recent studies suggest that the borderline group can now be subclassified into benign and malignant neoplasms. The survival for patients with serous borderline tumours confined to the ovaries is virtually 100%. Patients with ovarian serous borderline tumours with invasive peritoneal implants have a 34% mortality rate; therefore, these cases are classified as low grade carcinomas. Micropapillary serous carcinoma, a distinctive neoplasm that fails to display unequivocal evidence of invasion and therefore has been included in the borderline category, is strongly associated with invasive implants and recurs as invasive carcinoma. After these neoplasms with invasive implants are excluded from the group of tumours classified as borderline, the remaining advanced stage serous borderline tumours (those with non-invasive implants) have a disease-specific survival rate of nearly 100% and should be considered benign. In a similar fashion, the vast majority of mucinous borderline tumours reported to display aggressive behaviour have been associated with the clinical syndrome of pseudomyxoma peritonei. It is now clear that pseudomyxoma peritonei is a condition of appendiceal origin in virtually all cases. In addition, there is a small group of mucinous carcinomas typically from the pancreas and biliary system that present with relatively bland-appearing metastases to the ovaries that closely simulate mucinous borderline tumours. Once these metastatic carcinomas and mucinous tumours associated with pseudomyxoma peritonei are removed from the borderline category, the remaining mucinous borderline tumours are always confined to the ovaries and have a benign behaviour. Finally, review of the literature indicates the other epithelial types of borderline tumours (endometrioid, clear cell and transitional cell) behave in a benign fashion. Since borderline tumours can now be classified into benign and malignant types, the borderline category has no further utility and can be abandoned. This will be of great benefit to patients and clinicians, and will also help in more clearly focusing research efforts on ovarian cancer.     

Value of elastin staining in the assessment of peritoneal implants associated with ovarian serous borderline tumours

AIMS: To determine whether elastin stains aid in classifying peritoneal implants associated with ovarian serous borderline tumours (SBT). METHODS AND RESULTS: The study group comprised 80 implants (nine invasive and 71 non-invasive) from 28 patients with ovarian SBT. Elastin stains were performed using histochemical and immunohistochemical methods to demonstrate the peritoneal elastic lamina (PEL), and evaluated with regard to assessment of the subtype of implant. The elastin stains demonstrated the PEL in most anatomical sites other than the omentum and the bladder and were considered helpful in 44/80 (55%) cases. The stains were most useful in the assessment of poorly oriented or traumatized biopsy specimens and in confirming the superficial distribution of non-invasive implants. The staining was non-contributory in most of the remaining biopsies, because the PEL was not identified. CONCLUSIONS: Demonstration of the PEL using elastin stains can be useful in the subclassification of implants associated with ovarian SBT and is of most value in confirming the superficial distribution of non-invasive lesions. However, evaluation is limited by the absence of a defined elastic layer in a proportion of biopsy specimens, possibly reflecting their superficial location, as well as absence of a distinct PEL in sites such as the omentum.     

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.     

p53 protein expression in putative precursor lesions of epithelial ovarian cancer

p53 protein expression has been studied in epithelial inclusion cysts adjacent to and contralateral to serous carcinoma of the ovary and compared to epithelial inclusion cysts associated with borderline tumours and in normal ovaries. Atypia was found in epithelial inclusion cysts in eight of the thirteen advanced (stage III) serous ovarian carcinomas. Of these eight with atypical epithelial inclusion cysts, five showed immunoreactivity for p53. In the borderline tumours and normal ovaries no atypia in such cysts was found. p53 expression was also seen more frequently in surface epithelium associated with ovarian serous adenocarcinoma (ten of 13) than in normal ovaries (one of 13). We postulate that focal areas of atypia (ovarian intra-epithelial neoplasia) in epithelial inclusion cysts are the precursors of ovarian malignancy. In some cases, at least, p53 protein expression may precede overt cytological abnormalities.     

Ephrin B expression in epithelial ovarian neoplasms correlates with tumor differentiation and angiogenesis

Differential gene expression studies are identifying new sets of genes with a role in the classification, differential diagnosis, and prognosis of some human tumors. Ephrin B1, a factor involved in angiogenesis, has been shown to be up-regulated in ovarian carcinomas, making it a potential target for cancer treatment. This study investigates ephrin B expression in ovarian tumors to validate results from gene expression studies and evaluates its significance with a clinical-pathological correlation. Specimens from 112 benign, borderline, and malignant epithelial ovarian tumors were examined. Tissue microarrays were constructed, and ephrin B expression was studied by immunohistochemistry. To correlate ephrin B expression with angiogenesis, CD31 immunostaining was performed to assess microvessel density. Ephrin B was detected in 50% of ovarian tumors: clear cell carcinomas (93%), serous carcinomas (74%), mucinous carcinomas (29%), and endometrioid carcinomas (27%). High-grade carcinomas showed greatest ephrin B expression, whereas benign tumors and low-grade carcinomas were rarely positive. A correlation was found between ephrin B expression and microvessel density, supporting the angiogenic role of this factor in ovarian carcinomas. Ephrin B expression was associated with higher rates of disease recurrence and a decrease in overall survival. A distinctive pattern of ephrin B expression was observed in ovarian tumors: high-grade tumors and clear cell and serous carcinomas show higher expression, correlating with the aggressiveness. On the other hand, ephrin B expression correlated with microvessel density of the tumors. Because Eph receptors and ephrins are targets for new therapeutic inhibitors, this pattern of ephrin B expression should be considered in future clinical studies.     

Primary papillary serous neoplasia of the peritoneum: a clinicopathologic and ultrastructural study of eight cases

The well-documented but rare primary papillary serous peritoneal tumors are difficult problems for the pathologist and the clinician. Because of their unusual location, these tumors are often classified as mesothelioma or advanced ovarian carcinoma. In this study, we report the clinicopathologic features of eight primary peritoneal serous papillary tumors and compare their histologic and ultrastructural features to 12 serous ovarian tumors and 16 epithelial mesotheliomas (two peritoneal and 14 pleural). The eight peritoneal serous papillary tumors occurred in women aged 19 to 75 years; two were serous tumors of low malignant potential (borderline) and six were serous carcinomas. The tumors were located in the mesosalpinx, left pelvis, omentum, and/or surface of the ovary. The two patients with borderline neoplasms had long disease-free survival (11 years and 20 years), while three of the four patients with carcinoma with more than 1 year of follow-up died of disease. The peritoneal serous papillary tumors were morphologically identical to serous ovarian tumors of equivalent grade. Well-differentiated papillary structures with distinct fibrovascular cores and one or several layers of columnar, crowded cells, dense overlapping nuclei with a long axis perpendicular to the surface of the papillary cores, and numerous psammoma bodies were features of the peritoneal and ovarian serous tumors. In contrast, the tubulo-alveolar, solid, or poorly defined papillary structures lined by well-spaced polygonal to cuboidal cells with abundant cytoplasm, absence of nuclear polarity, and infrequent psammoma bodies characterized the mesotheliomas. Epithelial mucin and carcinoembryonic antigen (CEA) immunoreactivity, when present, supported a diagnosis of serous tumor in these generally mucin-poor and CEA-negative neoplasms. Ultrastructurally, the cells of serous tumors had slender, straight microvilli of variable length interspersed with or without cilia, while the nonciliated cells of mesothelioma had long, exuberant, wavy microvilli. The morphologic and clinical features of the peritoneal papillary serous tumors are distinctive enough to warrant their separation from mesotheliomas.