International Journal of Gynecological Pathology:
Histopathologic Grading of Ovarian Carcinoma: A Review and Proposal
Silverberg, Steven G M.D.
From the Director of Anatomic Pathology, University of Maryland Medical Center, Baltimore, Maryland, U.S.A.
Address correspondence and reprint requests to Dr. Steven G. Silverberg, Department of Pathology, University of Maryland Medical Center, 22 South Greene Street, Baltimore, MD 21201.
The histopathologic grade of ovarian epithelial carcinoma has generally been found to be of prognostic significance, but the grading system used has varied among published reports, and often has not been specified at all. The major proposed grading systems are reviewed, and a new system is proposed, which is modeled on the Nottingham system of breast cancer grading and is designed to be applied to all invasive epithelial carcinomas of the ovary. Results obtained in studies using this system are presented. When grading is compared with histopathologic typing of ovarian carcinoma, the latter is less valuable in predicting survival but better at predicting tumor responsiveness to chemotherapy, and can also suggest the chemotherapeutic agents to be used. Thus, both grade and type should be specified in the surgical pathology report for any ovarian carcinoma.
A little over a decade ago, I was invited to review the histologic prognostic factors in ovarian carcinoma for publication in an issue of Current Topics in Pathology(1). At that time, after a literature review comprising 21 series published between 1982 and 1986, and constituting more than 6,000 cases, I concluded that histologic grade was probably significant in the prognosis of cases in which platin-based treatment had not been used, and probably not significant in cases treated with what was at the time the more modern platin-based chemotherapeutic regimens. I noted, however, that it was difficult to interpret the results published in many of the reports for a number of reasons: 1.) Several publications at that time still included tumors of low malignant potential (borderline) among the carcinomas, and these would always improve the results for tumors interpreted as grade 1; 2.) In most reports, there was no specification of the grading system used, which in some series was architectural, in others cytologic (nuclear), in some both, but in the majority completely unspecified; 3.) The grading often was not done at the review level by a single pathologist, but was the product of multiple pathologists who initially saw the cases, often in more than one institution; and 4.) There was often an absence of uniform treatment within a single published series.
In preparation for the present review (to be published 11 years after the review cited above), it was interesting to survey the more recent literature to see if things had improved. In an admittedly cursory review of a relatively large series of ovarian carcinomas published within the past 2 years in which reference to tumor grading is made in the abstract, there is still a total lack of uniformity in how the grading system used is specified in the publications (Table 1). In the eight reports summarized in Table 1 (2–9), there is no specification of the grading system used in three of the reports, in two others there is only a vague comment that an architectural system or a combined architectural and cytologic system was used, in two the World Health Organization (WHO) system is specified, and in one the Gynecologic Oncology Group (GOG) system was used. Given this wide disparity, it is probably no surprise that the results expressed for the significance of tumor grade to prognosis are also highly variable. In four of the quoted studies, grade was said to be significant, in another two it was significant only by univariate analysis, and in the remaining two (with the smallest numbers of cases), grade was not significant at all.
These results suggest that at the end of the 20th century and the beginning of the 21st, ovarian cancer grading is still performed haphazardly, with several systems and nonsystems used in different studies from different institutions, and with little unanimity as to whether histologic tumor grade is significant at all, and even less as to its significance compared with other histopathologic, immunohistochemical, morphometric, flow and image cytometric, and molecular studies. The purpose of this review is to summarize some of the grading systems that have been offered in recent years and to present a system recently developed by my colleagues and myself, with analysis of the results of application of this system to a large series of cases treated in a uniform manner at a single institution.
OVARIAN CANCER GRADING SYSTEMS USED HISTORICALLY
The grading systems for epithelial ovarian carcinoma used most commonly throughout the world have been those of the International Federation of Gynecology and Obstetrics (FIGO) (10) and of the World Health Organization (WHO) (11). The FIGO system is based on architectural features, and the grade depends on the ratio of glandular or papillary structures versus solid tumor growth within an individual tumor. In this system, grade 1 is equivalent to <5% solid tumor growth, grade 2 represents 5 to 50% solid growth, and grade 3 tumors are >50% solid. In the WHO system, on the other hand, the grade is assigned by the observer's impression of both architectural and cytologic features, but this is not defined in a quantitative manner. Thus, Brugghe and colleagues (12) have characterized this sort of system as the “intuitive” method. It is noteworthy that although both FIGO and WHO have their own grading systems, neither is included in the ovarian cancer staging system of either FIGO (10) or WHO (11).
The other staging system most widely used, at least in the United States, is that of the Gynecologic Oncology Group (GOG) (13). In this system, the grading method employed depends on the histologic type of the tumor. For example, for endometrioid carcinomas, a system essentially equivalent to the FIGO system is used, which is also identical to the GOG method for grading of endometrioid carcinomas of the endometrium. On the other hand, transitional cell carcinomas of the ovary are graded in a manner similar to that for transitional cell carcinomas of the urinary bladder, while clear cell carcinomas are not graded at all. Thus, the grade assigned to a particular tumor is dependant on the observer's diagnosis of the histologic type of tumor, which has been shown in several studies to be poorly reproducible between pathologists (14–16). Furthermore, the GOG does not specify the grade to be used in the case of a carcinoma of mixed type (for example, endometrioid and clear cell or serous and transitional cell).
Because of the uncertainties and deficiencies associated with these three most popular grading systems, there have been several attempts to establish new grading systems using different features than those mentioned above. In 1986, Baak and colleagues (17) proposed a grading method based on mitotic activity index combined with the volume percentage of epithelium as estimated by a point counting method. The following year, Baak (with a different set of collaborators) (18) proposed a “decision rule” for ovarian epithelial tumor grading, which was based on three steps. In step 1, the decision is made as to whether the tumor has stromal invasion; if there is no stromal invasion, the tumor is called borderline and excluded from the following steps. In step 2, if the tumor is determined in step 1 to be an invasive carcinoma, it is further graded by the criteria of solid epithelial fields and hyperchromatic giant nuclei; the tumor is considered poorly differentiated if one ×40 microscopic field is filled with a solid epithelial sheet or if hyperchromatic giant nuclei are present. Step 3 is used for invasive carcinomas that are not considered poorly differentiated by step 2. In this step, the presence of one ×40 field with a cribriform growth pattern (defined as round [not oval or polygonal] lumina without intervening stroma) leads to the grading of the tumor as moderately differentiated. If the tumor is not considered either poorly or moderately differentiated by the application of steps 2 and 3, and is invasive by the application of step 1, then it is considered a well-differentiated carcinoma.
This grading system has not found wide application in the subsequent literature, but it was found to be both the most reproducible and the most prognostically significant system when compared with the “intuitive” method and the FIGO method by Brugghe and colleagues 9 years later (12). Parenthetically, in this study it was concluded that the assessment of histologic type was reproducible but prognostically not significant in the reported set of FIGO stage I patients, although the overall total agreement on histologic type was only 61%.
Another histopathologic grading system that was developed to overcome the shortcomings of existing systems was that of Bichel and Jakobsen (19). In this system, eight different parameters are evaluated, and each is given a score of from 1 to 3 points. The features evaluated are: 1.) tumor architectural structure (ratio of cystic or papillary structures to solid growth); 2.) nuclear polymorphism (size, shape, chromatin texture); 3.) nucleolar features (number, enlargement, and variability in shape and size); 4.) nuclear-cytoplasmic ratio; 5.) number of mitotic figures per 10 high-power-fields (MFs/10 HPFs); 6.) mode of invasion (well-defined versus infiltrative margins between tumor and surrounding stroma); 7.) capsular penetration (it is not defined whether this refers to the tumor capsule or the ovarian capsule); and 8.) vascular invasion. Each of these evaluated parameters is given a point score from 1 to 3, and a histologic grading index (HGI) is then defined as the mean of the values of the eight parameters and ranges from 1 to 3. In this study, the HGI correlated better (when cases were divided into tumors with an HGI ≤2.0 versus those >2.0) with both presence or absence of tumor at second-look surgery and 5-year survival than did the histologic grade alone (characterized by “the fraction of solid versus cystic or papillary structures”). As with the case of the system of Baak and colleagues described above (18), this system has not been applied widely in subsequent publications, and seems to be limited in use largely to the institution or institutions from which it arose.
An interesting comment on the variety of grading systems in existence appears in the recently published Third Series Armed Forces Institute of Pathology Fascicle on ovarian tumors by Scully and colleagues (20). The authors state:
“Almost all the reported studies of grading have shown a correlation with prognosis, at least at a univariate level, indicating that pathologists using a variety of grading methods can stratify ovarian cancers into several prognostic groups. The success in achieving this result is probably based on the existence of a subset of easily diagnosable grades 1, 2, and 3 (or 4) tumors. The poor reproducibility of grading, as shown by analysis of individual cases circulated among pathologists, however, indicates that disagreement exists on tumors with borderline grades. . . . The unfortunate conclusion is that unless a tumor is judged to belong indisputably within a grade, the grade assigned is an unreliable criterion on which to base therapy of an individual patient.”
PROPOSAL FOR A NEW GRADING SYSTEM
With the material presented above as a background, my colleagues and I began about 5 years ago to think about the development of a new grading system. We felt that the main criteria for a clinically useful grading system for ovarian carcinoma were that it should be: 1.) universal (that is, applicable to all histologic types of ovarian epithelial cancer); 2.) based on determinations that pathologists already know how to apply, so that it could be universal also in the sense of usable in many different institutions; and 3.) clinically valid, in the sense of being prognostically meaningful in both early and late stage ovarian cancer. To satisfy the first and second of these criteria, we turned for inspiration to the Nottingham system for grading of breast cancer, itself a modification of a system that has been in use for many years, and one whose clinical utility has been demonstrated across the spectrum of the numerous histologic types of mammary carcinoma (21,22). This apparent applicability to different histologic types of breast cancer was important to us, because it suggested that a modification of this system might satisfy our criterion of universality in ovarian cancer.
Since the Nottingham breast cancer system takes into account architectural pattern, nuclear pleomorphism, and mitotic activity, we felt that a similar three-tiered system might work for ovarian cancer, which is also an adenocarcinoma. In place of dependence on a tubular-ductal morphology alone for the architectural portion of the grading, together with dependence on a semiquantitative estimation of the proportion of a tumor showing this pattern as opposed to a solid one, we thought that it might be easier and more replicable for the pathologist simply to decide the architectural pattern displayed by the majority of the histologic fields in a given tumor. It also struck us that there were three rather than two major growth patterns in epithelial ovarian cancer: namely, glandular, papillary, and solid. Since glandular morphology was seen most prominently in ovarian carcinoma types with a generally favorable prognosis (endometrioid and mucinous), and the solid pattern was generally associated with loss of differentiation and aggressive behavior, we opted for a score of 1 for a predominantly glandular morphology, 2 for a papillary pattern, and 3 for solid growth.
The prognostic significance of this model was studied initially in a series of 461 epithelial ovarian cancers, divided fairly evenly among early (I/II) and advanced (III/IV) FIGO stage tumors, and with a good representation of the major histologic types (serous, clear cell, endometrioid, mucinous, transitional cell, and other) (23). In the initial determination, not only was this architectural grade related to survival in all ovarian cancers, early stage ovarian cancers, and advanced stage ovarian cancers, but it was also superior in these cases to the FIGO architectural grading system, and was also independent of the other parameters to be used in our system (that is, it had no significant correlation with either nuclear pleomorphism or mitotic activity). The architectural grade also proved to be prognostically useful for serous, endometrioid, and mucinous carcinomas, but there was no correlation of architectural grade with survival in either clear cell or transitional cell carcinoma.
Figs. 1 through 4 illustrate some of the patterns used in assigning the point score for architectural grade of an ovarian carcinoma in this system. Fig. 1 shows a glandular pattern, in this case seen in a well-differentiated endometrioid carcinoma. Figs. 2 and 3 both demonstrate a papillary growth pattern, seen in a serous carcinoma in Fig. 2 and a transitional cell carcinoma in Fig. 3. It should be noted that the glandular pattern is marked by round glands of either uniform or variable size, whereas the slit-like pattern sometimes encountered in serous carcinomas without a predominantly papillary pattern is interpreted as papillary (see Fig. 6). Fig. 4 depicts a solid growth pattern and is notable in that the solid sheets of cells contain numerous “holes” representing microcystic degeneration, which should not be misinterpreted as glands. In a true glandular pattern, the tumor cells will palisade around the central lumen with their long axes perpendicular to the lumen and to the basement membrane, whereas this orientation is lost in a microcystic degenerative focus, and cellular debris is usually noted within the pseudolumens.
The second factor to be analyzed and scored in our new grading system is the nuclear grade, which was also found to be independent of the other two parameters (23) and to work significantly as a prognostic indicator in both early and advanced stage ovarian carcinoma, as well as in early and advanced stage serous carcinoma, early stage clear cell carcinoma, early stage endometrioid carcinoma, and early and advanced stage mucinous carcinoma. Here again, the assignment of the score for nuclear pleomorphism must be described and illustrated. For this determination, the area of the tumor with the greatest degree of atypia in at least one-half of a low power (4× eyepiece, 10× objective lens) field should be chosen. For a score of 1 to be assigned (Fig. 5), there should be regular uniform vesicular nuclei (variation in diameter no greater than 2:1), a low nuclear:cytoplasmic ratio, and no chromatin clumping or prominent nucleoli. Score 2 is assigned for a variation in nuclear size between 2:1 and 4:1, as well as intermediate variation in shape. The nucleoli are recognizable but small, there is some chromatin clumping, and no bizarre cells are present (Fig. 6). Fields warranting a score of 3 (Fig. 7) contain cells with marked variation in nuclear size (greater than 4:1) and shape, a high nuclear:cytoplasmic ratio, prominent chromatin clumping, thick nuclear membranes, and large eosinophilic nucleoli. Bizarre cells are often present.
Mitotic activity was also shown in our initial study to be an independent variable, but there is some correlation between increasing mitotic count and increasing nuclear grade (23). It is probably the most difficult of the three histopathologic variables to reproduce from one observer to the next, as has been noted by numerous authors including myself (24). It has also been pointed out that if mitotic counting is to be used for any diagnostic purpose, it must be done compulsively and scrupulously (25). In our series, we evaluated the most mitotically active area in a tumor, which was usually at the periphery of the tumor where active growth was most likely. Strict criteria for the identification of mitotic figures were employed, and only nuclei with definite morphologic features of metaphase, anaphase, or telophase were counted. Hyperchromatic and apoptotic nuclei were excluded, as were inflammatory cells, degenerating cells, precipitated hematoxylin, and the like. A minimum of 30 fields was assessed, and the highest count of MFs/10 HPFs was recorded, using a Nikon Optiphot microscope (10× wide eye piece, 40× objective) with field diameter of 0.663 mm and field area 0.345 mm2. The number of MFs/10 HPFs that gave the best fit for prognostically significant information was 9 or fewer for score 1, 10 to 24 for score 2, and 25 or more for score 3. It was noted within the study for our initial publications on this grading system (23,26) that the mitotic activity of ovarian carcinomas was extremely variable, with some tumors displaying virtually no mitotic activity and others reaching mitotic counts of 150 to 200 per 10 HPFs. In general terms, the least mitotically active tumors were clear cell carcinomas, although they often had the most pleomorphic nuclei.
With the mitotic count score defined as above, it worked as a prognostic marker at a statistically significant level in stage I/II carcinomas, but was not significant (p = 0.0715) in stage III/IV disease. It also worked as a univariate prognostic marker in both early and advanced stage serous carcinoma and mucinous carcinoma, and in early stage endometrioid carcinoma. Because clear cell carcinomas had uniformly low mitotic counts (82% of 88 tumors with fewer than 10 MFs/10 HPFs), the cutoff numbers chosen did not predict prognosis in either early or advanced stage clear cell carcinoma, although by adjusting the numbers of MFs/10 HPFs downward for each point score, a prognostic significance could be developed.
Because each of the parameters summarized above (architectural pattern, nuclear pleomorphism, mitotic activity) proved to be independent variables (that is, independent of one another) in our series of cases, and because each of them correlated in univariate analysis with survival, it was deemed appropriate to combine them to create our final grading system (Table 2). As discussed above, each parameter is scored from 1 to 3, and the scores are then added, with a final score from 3 to 5 yielding a final grade of 1 (well-differentiated), 6 or 7 being equivalent to grade 2 (moderately differentiated), and 8 or 9 producing grade 3 (poorly differentiated), as in the Nottingham system (21,22). In our testing of this system in a series of 461 ovarian cancer patients with uniform treatment and follow-up (26), the final tumor grade correlated with survival in a statistically significant manner in both early and advanced stage disease and for all major histologic types of ovarian cancer except for clear cell carcinoma. The results for clear cell carcinoma approached but did not reach clinical significance. By multivariate analysis for a group of features including age, performance status, histologic tumor type, FIGO grade, and this new grade, only our new tumor grade and performance status were prognostically significant in stage I/II disease. In stage III/IV carcinomas, the new tumor grade was also significant by multivariate analysis, as were performance status, residual tumor size after initial operation, response to chemotherapy, and mucinous (unfavorable) or transitional cell (favorable) histologic type.
COMPARISON OF HISTOPATHOLOGIC GRADING AND TYPING
In my 1989 review of histopathologic prognostic factors in ovarian carcinoma, I reviewed 12 series, comprising more than 8,000 cases, published between 1982 and 1986, that had commented on the relationship of histopathologic type of epithelial ovarian carcinoma to survival. The general result was that mucinous and endometrioid carcinomas were considered favorable types, serous carcinoma less favorable, and undifferentiated carcinoma the most aggressive type of ovarian carcinoma. Interestingly, clear cell carcinoma (or “mesonephroid carcinoma,” as it was still frequently called) appeared somewhat indeterminate, in that about half of the publications placed it in the favorable category, and the other half considered it unfavorable. In virtually all of the published series, histopathologic type was less prognostically significant than clinical-pathologic stage, and usually less significant than grade as well, with multivariate analysis.
This analysis has changed little in recent years, but we were prompted to perform an analysis of the relation of grade to type in our own series of cases (27). We had already determined (26) that the only significant correlation of histopathologic type of carcinoma with survival by multivariate analysis was a favorable effect of transitional cell morphology and an unfavorable one of the mucinous phenotype in stage III/IV tumors. In stage I/II carcinomas, histopathologic type did not reach significance for any of the other patterns when compared with serous carcinoma, the most common type. In consideration of our results showing differences in advanced stage tumors, we wondered whether this might be due to chemotherapy responsiveness, and thus we analyzed response to chemotherapy in 251 ovarian carcinoma patients, 217 of whom were in stages III and IV. We found that high-stage serous, transitional cell, and endometrioid carcinomas responded well to a cyclophosphamide/doxorubicin/cisplatin regimen. The response to cyclophosphamide cisplatin alone was similar for serous and transitional cell carcinomas, but complete plus partial response rate fell for endometrioid carcinomas from 92.3 to 30.0%. No case of either mucinous or clear cell carcinoma responded to either regimen. On the other hand, chemotherapy response was not strongly influenced by grade (response rate in all cases 46% for grade 1, 57% for grade 2, and 51% for grade 3 carcinomas), although, as summarized above, survival was strongly grade-related. Interestingly, there was a significantly poorer response rate among grade 3 serous and endometrioid carcinomas compared with lower grade tumors of those histopathologic types. We have also more recently shown (unpublished data) that among patients with serous, endometrioid, and transitional cell carcinomas who are complete responders to initial chemotherapy, the subsequent duration of progression-free interval is significantly related to grade, with the interval not yet reached among 11 patients with grade 1 tumors, 85 months for grade 2 tumors, and 40 months for grade 3 tumors. Among partial responders as well, the progression-free interval declines as grade advances.
Thus, although grade predicts survival better than does type of ovarian carcinoma, histopathologic type is a better predictor of chemoresponsiveness, and can suggest the optimal type of chemotherapy to be used. It is thus recommended that the surgical pathology report on cases of ovarian carcinoma include both the grade and type of tumor seen.
Finally, it is worth mentioning that although the initial published and presented studies of the efficacy of our grading system are our own, at least two other studies have now appeared in which the system has been used with satisfactory results. In a presentation on prognostic implications of the cell cycle inhibitor p27kip1 in ovarian cancer, Shaw and colleagues noted that the most significant predictors of survival in a series of 101 cases were stage, our grade, age, and DNA index (28). The same group also noted that this grading system was useful in distinguishing between ovarian carcinomas associated with BRCA mutations and those occurring sporadically, with the former having a statistically significantly higher grade, as well as being exclusively of serous type (29). We eagerly await more studies on the validity of this grading system, and are currently engaged in interobserver reproducibility studies ourselves.
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OnkologieOvarian cancer treatment reality in northern Rheinland-Pfalz (Germany). Suboptimal surgical treatment as a possible cause for inferior survivalOnkologie
Clinical Cancer ResearchBoth germ line and somatic genetics of the p53 pathway affect ovarian cancer incidence and survivalClinical Cancer Research
Annals of OncologyPrognostic significance of histological grade in clear-cell carcinoma of the ovary: a retrospective study of Korean Gynecologic Oncology GroupAnnals of Oncology
Annual Review of Pathology-Mechanisms of DiseaseOvarian CancerAnnual Review of Pathology-Mechanisms of Disease
Bmc CancerImmunohistochemical profiling of benign, low malignant potential and low grade serous epithelial ovarian tumorsBmc Cancer
Modern PathologyActinin-4 gene amplification in ovarian cancer: a candidate oncogene associated with poor patient prognosis and tumor chemoresistanceModern Pathology
The AA Genotype of a L1C G842A Polymorphism Is Associated with an Increased Risk for Ovarian Cancer
Anticancer Research, 29(8):
Gynecologic OncologyVascular endothelial growth factor expression in serous ovarian carcinoma: Relationship with high mitotic activity and high FIGO stageGynecologic Oncology
Cancer Biology & Therapy
The metastasis-associated gene MTA1 is upregulated in advanced ovarian cancer, represses ER beta, and enhances expression of oncogenic cytokine GRO
Cancer Biology & Therapy, 7(9):
British Journal of CancerCross talk of signals between EGFR and IL-6R through JAK2/STAT3 mediate epithelial-mesenchymal transition in ovarian carcinomasBritish Journal of Cancer
Gynecologic OncologyRecurrent low-grade serous ovarian carcinoma is relatively chemoresistantGynecologic Oncology
Clinical Cancer Research
Cell-free 59 kDa immunoreactive integrin-linked kinase: A novel marker for ovarian carcinoma
Clinical Cancer Research, 10(7):
Human ReproductionConservative treatment in epithelial ovarian cancer: results of a multicentre study of the GCCLCC (Groupe des Chirurgiens de Centre de Lutte Contre le Cancer) and SFOG (Societe Francaise d'Oncologie Gynecologique)Human Reproduction
HistopathologyLesson of the Month - Grading of serous ovarian carcinoma: further evidence of a lack of agreement between conventional grading systemsHistopathology
British Journal of CancerAscites induces modulation of alpha 6 beta 1 integrin and urokinase plasminogen activator receptor expression and associated functions in ovarian carcinomaBritish Journal of Cancer
Histology and Histopathology
Fascin in ovarian epithelial tumors
Histology and Histopathology, 23(8):
Survival among women with borderline ovarian tumors and ovarian carcinoma - A population-based analysis
Gynecologic OncologyFactors associated with cytoreducibility among women with ovarian carcinomaGynecologic Oncology
Journal of Obstetrics and Gynaecology ResearchRole of human papillomavirus in the development of epithelial ovarian neoplasms in Italian womenJournal of Obstetrics and Gynaecology Research
American Journal of Surgical Pathology
Subdividing Ovarian and Peritoneal Serous Carcinoma Into Moderately Differentiated and Poorly Differentiated Does not Have Biologic Validity Based on Molecular Genetic and In Vitro Drug Resistance Data
American Journal of Surgical Pathology, 32():
Human CellPOU6F1 is the transcription factor that might be involved in cell proliferation of clear cell adenocarcinoma of the ovaryHuman Cell
International Journal of Biological Markers
Association of the AA genotype of the BCL2 (-938C > A) promoter polymorphism with better survival in ovarian cancer
International Journal of Biological Markers, 24(4):
Human PathologyExpression of hypoxia-inducible factor 1 alpha, hypoxia-inducible factor 2 alpha, and von Hippel-Lindau protein in epitheLiaL ovarian neoplasms and allelic loss of von Hippel-Lindau gene: nuclear expression of hypoxia-inducible factor 1 alpha is an independent prognostic factor in ovarian carcinomaHuman Pathology
British Journal of CancerEnhanced expression of peroxisome proliferator-activated receptor gamma in epithelial ovarian carcinomaBritish Journal of Cancer
Analytical and Quantitative Cytology and Histology
Expression of PTEN in ovarian epithelial tumors and its relation to tumor behavior and growth
Analytical and Quantitative Cytology and Histology, 27(4):
Gynecologic OncologyVEGF and HIF-1 alpha expression are increased in advanced stages of epithelial ovarian cancerGynecologic Oncology
Markers of proliferative activity are predictors of patient outcome for low-grade endometrioid adenocarcinoma but not papillary serous carcinoma of endometrium
Modern Pathology, 15(4):
Cancer LettersExpression of lysophosphatidic acid receptors and vascular endothelial growth factor mediating lysophosphatidic acid in the development of human ovarian cancerCancer Letters
Gynecologic OncologyCorrelation of tumor- and stromal-derived MT1-MMP expression with progression of human ovarian tumors in SCID miceGynecologic Oncology
International Journal of Gynecological Cancer
Expression of cyclooxygenase-2 in epithelial ovarian tumors and its relation to vascular endothelial growth factor and p53 expression
International Journal of Gynecological Cancer, 16():
Journal of Surgical OncologyClinical and molecular differences between clear cell and papillary serous ovarian carcinomaJournal of Surgical Oncology
Critical Reviews in Oncology HematologyOvarian cancerCritical Reviews in Oncology Hematology
Journal of Obstetrics and GynaecologyHistological grading of epithelial ovarian carcinomasJournal of Obstetrics and Gynaecology
British Journal of CancerAn immunohistochemical perspective of PPAR beta and one of its putative targets PDK1 in normal ovaries, benign and malignant ovarian tumoursBritish Journal of Cancer
Human PathologyTumor cell type can be reproducibly diagnosed and is of independent prognostic significance in patients with maximally debulked ovarian carcinomaHuman Pathology
American Journal of Clinical PathologyS100A1 Expression in Ovarian and Endometrial Endometrioid Carcinomas Is a Prognostic Indicator of Relapse-Free SurvivalAmerican Journal of Clinical Pathology
Virchows ArchivVascular endothelial growth factor C mRNA expression is a prognostic factor in epithelial ovarian cancer as detected by kinetic RT-PCR in formalin-fixed paraffin-embedded tissueVirchows Archiv
Clinical Cancer Research
ATP-binding cassette superfamily transporter gene expression in human primary ovarian carcinoma
Clinical Cancer Research, 8():
Journal of PathologyIntegrin-linked kinase expression increases with ovarian turnour grade and is sustained by peritoneal tumour fluidJournal of Pathology
CancerFive genes from chromosomal band 8p22 are significantly down-regulated in ovarian carcinoma - N33 and EFA6R have a potential impact on overall survivalCancer
European Journal of Obstetrics Gynecology and Reproductive BiologyRecurrent epithelial ovarian cancer: Validation and improvement of an established prognostic indexEuropean Journal of Obstetrics Gynecology and Reproductive Biology
International Journal of CancerAberrant expression of BARD1 in breast and ovarian cancers with poor prognosisInternational Journal of Cancer
Translational ResearchDifferential gene expression identifies subgroups of ovarian carcinomaTranslational Research
British Journal of CancerProteomic-based identification of haptoglobin-1 precursor as a novel circulating biomarker of ovarian cancerBritish Journal of Cancer
International Journal of CancerNeutrophil gelatinase-associated lipocalin (NGAL) an early-screening biomarker for ovarian cancer: NGAL is associated with epidermal growth factor-induced epithelio-mesenchymal transitionInternational Journal of Cancer
Turkiye Klinikleri Tip Bilimleri Dergisi
Grading of the ovarian serous cystadencarcinomas, and its correlation with BRCA1 and p53 immunoreactivity
Turkiye Klinikleri Tip Bilimleri Dergisi, 27(3):
Virchows ArchivHistological grading in a large series of advanced stage ovarian carcinomas by three widely used grading systems: consistent lack of prognostic significance. A translational research subprotocol of a prospective randomized phase III study (AGO-OVAR 3 protocol)Virchows Archiv
Cancer ScienceHedgehog signal pathway is activated in ovarian carcinomas, correlating with cell proliferation: It's inhibition leads to growth suppression and apoptosisCancer Science
Modern PathologyImmunophenotyping of serous carcinoma of the female genital tractModern Pathology
Journal of PathologyE2Fs mediate a fundamental cell-cycle deregulation in high-grade serous ovarian carcinomasJournal of Pathology
British Journal of CancerKi-67 expression and patients survival in lung cancer: systematic review of the literature with meta-analysisBritish Journal of Cancer
Journal of Reproductive Medicine
Current issues in the pathology of ovarian cancer
Journal of Reproductive Medicine, 50(6):
International Journal of Gynecological Cancer
Primary peritoneal carcinoma in a UK cancer center: comparison with advanced ovarian carcinoma over a 5-year period
International Journal of Gynecological Cancer, 16():
Gynecologic OncologyTesting of two binary grading systems for FIGO stage III serous carcinoma of the ovary and peritoneumGynecologic Oncology
Cancer ScienceStAR and progesterone producing enzymes (30-hydroxysteroid dehydrogenase and cholesterol side-chain cleavage cytochromes P450) in human epithelial ovarian carcinoma: Immunohistochemical and real-time PCR studiesCancer Science
International Journal of CancerTumor protein D52 (TPD52) is overexpressed and a gene amplification target in ovarian cancerInternational Journal of Cancer
Gynecologic OncologyPrognostic significance of CD3+ tumor-infiltrating lymphocytes in ovarian carcinomaGynecologic Oncology
Oncology ReportsMitochondrial ultrastructure-associated chemotherapy response in ovarian cancerOncology Reports
Modern PathologyIntraepithelial T cells and prognosis in ovarian carcinoma: novel associations with stage, tumor type, and BRCA1 lossModern Pathology
Gynecologic OncologyNeoadjuvant chemotherapy for low-grade serous carcinoma of the ovary or peritoneumGynecologic Oncology
Modern PathologyImmunohistochemical analysis of possible chemoresistance markers identified by micro-arrays on serous ovarian carcinomasModern Pathology
Gynecologic OncologyThe haplotype of two FSHR polymorphisms in ovarian cancer-A potential role of ethnology in risk modificationGynecologic Oncology
European Journal of Clinical InvestigationThe balance between extracellular cathepsins and cystatin C is of importance for ovarian cancerEuropean Journal of Clinical Investigation
CancerPathology and classification of ovarian tumorsCancer
Journal of PathologyExpression of BRCA I protein in benign, borderline, and malignant epithelial ovarian neoplasms and its relationship to methylation and allelic loss of the BRCA I geneJournal of Pathology
Bmc CancerOvarian carcinomas with genetic and epigenetic BRCA1 loss have distinct molecular abnormalitiesBmc Cancer
HistopathologyOverexpression of osteopontin in clear cell carcinoma of the ovary: close association with HNF-1 beta expressionHistopathology
International Journal of Biochemistry & Cell BiologyEpidermal growth factor-induced ovarian carcinoma cell migration is associated with JAK2/STAT3 signals and changes in the abundance and localization of alpha 6 beta 1 integrinInternational Journal of Biochemistry & Cell Biology
Key Advances in the Clinical Management of Ovarian Cancer
Pathology and its prognostic importance
Key Advances in the Clinical Management of Ovarian Cancer, ():
Cancer ScienceNuclear expression of S100A4 is associated with aggressive behavior of epithelial ovarian carcinoma: An important autocrine/paracrine factor in tumor progressionCancer Science
PathologyAGR2 expression in ovarian tumours: a potential biomarker for endometrioid and mucinous differentiationPathology
Histology and Histopathology
Phenotypic characterization of hereditary epithelial ovarian cancer based on a tissue microarray study
Histology and Histopathology, 28(1):
The American Journal of Surgical PathologyDescription of a Novel System for Grading of Endometrial Carcinoma and Comparison With Existing Grading SystemsThe American Journal of Surgical Pathology
The American Journal of Surgical PathologyGrading Ovarian Serous Carcinoma Using a Two-Tier SystemThe American Journal of Surgical Pathology
The American Journal of Surgical PathologyTwo-Tier Grading System for Ovarian Epithelial Cancer: Has its Time Arrived?The American Journal of Surgical Pathology
Obstetrics & GynecologyClinical Behavior of Stage II-IV Low-Grade Serous Carcinoma of the OvaryObstetrics & Gynecology
International Journal of Gynecological CancerImmunohistochemical localization of metallothionein in benign and malignant epithelial ovarian tumorsInternational Journal of Gynecological Cancer
International Journal of Gynecological CancerClear Cell Carcinoma Compared to Serous Carcinoma in Early Ovarian Cancer: Same Prognosis in a Large Randomized TrialInternational Journal of Gynecological Cancer
International Journal of Gynecological CancerSignificance of E2F‐1 overexpression in epithelial ovarian cancerInternational Journal of Gynecological Cancer
International Journal of Gynecologic PathologyPrognostic Value of Histologic Grading of Ovarian CarcinomasInternational Journal of Gynecologic Pathology
International Journal of Gynecologic PathologyRelation Between Laminin-5 γ2 Chain and Cell Surface Metalloproteinase MT1-MMP in Clear Cell Carcinoma of the OvaryInternational Journal of Gynecologic Pathology
International Journal of Gynecologic PathologyEzrin Promotes Ovarian Carcinoma Cell Invasion and Its Retained Expression Predicts Poor Prognosis in Ovarian CarcinomaInternational Journal of Gynecologic Pathology
International Journal of Gynecologic PathologyHistologic Subtypes of Ovarian Carcinoma: An OverviewInternational Journal of Gynecologic Pathology
International Journal of Gynecologic PathologySubclassification of Ovarian Surface Epithelial Tumors Based on Correlation of Histologic and Molecular Pathologic DataInternational Journal of Gynecologic Pathology
International Journal of Gynecologic PathologyGrading of Ovarian CarcinomasInternational Journal of Gynecologic Pathology
International Journal of Gynecologic PathologyThe Clinical Importance of Ki-67, p16, p14, and p57 Expression in Patients With Advanced Ovarian CarcinomaInternational Journal of Gynecologic Pathology
Ovary; Carcinoma; Grading
© 2000 Lippincott Williams & Wilkins, Inc.
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