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.     

Expression of hepatocyte nuclear factor-1beta (HNF-1beta) in clear cell tumors and endometriosis of the ovary.

Clear cell tumors of the ovary are frequently associated with ovarian endometriosis. Clinicopathologically, it has been suggested that clear cell tumors develop from endometriosis, but there has been little molecular evidence supporting this speculation. Microarray analysis revealed recently that hepatocyte nuclear factor-1beta (HNF-1beta) was significantly upregulated in clear cell carcinoma of the ovary. In the present study, we examined 30 clear cell tumors (26 malignant, three borderline, and one benign) and 40 endometriotic cysts to clarify if differentiation into the clear cell lineage already begins in ovarian endometriosis. All of the 30 clear cell tumors, including borderline and benign ones, showed immunohistochemical expression of HNF-1beta in the nucleus, while other types of ovarian epithelial tumors (endometrioid, serous, mucinous, and Brenner tumors) rarely expressed it. Among 30 clear cell tumors, 17 (56%) cases were associated with endometriosis, and endometriotic epithelium was identified in 12 cases. In nine of the 12 cases, distinct nuclear immunostaining for HNF-1beta was detected in the endometriotic epithelium, as well as in the clear cell tumor. HNF-1beta expression was observed either in atypical endometriosis (four cases), or in endometriosis of a reactive nature (five cases). Furthermore, 16 of 40 (40%) endometriotic cysts without a neoplasm also expressed HNF-1beta, and the expression was almost exclusively observed in the epithelium showing inflammatory atypia. Our results indicate that HNF-1beta is an excellent molecular marker for ovarian clear cell tumors, including benign, borderline and malignant lesions. Early differentiation into the clear cell lineage takes place in ovarian endometriosis, not only in atypical endometriosis, but also in endometriosis with degenerative and regenerative changes, and this is probably responsible for the frequent occurrence of clear cell carcinoma in ovarian endometriosis.     

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.     

Histological classification of ovarian cancer

The histology of ovarian tumors exhibits a wide variety of histological features. The histological classification of ovarian tumors by the World Health Organization (WHO) is based on histogenetic principles, and this classification categorizes ovarian tumors with regard to their derivation from coelomic surface epithelial cells, germ cells, and mesenchyme (the stroma and the sex cord). Epithelial ovarian tumors, which are the majority of malignant ovarian tumors, are further grouped into histological types as follows: serous, mucinous, endometrioid, clear cell, transitional cell tumors (Brenner tumors), carcinosarcoma, mixed epithelial tumor, undifferentiated carcinoma, and others. Clear cell and endometrioid carcinomas are highly associated with endometriosis. In stage distribution, serous carcinoma is found predominantly is stage III or IV. In contrast, clear cell and endometrioid carcinomas tend to remain confined to the ovary. Clear cell and endometrioid carcinomas may be unique histological types compared with serous carcinomas with respect to stage distribution and association with endometriosis.     

Ovarian epithelial tumours: common problems in diagnosis

Ovarian cancer is the most lethal gynaecological malignancy, with epithelial tumours being the largest group (90%). Although most ovarian tumours create no histological diagnostic problems, a small proportion may be subject to misinterpretation resulting in serious clinical implications. The following are the most commonly encountered problems in surgical pathology practice: (1) deciding whether a malignant ovarian tumour is primary or secondary; (2) the problem of borderline epithelial tumours; (3) misinterpretation of some variants of endometrioid carcinoma; (4) realizing the existence of an admixture of epithelial patterns in a single tumour—e.g. serous plus endometrioid, endometrioid plus clear cell plus serous, etc.; and (5) distinguishing poorly differentiated carcinomas from non-epithelial undifferentiated tumours. In this review an attempt to address these problems is presented with some illustrative examples.     

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.     

Ovarian tumors associated with atypical endometriosis

We present five cases in which ovarian neoplasms (three clear cell carcinomas, two endometrioid carcinomas) were associated--and in four cases contiguous--with atypical glandular epithelial changes in endometriosis. This association has not been reported previously in the ovary, but four cases of extragonadal malignant tumors have been noted to occur with or after atypical endometriosis. We propose that a diagnosis of atypical endometriosis be followed by careful long-term observation of the patient to detect possible subsequent development of neoplasia.     

Preneoplasias of ovarian carcinoma: biological and clinical aspects of different pathways of tumorigenesis

Ovarian carcinomas consist of a heterogeneous group of malignant epithelial neoplasms with specific pathogenic mechanisms. This review provides a brief introduction to the different pathways of tumor progression and the associated molecular changes. However, the main focus will be on two areas with major paradigm shifting developments in recent years. Mutational analysis of ovarian clear cell carcinomas, endometrioid carcinomas and endometriotic lesions identified mutations in the ARID1A gene as common and early genetic changes in carcinomas with associated endometriosis and in atypical endometriosis itself. Extensive pathological work-up of the fallopian tubes of BRCA1/2 mutation carriers have demonstrated the existence of serous tubal intraepithelial carcinomas (STIC). Further studies showed that this lesion can also be found in 50-60% of patients with serous ovarian carcinomas without BRCA1/2 germline mutations. Pre-precursors which share the p53 mutations with STICs but proliferate very little are called p53-signatures and provide conclusive evidence that STICs develop in the fallopian tubes.     

In ovarian neoplasms, BRAF, but not KRAS, mutations are restricted to low-grade serous tumours

Genes of the RAF family, which mediate cellular responses to growth signals, encode kinases that are regulated by RAS and participate in the RAS/RAF/MEK/ERK/MAP-kinase pathway. Activating mutations in BRAF have recently been identified in melanomas, colorectal cancers, and thyroid and ovarian tumours. In the present study, an extensive characterization of BRAF and KRAS mutations has been performed in 264 epithelial and non-epithelial ovarian neoplasms. The epithelial tumours ranged from adenomas and borderline neoplasms to invasive carcinomas including serous, mucinous, clear cell, and endometrioid lesions. It is shown that BRAF mutations in ovarian tumours occur exclusively in low-grade serous neoplasms (33 of 91, 36%); these included serous borderline tumours (typical and micropapillary variants), an invasive micropapillary carcinoma and a psammocarcinoma. KRAS mutations were identified in 26 of 91 (29.5%) low-grade serous tumours, 7 of 49 (12%) high-grade serous carcinomas, 2 of 6 mucinous adenomas, 22 of 28 mucinous borderline tumours, and 10 of 18 mucinous carcinomas. Of note, two serous borderline tumours were found to harbour both BRAF and KRAS mutations. The finding that at least 60% of serous borderline tumours harbour mutations in two members of the ERK-MAP-kinase pathway (BRAF 36%, KRAS 30%) compared with 12% of high-grade serous carcinomas (BRAF 0%, KRAS 12%) indicates that the majority of serous borderline tumours do not progress to serous carcinomas. Furthermore, no BRAF mutations were detected in the other 173 ovarian tumours in this study.     

Loss of BAF250a (ARID1A) is frequent in high-grade endometrial carcinomas

Mutation of the ARID1A gene and loss of the corresponding protein BAF250a has recently been described as a frequent event in clear cell and endometrioid carcinomas of the ovary. To determine whether BAF250a loss is common in other malignancies, immunohistochemistry (IHC) for BAF250a was performed on tissue microarrays (TMAs) in more than 3000 cancers, including carcinomas of breast, lung, thyroid, endometrium, kidney, stomach, oral cavity, cervix, pancreas, colon and rectum, as well as endometrial stromal sarcomas, gastrointestinal stromal tumours, sex cord-stromal tumours and four major types of lymphoma (diffuse large B cell lymphoma, primary mediastinal B cell lymphoma, mantle cell lymphoma and follicular lymphoma). We found that BAF250a loss is frequent in endometrial carcinomas but infrequent in other types of malignancies, with loss observed in 29% (29/101) of grade 1 or 2 and 39% (44/113) of grade 3 endometrioid carcinomas of the endometrium, 18% (17/95) of uterine serous carcinomas and 26% (6/23) of uterine clear cell carcinomas. Since endometrial cancers showed BAF250a loss, we stained whole tissue sections for BAF250a expression in nine cases of atypical hyperplasia and 10 cases of atypical endometriosis. Of the nine cases of complex atypical endometrial hyperplasia, all showed BAF250a expression; however, of 10 cases of atypical endometriosis (the putative precursor lesion for ovarian clear cell and endometrioid carcinoma), one case showed loss of staining for BAF250a in the atypical areas, with retention of staining in areas of non-atypical endometriosis. This was the sole case that recurred as an endometrioid carcinoma, indicating that BAF250a loss may be an early event in carcinogenesis. Since BAF250a loss is seen in endometrial carcinomas at a rate similar to that seen in ovarian carcinomas of clear cell and endometrioid type, and is uncommon in other malignancies, we conclude that loss of BAF250a is a particular feature of carcinomas arising from endometrial glandular epithelium.     

Hyaline globules in ovarian tumours

Hyaline eosinophilic globules have so far been described in a restricted variety of tumour types. We have noted their presence in a variety of gynaecological malignancies, in particular mixed Müllerian tumours and other epithelial ovarian tumours. We therefore studied their incidence and distribution in a series of malignant, borderline and benign epithelial ovarian tumours, and endometrial and endocervical adenocarcinomas. Hyaline eosinophilic globules were found in all 30 mixed Müllerian tumours from various sites in the female genital tract, 22 of 30 clear cell carcinomas, seven of 30 serous, two of 30 mucinous, and one of 30 endometrioid carcinomas examined, and were also seen in metastases from these tumours. They were present in only two of 25 borderline serous, one of 25 borderline mucinous tumours, and in four of 50 benign serous and one of 50 benign mucinous tumours. The globules were not found in any of 25 Brenner tumours examined, nor in 30 endometrial or 30 endocervical adenocarcinomas. The globules were periodic acid–Schiff positive after diastase, stained positively with PTAH, and were immunoreactive for α-1-antitrypsin. This study therefore demonstrates that eosinophilic globules are not specific for any particular tumour. However, their frequency in malignant mixed Müllerian tumours suggests that this diagnosis should be carefully excluded whenever these globules are present in epithelial tumours of the female genital tract.     

The 'incessant menstruation' hypothesis: a mechanistic ovarian cancer model with implications for prevention

Serous, endometrioid, clear cell and mucinous histotypes are the most common epithelial ovarian cancer. Most serous cancers appear to originate from precursor lesions at the fimbriated tubal end, whereas most endometrioid and clear cell cancers seem to derive from atypical endometriosis. Data regarding hormonal factors and associated gynaecologic conditions were critically analysed with the objective of defining a carcinogenic model for sporadic epithelial ovarian cancer complying with epidemiologic and pathologic findings. Oral contraceptives and tubal ligation substantially reduce the risk of serous, endometrioid and clear cell subgroups, but have no significant effect on mucinous tumours, which probably follow a different oncogenic pathway. We hypothesize that serous, endometrioid and clear cell cancers share a common pathogenic mechanism, i.e. iron-induced oxidative stress derived from retrograde menstruation. Fimbriae floating in bloody peritoneal fluid are exposed to the action of catalytic iron and to the genotoxic effect of reactive oxygen species, generated from haemolysis of erythrocytes by pelvic macrophages. This would explain the distal site of tubal intraepithelial neoplasia. Collection of blood inside endometriomas would lead to the same type of genotoxic insult on gonadal endometrial implants. This would explain why endometriosis-associated cancers develop much more frequently in the ovary than at extragonadal sites. In women not seeking conception, bilateral salpingectomy could be advised whenever planning surgery for independent indications, thus possibly reducing cancer risk, while preserving ovarian function. The use of oral contraceptives should be favoured for prolonged periods of time, especially in women with endometriosis, a population at doubled risk of gonadal malignancy.     

Loss of cables, a novel gene on chromosome 18q, in ovarian cancer.

Cables, a cyclin-dependent kinase (cdk) interacting protein, has recently been identified and mapped to human chromosome 18q11. Cables appears to be primarily involved in cell cycle regulation and cell proliferation. Overexpression of Cables in Hela and other cell lines inhibits cell proliferation and tumor formation. We hypothesize that loss of Cables expression is associated with ovarian cancer. To test our hypothesis, we examined Cables expression in the four most common subtypes of ovarian carcinomas: serous, endometrioid, mucinous, and clear cell. In addition, mucinous and serous borderline tumors were also included. Loss of Cables expression was observed at high frequency in ovarian serous (11 of 14 cases, 79%) and endometrioid (5 of 10 cases, 50%) carcinomas. In contrast, strong Cables staining was detected in all clear cell carcinomas (10 cases) and mucinous tumors (5 carcinomas and 5 borderline tumors). The majority of serous borderline tumors (11 of 14 cases, 79%) showed positive Cables staining, with the rest showing focal loss of Cables expression. Furthermore, RT-PCR revealed the lack of Cables mRNA in a human ovarian cancer xenograft. No correlation was noted between loss of Cables and histologic grade, tumor stage, and survival. In conclusion, our results indicate that loss of Cables is common in ovarian serous and endometrioid carcinomas and imply that Cables may be involved in the pathogenesis of these two types of ovarian carcinomas.     

Metallothionein expression and nuclear size in benign,borderline, and malignant serous ovarian tumours

Metallothioneins (MTs) are low-molecular-weight proteins involved in metalloregulatory functions such as cell proliferation, growth, and differentiation. In recent years, MT expression has been linked with carcinogenesis, resistance to cancer therapy, and tumour progression. However, the significance of MT expression in ovarian cancers is at present inadequately documented. In this study, MT immunohistochemistry was performed in 12 benign, 14 borderline, and eight malignant serous tumours of the ovary. The intensity of the immunostaining was evaluated by image analysis. There was a significantly higher number of MT-immunopositive cells in the multilayered epithelial cells of borderline serous tumours (atypical proliferative serous tumours) than in the single layered epithelial cells within the same tumour, and in the single cell layer of benign serous tumours. There was no difference in the expression of MTs in the single layered tumour cells of benign and borderline serous tumours. Significantly higher numbers of MT-immunopositive cells were observed in both the single and the multilayered epithelial cells of serous carcinomas, the highest number being observed in the multiple layers of serous carcinomas. The positively stained malignant tumour cells in both single and multiple layers were larger than the negatively stained cells in benign, borderline, and malignant serous ovarian tumours. There was moderate to intense staining. These findings indicate that there is increased expression of MTs in the progression of malignancy, which could be used as a marker in grading the three groups of ovarian serous tumours and for determining prognosis. Copyright © 1999 John Wiley & Sons, Ltd.     

Emi1 protein accumulation implicates misregulation of the anaphase promoting complex/cyclosome pathway in ovarian clear cell carcinoma.

Clear cell carcinoma is a clinically and pathologically distinct entity among surface epithelial ovarian neoplasms, recognized for its resistance to standard platinum-based chemotherapy at advanced stage disease and poor prognosis. Despite advances in our understanding of the biology of other surface epithelial ovarian neoplasms, very little is known about the molecular genetic mechanisms that are involved in clear cell tumorigenesis. Early mitotic inhibitor-1 (Emi1) protein is a key cell cycle regulator, that promotes S-phase and mitotic entry by inhibiting the anaphase promoting complex. In cell culture systems, overexpression of Emi1 leads to tetraploidy and genomic instability, especially in the absence of normal p53 function. We investigated Emi1 protein expression in ovarian neoplasms using a tissue microarray constructed from 339 primary ovarian surface epithelial (serous, endometrioid, clear cell, and mucinous) and peritoneal (serous) neoplasms, stromal and mesenchymal tumors, germ cell tumors, and normal ovarian tissue. Significant overexpression of Emi1 protein was present in 82% (27/33) clear cell carcinoma, including one borderline tumor in a diffuse, granular cytoplasmic and perinuclear staining pattern, independent of patient age, presence of ovarian and/or pelvic endometriosis, and FIGO stage. In contrast, only 10% (17/177) primary ovarian and primary peritoneal serous carcinomas, 0% (0/10) mucinous carcinomas, and 19% (6/32) endometrioid carcinomas exhibited significant Emi1 protein overexpression. Accumulation of Emi1 protein was not linked to Ki-67 labeling index, but was directly correlated with cyclin E and inversely correlated with ER in clear cell carcinoma (P<0.001). Emi1 protein expression was present in mixed endometrioid/clear cell tumors but absent in tumors with mixed serous/clear cell histology. These findings represent a potentially important insight into the molecular pathway underlying ovarian carcinogenesis and provide a possible cell cycle model for the development and progression of ovarian clear cell carcinoma.     

Endometriosis-related ovarian neoplasms: pathogenesis and histopathologic features

A variety of neoplasms have been described to arise in association with ovarian endometriosis, characterized by younger age, earlier detection at lower stages, and better survival. The molecular pathogenesis of these tumours has become a focus of recent studies. Representative endometriosis-associated neoplasms include endometrioid carcinoma, clear cell carcinoma, seromucinous borderline tumour (endocervical-like mucinous borderline tumour; Müllerian mucinous borderline tumour), squamous cell carcinoma, Müllerian adenosarcoma, and endometrioid stromal sarcoma. Inflammation, oxidative stress by reactive oxygen species, and hyperestronism are implicated in the carcinogenesis of these tumours. A subset of endometriosis are monoclonal in nature and atypical endometriosis is considered to be a source of clear cell and endometrioid carcinomas through a variety of genetic alterations, including somatic mutations of PTEN, PIK3CA, or ARID1A. It is crucial to understand the clinicopathologic features and genetic background of endometriosis-related neoplasms in order to establish strategies for early detection and molecular-targeted therapy.     

卵巢不典型子宫内膜异位症的恶变潜能研究

目的：探讨卵巢不典型子宫内膜异位症的恶变潜能。方法：观察12例合并子宫内膜异位症的子宫内膜样卵巢癌手术标本的形态学特点,并对各例癌组织和癌变子宫内膜异位症组织分别采用微卫星标记检测10q23.3部位的杂合子缺失,结果：12例癌旁子宫内膜异位症的形态学观察结果显示,8例合并嗜酸性上皮化生,5例同时有明显的细胞异型性,符合不典型子宫内膜异位症,并可见与周围癌组织有移行现象,从不典型子宫内膜异位症的病普组织中,有2例检测出与周围癌组织相同位点的基因改变。结论：卵巢的不典型子宫内膜异位症可能是具有恶变潜能的癌前,病变。     

Precursor lesions of ovarian epithelial malignancy

Most ovarian carcinomas arise from the mesothelial surface lining of the ovaries, or from invaginations of this lining into the superficial ovarian cortex to form cortical inclusion cysts. The native ovarian surface mesothelium is of an 'uncommitted' phenotype, and has potential to modulate to epithelial or mesenchymal phenotypes in response to signals such as those associated with ovulation. The exposure of the mesothelial lining of an inclusion cyst to the ovarian stromal microenvironment may be responsible for the phenotypic change to Müllerian epithelium so commonly seen in these cysts. Müllerian metaplasia is usually to a serous phenotype, and it is possible that undefined molecular events occurring in an inclusion cyst that has undergone Müllerian metaplasia may initiate neoplastic change in these cysts. This may be the developmental pathway of most invasive serous carcinomas. Occasional rare cases of ovarian intraepithelial neoplasia, manifested by epithelial atypia in an inclusion cyst or on the surface epithelium without invasive carcinoma, are identified histologically. Serous borderline tumours represent a separate category and in most cases probably do not progress to frank carcinoma. Mucinous carcinomas may in some cases have arisen from pre-existing benign and borderline mucinous tumours. Endometriosis of the ovary is associated with genetic abnormalities and is frequently found in association with clear cell and endometrioid carcinomas, suggesting that in many cases these latter two types of carcinoma may have arisen directly from endometriotic deposits. Ovaries removed prophylactically from women with a family history of ovarian carcinoma or with a mutation in one of the genes predisposing to ovarian carcinoma should be processed in their entirety, and examined closely not just for obviously neoplastic lesions, but also for more subtle morphological abnormalities of the surface epithelium or the epithelium lining cortical inclusion cysts.     

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.     

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.