Quantitation of borderline and malignant mucinous ovarian tumours

Discrimination between borderline and malignant mucinous ovarian tumours is a well-known diagnostic problem. In order to obtain objective reproducible and consistent features for differential diagnosis, 32 quantitative microscopical features were assessed in 10 benign, 10 borderline and 22 malignant mucinous ovarian tumours. There were many significant differences between the three groups, but using multivariate analysis there was 93% agreement between the histopathological assessment of these sections and the qualitative analyses. The following features were useful in the quantitative classification: the mean area, the mean perimeter and the mean of the short axis of the nucleus; the volume percentage of the epithelium; the mitotic activity. In three cases, there was a difference between the original histopathological and computer classification. It was debatable whether the original diagnosis was correct, and therefore, all the cases were independently reassessed blind by three pathologists. Their diagnoses lend strong support to the computer classification in two of the three cases. The computer classification seems therefore to be even better than 93%. The present quantitative techniques are inexpensive, relatively easy to use, and, we believe, have a useful place in diagnostic histopathology.     

Results of conservative management of epithelial malignant and borderline ovarian tumours

Conservative management of at least part of both the ovary and uterus can be proposed in patients with borderline ovarian tumour, in order to preserve fertility potential. This conservative management could be carried out even in patients with borderline ovarian tumour associated with non-invasive peritoneal implants (if complete resection of peritoneal disease has been performed). When facing persistent infertility after this conservative surgery, ovarian induction or an in-vitro procedure could be proposed in patients with an early-stage disease, though the number of attempts must be limited. Removal of the preserved ovary after completion of pregnancy(ies) is unnecessary if patients agree to careful follow-up. In patients with epithelial ovarian cancer, conservative management could safely be performed in young patients who wish to preserve fertility function and who fulfil the following criteria: unilateral tumour (stage IA), grade 1 (and 2?), adequate staging surgery and careful follow-up. Removal of the preserved ovary should be carried out after completion of pregnancy(ies) in order to reduce the risk of ovarian tumour recurrence.     

Benign endometrioid tumours of the ovary and the Müllerian concept of ovarian epithelial tumours

The difficulties of a consistent Müllerian interpretation of the epithelial ovarian tumours include their inconstant hormonal responsiveness, the doubtful nature of the clear cell tumour and the apparent rarity of benign endometrioid forms. The reported frequency figures for the different types of endometrioid tumour suggest that their nature is made evident by proliferation. The appearance of indolent forms is explored by a study of inactive neoplastic areas associated with endometrioid carcinomas, or with proliferating endometrioid tumours or arising in endometriosis. These jointly suggest that most such tumours are identical with inactive 'serous' adenofibromas of glandular pattern and have senile endometrium as their prototype. Increasing proliferation develops more overt endometrioid forms which, if luxuriant, may be associated with corpus carcinoma. The endometrium of pregnancy is probably the prototype of the clear cell tumour, with a corresponding range of cell types. There is tenuous evidence that tumours may respond to steroid hormones if they arise in endometriosis and a difficulty of deducing such an origin is noted. The term 'serous' may be generic and comprise several different tissue types.     

DNA-cytophotometry and immunocytochemistry in ovarian tumours of borderline malignancy and related peritoneal lesions

Summary A total of 34 surgical specimens, obtained from 13 patients with ovarian tumours of borderline malignancy (OTBM), were investigated by conventional histology, immunocytochemistry and DNA cytophotometry. The lesions were obtained by primary ovarian surgery or second-look procedures and altogether comprised 19 (single and bilateral) OTBM, 8 cases of endosalpingiosis, 4 in situ and 2 invasive peritoneal implants and 1 overt adenocarcinoma. The morphological findings were related to follow-up data, which showed neoplasms with clinically malignant behaviour in 2 patients. The histology of the extra-ovarian manifestations was not associated with their immunocytochemical properties or with their DNA content. There were no correlations between the evolution of disease and microscopical features but the clinical course appeared to be linked to the DNA content of the extra-ovarian lesions, which was of greater prognostic importance than DNA ploidy of the ovarian tumours. Recurrence-free survival was noted in all 5 patients with diploid or euploid extra-ovarian proliferations, while the 2 clinically malignant cases fell into the group of 3 patients with noneuploid or aneuploid specimens. DNA estimations may be a methodology which increases the prognostic value of second-look procedures in OTBM patients.Supported by grants from the Hamburger Krebsgesellschaft and the Hamburger Gesellschaft zur Förderung der Krebsbekämpfung     

Impact of gonadotrophins and steroid hormones on tumour cells derived from borderline ovarian tumours

BACKGROUND: Conservative surgery is currently proposed for young patients with borderline ovarian tumours (BOT). For those experiencing infertility, the question of medically assisted procreation is raised. We have evaluated in vitro the proliferation of cultured BOT cells in response to FSH or estradiol (E(2)). METHODS: Primary cell cultures were prepared from BOT. The presence of FSH and E(2) receptors was evaluated by immunochemistry. Cultures in vitro were stimulated with FSH (40 and 200 mUI/ml) or E(2) (300 and 2000 pg/ml) for 96 h and proliferation was evaluated with the WST-1 test. RESULTS: Four primary cultures were obtained that expressed FSH and E(2) receptors to different extents. Growth was generally similar to controls when treated with either FSH or E(2) although 300 pg/ml E(2) caused a significant inhibitory effect on cell proliferation (P = 0.035). CONCLUSION: No stimulatory effect of FSH or E(2) on cultured BOT cells was found, despite the presence of receptors. Although preliminary, these results suggest that gonadotrophins and E(2) could be used in patients experiencing infertility after conservative surgery.     

Expression of a homeobox gene (SIX5) in borderline ovarian tumours

AIMS: To assess the expression of SIX5 (a homeobox gene) mRNA in surface coelomic epithelium, endocervical epithelium, Fallopian tube epithelium, and benign, borderline, and malignant epithelial ovarian tumours. METHODS: 10 normal premenopausal ovaries, 10 normal Fallopian tubes, 10 normal cervices, 10 normal postmenopausal ovaries, 10 benign epithelial ovarian tumours, 10 malignant epithelial ovarian tumours, and 40 borderline epithelial ovarian tumours were studied retrospectively. The tissues had been fixed in formalin and embedded in paraffin wax. The tumours had previously been typed into mucinous, serous, or mixed tumours and assigned to the borderline category according to the FIGO/WHO criteria. Expression was assessed by in situ binding of SIX5 specific sense and antisense riboprobes. Hybridization of the riboprobes was detected using a standard immunohistochemical technique and the results correlated with expression in the normal epithelium of the endocervix, Fallopian tube, surface coelomic epithelium, and ovarian tumours. RESULTS: Expression of SIX5 mRNA was demonstrated in normal Fallopian tube epithelium and normal endocervical epithelium. SIX5 mRNA was not detected in normal ovarian epithelial tissue at any of the times studied during the menstrual cycle. Expression of SIX5 was not shown in benign epithelial ovarian tumours or in any of the malignant epithelial ovarian tumours. In 31 of 37 borderline epithelial ovarian tumours (84%), SIX5 expression was found in the epithelial cells. CONCLUSIONS: SIX5 expression is present in the normal epithelium throughout most of the female reproductive tract, suggesting it may have a role in maintaining epithelial differentiation in these tissues. SIX5 expression appears to be restricted to borderline epithelial ovarian tumours and may be a marker of epithelial differentiation in these tumours; thus borderline ovarian tumours may not be part of a continuum of disease between benign and malignant epithelial ovarian tumours. Further investigation of expression of SIX5 may clarify the molecular processes that promote differentiation of the ovarian surface epithelium.     

Serous borderline tumours of the ovary

Serous borderline tumours of the ovaryIn this Expert Opinion we have invited articles from two leading groups, to discuss serous borderline tumours (serous tumours of low malignant potential) of the ovary from their own perspectives. Controversy remains over heterogeneity within this group of tumours and their relationship to ovarian cancer. Our authors discuss the histopathological classification of these tumours in relation to morphological appearances, molecular and clinical data. The significance of a micropapillary pattern is discussed, and issues related to extra-ovarian implants.     

Ultrastructure of the benign and borderline Brenner tumours

One benign Brenner tumour and one Brenner tumour of borderline malignancy were investigated by electron microscopy. The cells of the benign Brenner tumour nests and the cells in the borderline tumour were similar in ultrastructure. The intercellular spaces were large and reinforced by a moderate number of desmosomes. The nuclei were round or oval. The nuclear membrane was irregular in shape with deep infoldings corresponding to the characteristic nuclear groovings seen by light microscopy. Only few secreting cells could be found in the benign of Brenner tumour. The cystic cavities of the borderline Brenner tumour were lined by nonciliated secreting and ciliated nonsecreting cells. The secretory granules were PAS-positive and diastaseresistant. The granules stained homogeneously and strongly with the PASM-method at the electron microscopical level indicating the presence of 1.2-hydroxyl groups. The Brenner tumours have many similarities to the transitional epithelium and to the Muellerian-derived tubular structures. The findings support the theory that Brenner tumours are of coelomic origin and develop by direct metaplasia from the ovarian surface epithelium.     

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.     

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.     

Brenner tumours of the ovary: a study of the histology, immunohistochemistry and cellular DNA content in benign, borderline and malignant ovarian tumours

Brenner tumours are now generally regarded as being of ovarian epithelial origin. Most have a limited growth potential and are benign. For this reason they are usually found incidentally at hysterectomy. In common with other epithelial ovarian tumours there is a histopathological spectrum of appearances ranging from benign through borderline to invasive malignancy. In this series all 54 tumours were graded according to the degree of cytological atypia, presence of mitoses and tumour necrosis. Heterogeneity of DNA content was observed in the higher grade tumours, two of the four being diploid and two being aneuploid (all benign tumours being diploid). The presence of aneuploidy correlated with the histological features and a poor clinical prognosis. Immunohistochemical staining for keratoprotein was found to be of limited value in the diagnosis of Brenner tumours and their metastases.     

Comparison of two fertility-sparing approaches for bilateral borderline ovarian tumours: a randomized controlled study

BACKGROUND: During the childbearing years, the standard fertility-sparing treatment for bilateral borderline ovarian tumours (BOTs) is the unilateral oophorectomy plus controlateral cystectomy. The aim of the present study was to compare the effects of two laparoscopic fertility-sparing surgical procedures for the treatment of bilateral BOTs on recurrence and fertility in young women who desire to conceive as soon as possible. METHODS: Thirty-two women affected by bilateral early-stage BOTs who desired to conceive were randomized to receive bilateral cystectomy (experimental group, n=15) or oophorectomy plus controlateral cystectomy (control group, n=17). At the first recurrence after childbearing completion, each patient was treated with non-conservative standard treatment. Recurrences and reproductive events were recorded. RESULTS: After a follow-up period of 81 months (19 inter-quartile; 60-96 range), the cumulative pregnancy rate (CPR) (14/15 versus 9/17; P=0.003) and the cumulative probability of first pregnancy (P= 0.011) were significantly higher in the experimental than in control group. No significant (P=0.358) difference between groups was detected in cumulative probability of first recurrence. CONCLUSIONS: The laparoscopic bilateral cystectomy followed by non-conservative treatment performed at the first recurrence after the childbearing completion is an effective surgical strategy for patients with bilateral early-stage BOTs who desire to conceive as soon as possible.     

Expression of MAGE-C1/CT7 and selected cancer/testis antigens in ovarian borderline tumours and primary and recurrent ovarian carcinomas

MAGE-C1/CT7, NY-ESO-1, GAGE and MAGE-A4 are members of the cancer/testis (CT) antigen family, which have been proposed as potential targets for cancer immunotherapy. To determine the prevalence and biologic relevance of the novel CT antigen MAGE-C1/CT7 and other antigens, 36 ovarian borderline tumours (BTs), 230 primary ovarian carcinomas (OCs) and 80 recurrent OCs were immunohistochemically analysed using the monoclonal antibodies CT7-33 (MAGE-C1/CT7), E978 (NY-ESO-1), clone 26 (GAGE) and 57B (MAGE-A4). Positivity of at least one CT antigen was present in 39.5 % (81/205) of primary OC and in 50 % (26/52) of all recurrences. Expression of the novel CT antigen MAGE-C1/CT7 was most commonly seen with positivity in 24.5 % of primary and 35.1 % of recurrent OC. MAGE-A4, GAGE and NY-ESO-1 expressions were seen in 22.7, 13.9 and 7.1 % of primary and 22.6, 17.5 and 8.9 % of recurrent OC, respectively. Analysis of histological subtypes (serous, endometrioid, clear cell, mucinous and transitional) exhibited variable expression with negativity in all mucinous OC. High-grade serous OC revealed CT antigen expression in 5.6 to 28 % with MAGE-C1/CT7 being the most frequent, but without correlation with stage or overall survival. MAGE-C1/CT7 expression and coexpression of CT antigens were significantly correlated with grade of endometrioid OC. None of the BT showed CT antigen expression. No significant correlation was seen with stage, overall survival or response to chemotherapy. In summary, CT antigens are expressed in a certain subset of OC with no expression in BT or OC of mucinous histology. These findings may have implications for the design of polyvalent vaccination strategies for ovarian carcinomas.     

Glomeruloid peritoneal implants in ovarian serous borderline tumours – distinction between invasive and non-invasive implants and pathogenesis

Aims:  To determine whether or not the glomeruloid implants (GI) composed of papillary cores within clear spaces lined by mesothelial cells or tumour cells located in superficial or deep peritoneal tissue in ovarian serous borderline tumours (SBTs) are invasive.
Methods and results:  We examined the differences in incidence, histological and immunohistochemical findings among three groups: 100 GI with mesothelial cells lining clear space (type I), 100 GI with tumour cells lining clear space (type II), and 100 invasive implants with clefts but no lining cells from 30 cases of SBT with peritoneal implants. The type I lesion had characteristics of non-invasive implants with a tendency for smooth contours (100/100), superficial location (71/100), absence of desmoplasia (100/100) and absence of surrounding destructive invasion (100/100), In contrast, type II GI had irregular contours (67/100), deep location (93/100), presence of desmoplastic reaction (100/100) and presence of destructive invasion (12/100). Immunohistological studies suggested intermediate forms between the two types of lesions.
Conclusions:  Type I GI are non-invasive implants, whereas type II GI are invasive implants and it is important to evaluate the presence and nature of cells lining the clear space in determining whether implants associated with ovarian SBTs are invasive or not.     

Flow cytometric analysis of cellular DNA content as an adjunct to the diagnosis of ovarian tumours of borderline malignancy

Flow cytometric analysis of cellular DNA content was performed on tissue from 44 borderline ovarian tumours (tumours of low malignant potential). Forty-two tumours (95%) were diploid and associated with both an indolent biological behaviour and good prognosis. Aneuploidy was identified in only 2 tumours (5%), and one of the associated patients died of progressive disease within months of the initial diagnosis. Careful review of the histopathology of these 2 aneuploid tumours revealed areas of invasion in the omental and peritoneal "implants" of each. This study has reinforced the currently advocated separation of so-called borderline tumours from invasive ovarian carcinomas and the interpretation of the pathological criteria used to categorize such neoplasms. Our results indicate that flow cytometric analysis of cellular DNA content may complement conventional histopathological diagnosis by providing an objective parameter which correlates with biological behaviour and may identify the few genuine borderline ovarian epithelial neoplasms which show clinical progression.