Volume Percentage Of Epithelium Research Articles

Clinical Value of Morphometric and DNA Flow Cytometric Variables as Independent Predictors of Survival in Epithelial Ovarian Carcinoma: A 5-year Follow-up Study

The aim of this follow-up study is to validate the clinical significance of quantitative morphometric and DNA flow cytometric variables as independent prognostic factors of overall survival and progression-free survival in epithelial ovarian carcinoma. Tumor samples were collected from 135 patients with epithelial ovarian carcinoma at 3 hospitals in the Netherlands. Evaluated clinico-pathologic variables were age, histologic subtype, differentiation grade, clinical stage [International Federation of Gynecology and Obstetrics (FIGO)], presence of ascites, serum CA-125, and the completeness of debulking surgery. Morphometry and DNA flow cytometric techniques were assessed on each tumor sample to determine the mitotic activity index (MAI), volume percentage epithelium, mean nuclear area (MNA), standard deviation of MNA (SD MNA), nuclear perimeter (NP), and DNA ploidy. Univariate analysis showed that differentiation grade, FIGO stage, presence of ascites, preoperative CA-125 levels, DNA ploidy, and MAI, NP, and MNA were of significant prognostic value. After multivariate analysis (using forward Cox proportional hazard analysis), only differentiation grade and FIGO stage remained significant. From this study, we can conclude that morphometry and DNA flow cytometry are not independent prognosticators and therefore have no clinical value in predicting prognosis in ovarian carcinoma.

The Prognostic and Clinical Value of Morphometry and DNA Cytometry in Borderline Ovarian Tumors: A Prospective Study

To evaluate if morphometric features (mitotic activity index, volume percentage of epithelium, and DNA ploidy) are prognostic markers in borderline ovarian tumors (BOTs). Ninety-three serous and mucinous consecutive BOTs diagnosed between 1989 and 2002 were studied. In all tumors, mitotic activity index, volume percentage of epithelium, and DNA ploidy were determined prospectively. Consecutively, age at diagnosis, calculated tumor volume, International Federation of Gynecology and Obstetrics (FIGO) stage, and treatment by extensive staging were evaluated after a median follow-up of 52 months. Serous BOTs presented at a younger age (P<0.05), with smaller volume (P<0.001), with higher FIGO stage (P<0.001), and were more frequently bilateral (P<0.001) than mucinous BOTs. Patients with serous BOT (P<0.05) and beyond stage Ia (P<0.01) showed worse recurrence-free survival. No prognostic significance could be established for DNA ploidy or morphometry. The previously claimed prognostic power of DNA ploidy and morphometry could not be corroborated in this prospective study and can therefore not be recommended to direct clinical management in BOTs. In contrast, histologic subtype and FIGO stage seem to be stable prognosticators in BOTs.

Biopsy histomorphometry predicts uterine myoinvasion by endometrial carcinoma: a Gynecologic Oncology Group study

A barrier to nonsurgical management of premalignant endometrial disease is the need to perform hysterectomy to exclude concurrent myoinvasive endometrioid adenocarcinoma. Occult adenocarcinoma rates for premalignant disease diagnosed by biopsy or curettage are approximately 40%. We applied the histomorphometric 4-class rule ("4C," which measures epithelial abundance, thickness, and nuclear variation) to diagnostic biopsies to predict myoinvasive cancer outcomes at hysterectomy. Women with endometrial biopsies or curettages having a community diagnosis of atypical endometrial hyperplasia were enrolled in a clinical trial in which subsequent hysterectomy was scored for endometrial adenocarcinoma, and 4C rule ability to predict cancer outcomes was measured. Qualifying biopsies were stratified into high- and low-risk histomorphometric subgroups. Two-hundred thirty-three women had biopsies suited to morphometry and scorable hysterectomy outcomes, of which 46% contained adenocarcinoma. Assignment to a high-risk category by the 4C rule was highly sensitive in predicting any (71%) or deeply (92%) myoinvasive adenocarcinoma at hysterectomy, and assignment to a low-risk group had a high negative predictive value for absence of any (90%) or deeply (99%) myoinvasive disease. Volume percentage epithelium was associated with myoinvasive cancer outcomes above a threshold of 50% (P < .001), and a measure of nuclear pleomorphism was significantly increased (P = .004) in deeply myoinvasive cancers. Formal histomorphometry of endometrial biopsies using the 4C rule has been validated as a means to identify a subset of women with premalignant disease who are unlikely to have concurrent myoinvasive adenocarcinoma and who may qualify for alternative nonsurgical therapies.

Nuclear size distinguishes low- from high-grade ovarian serous carcinoma and predicts outcome

A dualistic model for ovarian serous carcinogenesis based on morphological and molecular genetic studies has recently been proposed. This model divides serous carcinoma into low- and high-grade tumors, which develop along distinct molecular pathways. In this report, we evaluated computerized morphometry to determine its utility in distinguishing low- and high-grade serous carcinoma. The mean nuclear area (MNA) and the volume percentage of epithelium (VPE) in 93 high-grade serous carcinomas was measured and compared with 16 low-grade serous carcinomas and 21 serous borderline tumors, the putative precursor of low-grade serous carcinoma. We found that both MNA and VPE were significantly higher in high-grade serous carcinoma compared with low-grade serous carcinoma and serous borderline tumors (P < .001 and P = .02, respectively). There was no significant difference in MNA and VPE between low-grade carcinoma and serous borderline tumors (P > .3). Among high-grade serous carcinomas, those with an MNA of 46 microm2 or higher had a poorer survival (P = .035) than those with an MNA below 46 microm2. In contrast, VPE and tumor grade (moderately versus poorly differentiated) had no significant prognostic value. The morphometry findings lend further support to the dualistic model of ovarian serous carcinogenesis and suggest that MNA is an excellent adjunctive tool for distinguishing low- from high-grade serous carcinomas. In addition, MNA is an independent prognostic factor for high-grade serous carcinoma.

Morphological effects of chemotherapy on ovarian carcinoma.

Traditionally, advanced stage ovarian carcinoma is treated by debulking surgery followed by chemotherapy. However, in some circumstances preoperative chemotherapy may be given before optimal surgical debulking. This study aims to describe the morphological features found in ovarian carcinoma after chemotherapy because these have not been detailed previously. Histological sections were examined from 18 cases of ovarian carcinoma that had been treated by preoperative chemotherapy. The morphology was compared with any pre-chemotherapy biopsies that had been performed. Tumours were classified as showing morphological features suggesting a good response to chemotherapy (n = 14) or as showing little or no response (n = 4). Serum CA125 values before and after chemotherapy were compared. In all cases, the mitotic activity index (MAI), volume percentage of epithelium (VPE), and mean nuclear area (MNA) of tumour cells were calculated. The preoperative biopsies were all typical ovarian serous or endometrioid adenocarcinomas. Morphological features present in the group responding to chemotherapy included the presence of small groups or single tumour cells in a densely fibrotic stroma. Tumour cells were characterised by both nuclear and cytoplasmic alteration, making accurate tumour typing and grading impossible. Nuclear features included the presence of bizarre enlargement with hyperchromatism, irregularity of outline, and chromatin clumping or smudging. Cytoplasmic alterations included intense eosinophilia, vacuolation, or foam cell change. There were pronounced stromal changes of fibrosis, inflammation, collections of foamy histiocytes, cholesterol cleft formation, haemosiderin deposition, fat necrosis, and dystrophic calcification, including the presence of many free psammoma bodies. There was no correlation between morphological response and biochemical response, as determined by serum CA125 values. In all nine cases in which pre-chemotherapy and post-chemotherapy biopsies were available, the MNA increased post-chemotherapy (p = 0.007, paired Wilcoxon test) and in six of nine cases the MAI decreased (p = 0.093). Because preoperative chemotherapy is being used increasingly in the management of ovarian cancer, pathologists should be aware of the resultant morphological effects. Accurate tumour typing and grading is impossible. In some cases, it may be difficult to confirm the presence of residual tumour, making it imperative that pre-chemotherapy tissue biopsies are obtained. Definite confirmation of residual tumour may require the examination of multiple histological sections from areas showing pronounced stromal changes, sometimes with multiple levels and immunohistochemistry. In the absence of definite residual tumour, the report should state that the features are consistent with the prior presence of tumour.

Expression of multidrug resistance-associated markers, their relation to quantitative pathologic tumour characteristics and prognosis in advanced ovarian cancer.

Mean nuclear area has been consistently shown by different researchers to be a strong and independent prognostic factor in advanced ovarian carcinoma. However, the biological background of the prognostic value of nuclear area remains unclear. Others have found that the multidrug‐resistance (MDR) related protein LRP has strong prognostic value. In the present study we have analysed whether the mean nuclear area and LRP are related in tumour tissue of the ovary obtained at the debulking operation before the administration of chemotherapy in 40 patients. The mitotic activity index, volume percentage epithelium, standard deviation of nuclear area and the other MDR‐related proteins P‐glycoprotein (JSB‐1, MRK‐16) and MRP have been investigated additionally for correlations and prognostic value. No correlations were found between the morphometrical features and MDR‐related proteins. Mean nuclear area tended to be larger in LRP positive tumours, but the correlation was not significant. In multivariate analysis LRP‐protein expression and mean nuclear area had independent prognostic value. Further studies are required to elucidate the biological background of the strong prognostic value of mean nuclear area in advanced ovarian cancer.

Quantitative Prognostic Features in FIGO I Ovarian Cancer Patients without Postoperative Treatment

To identify FIGO I ovarian cancer patients at high risk, prognostic values of quantitative pathological features (volume percentage of epithelium, mitotic activity index, mean (MNA) and standard deviation of nuclear profile area, and volume-weighted mean nuclear volume (MNV) have been investigated in comparison with clinical features, histological grade, and type in 102 adequately staged patients with FIGO Ia, Ib, and Ic ovarian cancer of the common epithelial types. None of these patients received any postoperative treatment. Overall survival of patients alive and well was 78%, and 90% were alive. Of the clinical features, FIGO substage was the strongest prognosticator (Mantel–Cox = 7.2,p= 0.03, hazard ratio (HR) = 4.6). Histologic grade had significant prognostic value as well (Mantel–Cox = 9.7,p= 0.008, HR = 5.9), but histologic type did not. MNA and MNV were the strongest single prognostic factors for overall survival (Mantel–Cox = 12.3 for both;p= 0.0004 and 0.0005). If MNA ≤ 55.6 μm2, none of the patients (n= 52) died; if MNA >55.6 μm2, 6-year overall survival was 69%. For MNV ≤460 μm2, none of the patients (n= 53) died; if MNV >460 μm2, 6-year overall survival was 70%. A multivariate combination of MNA and FIGO (early cancer of the ovary prognostic score, ECOPS) had the strongest prognostic value (p< 0.0001 and Mantel–Cox value = 22.8, HR = 29.2). If ECOPS ≤ 5.4 (n= 66), 6-year overall survival was 97%; if ECOPS >5.4 (n= 36), 6-year overall survival was 54%. The results from this and earlier studies emphasize the strong prognostic value of easy to assess and highly reproducible morphometric nuclear features in ovarian tumors and offer a useful instrument for the definition of patient groups for future clinical trials.

DNA Index Reflects the Biological Behavior of Ovarian Carcinoma Stage I–IIa

The prognostic significance of histologic grade, morphometric analysis, and DNA flow cytometry was evaluated in 64 patients with well-differentiated (group A) and 30 patients with moderately and poorly differentiated (group B) early-stage (FIGO stages Ia, Ib, Ic, and IIa) epithelial ovarian cancer. The extent of the well-defined staging procedure was assessed strictly in every patient. Of 94 patients, 13 had recurrent ovarian cancer (5 from group A and 8 from group B) and 12 of these patients died. A significant difference was found between groups A and B for 5-year disease-free survival (91% versus 75%), the menopausal status, surgical staging procedure, volume percentage epithelium (VPE), morphometric category, DNA ploidy, and DNA index, but not for histologic cell type. For the 94 patients from groups A and B together, a significant difference was observed between diploid and aneuploid tumors with regard to mean mitotic activity index (MAI), mean VPE, and the morphometric categories that combined MAI and VPE characteristics. Prognostic reliability for the occurrence of tumor relapse was highest for DNA index class, followed by tumor grade and DNA ploidy pattern. With multivariate analysis the primary prognostic factor for disease-free survival appeared to be the DNA index. DNA index class was the only parameter that added prognostic information when histologic grade was selected as the primary prognostic factor. If the DNA index was taken as primary prognostic factor, none of the tested parameters including tumor grade added useful information. It was concluded that the DNA index is a primary prognostic factor for disease-free survival in early-stage ovarian cancer patients. Morphometric measurements do not add supplementary prognostic information.

The prognostic value of morphometry in advanced epithelial ovarian cancers.

The relationship between morphometric and clinical data was assessed in a series of 60 advanced ovarian carcinomas. Morphometric parameters included nuclear area, nuclear perimeter, shortest and longest nuclear axis, roundness coefficient, volume percentage of epithelium (VPE) and mitotic index. All patients had at least 5 years of follow-up. Univariate survival analysis showed that FIGO stage (P < 0.001), VPE (P < 0.001), mean nuclear area (P < 0.001) and size of residual tumour (P < 0.001) are significantly associated with survival. When the response rate of these patients to cisplatin combination chemotherapy was evaluated, variables with good prognostic outcome were residual tumour size (P = 0.01), mean nuclear area (P = 0.0006) and s.d. of nuclear area (P = 0.0019). We conclude that morphometric parameters are able to support diagnostic and therapeutic decisions.

The significance of differences in prognostic value of quantitative pathologic features in FIGO stage III and IV serous adenocarcinoma of the ovary between a group of Danish patients and other groups.

Previous studies have shown DNA cytometric, morphometric and stereologic features to be strong prognosticators in advanced ovarian cancer. However, in one Danish study a new stereologic parameter, the volume-weighted mean nuclear volume ( nuv), was not of prognostic significance. In that study, sampling was performed in the whole tumor section, contrary to that in other studies where measurements were performed in the worst differentiated area (the measurement area). The aim of the present investigation was, therefore, to confirm or reject the hypothesis that random estimates of nuclear {ovbar|nu}v over the whole tumor, rather than in the measurement area, are the cause for the lack of prognostic value in the Danish patients. Additionally, the mitotic activity index (MAI), volume percentage of epithelium (VPE), mean nuclear area (MNA) and standard deviation of the nuclear area (SDNA), which have proved to be of strong prognostic significance in advanced ovarian cancer, were assessed in the measurement area. The MAI, VPE, MNA, SDNA and nuclear {ovbar|nu}v were well reproducible, but prognostically not significant. This study thus excludes differences in microscopic sampling as an explanation for the contrasting findings in the Danish study and other ones. Possible remaining explanations are: (i) differences in sampling at the macroscopic level; (ii) fixation differences; (iii) patient selection bias; and (iv) geographic differences in the degree of malignancy of advanced ovarian cancer in Denmark and the Netherlands. As to the latter, in comparison with two Dutch studies the Danish ovarian cancers in this series had residual disease <2 cm (33% vs 50%) less often, were less often well differentiated (4% vs 19%), and less often had favorable morphometric characteristics (6% vs 15%). Further studies are required to analyze whether other Danish patient groups with advanced ovarian cancers differ from the Dutch.

Prognostic Value of Microvessel Quantitation in Cisplatin Treated Figo 3 and 4 Ovarian Cancer Patients

Primary ovarian carcinomas of 49 patients have been used to study the relation between microvessel counts and prognosis. All tumours were of the common epithelial type, FIGO 3 or 4, were treated by debulking surgery and cisplatin based chemotherapy. Primary tumour tissue obtained at surgery was embedded in paraffin, cut at 4 microns and stained with Ulex to accentuate the microvessels. The number of microvessels per unit area was counted according to a standardized protocol at a magnification of x 250 in 4 fields, which showed high field (R = 0.98) and acceptable case reproducibility (R = 0.70). Microvessell counts did not show associations with other prognostic variables such as FIGO stage, bulky disease-or-not, differentiation grade, DNA ploidy, volume percentage epithelium, mitotic activity index and mean nuclear area. In survival analysis, a tendency for worse prognosis with higher microvessel counts was found, although statistical significance was not reached (p = 0.25). Correction for volume percentage epithelium did not improve this result. Multivariate survival analysis did not reveal additional prognostic value of microvessel counts to other prognostic factors such as FIGO stage, bulky disease-or-not, volume percentage epithelium, mitotic activity index and mean and SD of nuclear area. In conclusion, although a tendency for worse survival with higher microvessel counts has been found, vascularity does not seem to have a significant impact on survival of adequately debulked advanced ovarian cancer patients treated with cisplatin.

Quantitative pathologic features as predictors of long-term survival in patients with advanced ovarian cancer treated with cisplatin.

The prognostic value of morphometric and DNA flow cytometric features were studied and compared with FIGO stage, preoperative tumor load, residual disease status, Karnofsky index and classic pathologic features such as Broders' grade and histologic type in 58 FIGO stage III and IV adequately debulked ovarian patients with long-term follow-up. The mitotic activity index, volume percentage of epithelium, and mean and SD of nuclear area were assessed by interactive morphometry, and tumor material was routinely processed for DNA flow cytometric assessment of DNA ploidy and S-phase fraction. Survival analysis (Kaplan-Meier curves, Mantel-Cox test), revealed FIGO stage (P = 0.013) and the mean and SD of nuclear area to be significant prognosticators (P = 0.027 and P = 0.012, respectively). In multivariate survival analysis (Cox model), a multivariate combination of FIGO stage, preoperative tumor load and mean nuclear area was the best prognostic combination of features (P = 0.0034). These results confirm the findings of previous studies. We conclude that, in accord with previous studies, morphometric features are good predictors of survival after cisplatin treatment in advanced ovarian cancer, especially in combination with FIGO stage and preoperative tumor load.

Prognostic factors in well-differentiated early-stage epithelial ovarian cancer

The prognosis of patients with early ovarian cancer is good as compared with that of patients with advanced disease. However, there are no methods for predicting prognosis of early ovarian cancer, on which treatment decisions can be based. The prognostic significance of DNA flow cytometric and morphometric analysis was evaluated in 64 surgically treated patients with well-differentiated early-stage (International Federation of Gynecology and Obstetrics [FIGO] Stage IA, IB, IC, and IIA) epithelial ovarian cancer. The extent of the well-defined staging procedure was assessed strictly in every patient. Only five patients died of recurrent ovarian cancer; all of these patients belonged to the inaccurately staged group. No significant relationship was found between clinicopathologic characteristics, such as menopausal status, FIGO stage, histologic cell type, and 5-year disease-free survival rate. Forty-two of the tumors had a mitotic activity index (MAI) of less than 30, and 43 of the tumors showed a volume percentage epithelium (VPE) of less than 65. Neither as a single parameter nor in combination did MAI and VPE correlate significantly with disease-free survival. Thirty-two tumors (50%) were DNA diploid, 15 were considered wide-CV-diploid, and 17 were aneuploid. Nearly 90% of the tumors showed DNA indices (DI) of 1.40 or less. The 5-year disease-free survival rate was significantly lower (61%) for patients with DI greater than 1.40 than for those with DI of 1.40 or less (96%) (P < 0.005). From the total number of five patients who died of their disease, three had tumors with DI in the tetraploid range.

Intra-patient variation between breast cancer axillary lymph node metastases using quantifiable features.

The intra-patient variations of some clinically relevant quantifiable features, between axillary lymph node metastases were evaluated in 44 breast cancer patients. In all lymph node metastases detected (range 2-33 per patient), the mitotic figures were counted, the volume percentage epithelium was assessed and the mean nuclear area was measured. The intra-patient variation for each quantifiable feature was expressed by the coefficient of variation (CV). Since the measurement techniques used introduce a certain, well known variation themselves because of sampling and measurement errors, the CVs found had to be greater than methodological tolerance limits (established in previous studies) to be interpreted as indicating biological variation. The CVs exceeded the methodological tolerance limits in 86% of the cases for the mitotic count, in 48% of the cases for the volume percentage epithelium, and in 47% of the cases for the mean nuclear area. This indicated that in these cases, the variation found in the quantifiable features could not be explained by sampling or measurement errors and should be regarded as real biological variation. Furthermore, the variation in the quantifiable features studied showed a significant positive correlation with the number of lymph node metastases. Thus, there may be considerable intra-patient variation in quantifiable features between axillary lymph node metastases in breast cancer. This may indicate that these lymph node metastases originate independently from different clones within the primary tumour, that they are independently formed in different stages of tumour development, or that they, as an expression of intrinsic tumour heterogeneity, may develop in different directions from the start.

Syntactic structure analysis in invasive breast cancer: Analysis of reproducibility, biologic background, and prognostic value

The reproducibility, biologic background, and prognostic value of syntactic structure analysis were studied in a group of 94 patients with invasive primary breast cancer. Using an interactive digitizing video overlay system, the centers of malignant breast cancer nuclei were marked in the five (subjectively) most cellular fields of vision for each case at a final magnification of × 1,200, and the corresponding minimum spanning tree was composed for each field. From each minimum spanning tree, 10 syntactic structure features were derived; subsequently, the mean, standard deviation, minimum, and maximum values of the five fields analyzed were calculated for further statistical analysis. Forty statistics thus were available for each case. The reproducibility of repeatedly measuring the same field (independent of nuclearity) and the same patient twice by the same or different observers was good for most of the syntactic structure features. When comparing the statistics of the syntactic structure features with other established prognosticators, correlations were found with (in this order) standard deviation and mean nuclear area (expressing nuclear differentiation), volume percentage epithelium (expressing architectural differentiation), and mitotic activity index. In univariate survival analysis several syntactic structure statistics yielded prognostic significance, the best being the maximum of the number of nuclei with two neighbors ( P = .002; Mantel-Cox test, 12.4). Multivariate analysis revealed that syntactic structure features did not provide additional prognostic values with regard to each other. However, they did show additional prognostic values with regard to the multivariate prognostic index (currently one of the best prognosticators in breast cancer), which combines the mitotic activity index, lymph node status, and tumor size. Measurement of syntactic structure features could therefore contribute to an improved prediction of prognosis of breast cancer patients. In conclusion, syntactic structure analysis is a simple, fast, and highly reproducible technique that shows prognostic value in invasive breast cancer and also has important prognostic value with regard to the well-established and prognostically strong morphometric features. It seems to be a promising new method of analyzing tissue architecture in breast cancer and perhaps in many other tumors.

Prediction of Response to Adjuvant Chemotherapy in Premenopausal Lymph Node Positive Breast Cancer Patients with Morphometry, DNA Flow Cytometry and Her-2/Neu Oncoprotein Expression: Preliminary Results

The value of morphometry, DNA flow cytometry and HER-2/neu oncoprotein expression for prediction of response to adjuvant chemotherapy in premenopausal lymph node positive breast cancer patients was evaluated in a group of CMF treated patients and controls with long-term follow-up. In the treated group, the Morphometric Prognostic Index (cutpoint 1.1) was the best prognosticator (p less than 0.0001, MC = 16.9), followed by the Mitotic Activity Index, the volume percentage epithelium and the number of positive nodes. For the controls, only the % HER-2/neu oncoprotein expression revealed significant differences (p less than 0.0001, MC = 16.3). When directly comparing treated patients and controls stratified for a certain parameter, no significant differences were obtained, although a trend towards improved survival in the treated group was present for some of the subgroups for several parameters. These preliminary results indicate that morphometric features and quantitative HER-2/neu oncoprotein expression may be important factors for identifying cases that will or will not respond to adjuvant chemotherapy.

The prognostic value of morphometrical features and cellular DNA content in cis-platin treated late ovarian cancer patients.

In 73 CAP-1 treated stage III and IV ovarian cancers, the prognostic significance of morphometric features and cellular DNA content has been evaluated in comparison with histologic type, grade of differentiation and a number of clinical characteristics. Borderline tumours were excluded from the study. Median follow-up was 44 months, median survival time 36 months. Single features associated with prognosis were (in order of decreasing significance according to single variate analysis): FIGO stage (P = 0.0002), bulky disease (P = 0.004), standard deviation and mean of nuclear area (P = 0.0006 and P = 0.01), cellular DNA content (P = 0.01), mitotic activity index (P = 0.08) and volume percentage epithelium (P = 0.13, not quite significant). Tumours with a mean nuclear area greater than 70 micron2 (which occurred in 35% of the cases) were nearly all aneuploid. Multivariate analysis showed that the statistically most significant prognostic combination of features consisted of mean nuclear area, presence or absence of bulky disease and FIGO stage (in order of decreasing importance) (Mantel-Cox = 23.07, P less than 0.00001). A low value for the multivariate function of this combination of features was associated with a poor prognosis within 24 months, a high value with a favourable outcome. Another favourable combination of features appeared to be diploid cellular DNA content and a low mitotic activity index (11 patients, one died). However, even with the prognostically most favourable combination of these features, several patients died. Of all combinations of features investigated, only two were associated with an excellent prognosis (low mitotic activity index and low volume percentage epithelium). Cancers of 7 patients (10%) displayed such features, and none of them died during the follow-up period (minimally 20 and maximally 54 months). It is concluded that morphometric and flow cytometric analysis can provide significant and objective information to predict the prognosis of cis-platin-treated advanced ovarian cancer patients.

Proposal for therapeutic approach based on prognostic factors including morphometric and flow-cytometric features in stage III-IV ovarian cancer.

In 73 patients with International Federation of Gynecology and Obstetrics (FIGO) Stage III and IV ovarian cancer the prognostic significance of morphometric and flow-cytometric features has been evaluated in comparison with more commonly used prognostic factors such as stage and tumor mass. Single features associated with prognosis were as follows: FIGO stage, bulky disease, mean and standard deviation of nuclear area, cellular DNA content, mitotic activity index, and volume percentage epithelium. Multivariate analysis showed that the most significant prognostic combination of features consisted of mean nuclear area, presence or absence of bulky disease, and FIGO stage (in sequence of decreasing importance; Mantel-Cox = 23.07, P less than 0.00001). On the basis of these factors patients with a poor prognosis can be identified. On the other hand two features were associated with an excellent prognosis namely a low mitotic index and a low-volume percentage epithelium. It is concluded that morphometric and flow-cytometric analysis in combination with clinical features can provide significant information to predict the prognosis of patients with advanced ovarian cancer treated with debulking surgery and platinum-based chemotherapy. On the basis of our data a tentative proposal for future therapeutic approaches is made.

Morphometric data to FIGO stage and histological type and grade for prognosis of ovarian tumours.

The prognostic value of using histological typing, grading, and morphology, in addition to clinical staging, was assessed in 98 cases of invasive ovarian cancer of the common epithelial types (serous, mucinous, and endometrial). All of these cases had at least five years of follow up. When regression analysis was used, the International Federation of Gynaecology and Obstetrics' (FIGO) staging system was the best indicator for prognosis. Analysis of a combination of morphometric features was the second best indicator, being especially useful for the those patients with stage I disease. Variables that indicated a relatively poor prognostic outcome were mitotic index above 30; volume percentage epithelium above 65%; shortest nuclear axis above a mean of 1 X 1 micrometers. Histological typing of ovarian tumours was of limited value; mucinous tumours have a somewhat better prognosis than serous tumours, but the prognostic value of typing alone was found to be limited. Qualitative histological grading was useful, but the prognostic value of morphometric grading was better. Measurement of morphological features with an interactive computer program is simple and can be done by a pathologist or a technician: in future it is likely that such automated systems of measurement will improve the objectivity of tissue analysis.