The premalignant disease of the endometrium: endometrial intraepithelial neoplasia

The WHO 1994 classification for endometrial hyperplasias is based on the morphologic features of the lesions. This system characterizes the nuclear cytologic morphology as typical or atypical and describes the glandular architectural pattern as simple or complex. The main problem of this classification is the poor reproducibility. Although the predictive value of the atypical category is high, there are many typical hyperplasia cases with cancer progression. Modern molecular data related to endometrial tumorigenesis and precise computerized morphometric analysis have identified the lesion that may be considered as a precursor of endometrioid adenocarcinoma. By definition, this endometrial intraepithelial neoplasia (EIN) is a clonal proliferation of architecturally and cytologically altered endometrial glands which are prone to malignant transformation to endometrioid (type I) endometrial adenocarcinoma. The morphometric basis of EIN diagnosis is the D-score (DS), which is a logical combination of three morphometric features that represent the glandular complexity, glandular volume and cytological alterations. PTEN inactivation and K-ras mutation are the earliest genetic changes that can be revealed in these lesions. Hyperplasia cases that do not fit into the EIN categories are considered as benign or hormonal endometrial hyperplasia. This is the theoretical basis of a new classification system in premalignant endometrial diseases. Retrospective clinical data proved the high predictive value of the EIN scheme, so the decision on therapy can be more established. The reproducibility is excellent with application of precise definitions and PTEN immunohistochemistry. In the "Blue book" published in 2003 the WHO introduces the new morphometric- and molecular-based EIN system, and recommends it as an alternative classification method.     

The principles and advances of quantitative pathology

This article gives an overview of the quantitative pathologic techniques used today, with special emphasis on interactive morphometry and its application in the clinical setting. At present, stereologic calculations may be necessary, but in a diagnostic setting have only rarely proved to be essential. The reproducibility of the measurements is discussed in relation to the definition of the particles and staining methods. A number of technical factors that cause random errors are mentioned, such as quality of the slides, magnification, definition of the particles to be measured and measuring protocol. Large-scale experiments have revealed that the means of nuclear morphometric and certain stereologic features are reproducible, such as in the volume percentage of epithelium, the surface densities of glands and the mitotic activity index. The diagnostic applications of the standard deviation and shape factors of nuclear quantitative features require additional precautions, however. Having quantified cell and tissue features, multivariate analysis may result in a better discrimination of two or more groups under study. The quantitative pathologic examination of cells and tissues can provide important diagnostic and prognostic information. Quantitation in pathology is especially useful in so-called continuous lesions, in which interobserver and intraobserver disagreement is considerable. An important requirement of diagnostic morphometry is object selection by a skilled pathologist; the use of morphometry as a black box can result in dramatic errors. The criteria used for a morphometric classification rule that can be used for clinical applications are summarized. Quality control of the whole measuring system is essential. Application of these techniques for more than six years in diagnostic pathology has repeatedly corrected previous qualitative diagnoses.(ABSTRACT TRUNCATED AT 250 WORDS)     

Nucleolar organizer regions in the normal,hyperplastic and carcinomatous epithelium of endometrium

A silver colloid technique to identify nucleolar organizer region associated protein (AGNORs) has been applied to paraffin sections in a total of 43 endometrial hyperplasias (24 adenomatous and 19 adenocystic) 26 endometrial carcinomas and 22 normal endometria (11 of proliferative and 11 of secretory phase). A morphometric analysis of highly magnified photographic images of AGNORs in light microscopic preparations was performed. Malignant tumor cells showed significantly higher AGNOR numbers, maximum diameter and mean area compared with normal and hyperplastic endometrium, with the exception of adenocystic hyperplasia whose D_max and mean area were significantly larger. Regarding the distribution pattern of AGNOR dots in the cases studied, it was found that normal and hyperplastic endometrium had a mainly clustered distribution while endometrial adenocarcinomas revealed a scattered one. The significant differences observed in the number of AGNORs, their size and mean area between benign and malignant endometrial epithelia suggest that the AG-NOR staining technique is of diagnostic importance in distinguishing between these two groups.     

Nucleolar organizer regions in the normal, hyperplastic and carcinomatous epithelium of endometrium.

A silver colloid technique to identify nucleolar organizer region associated protein (AGNORs) has been applied to paraffin sections in a total of 43 endometrial hyperplasias (24 adenomatous and 19 adenocystic) 26 endometrial carcinomas and 22 normal endometria (11 of proliferative and 11 of secretory phase). A morphometric analysis of highly magnified photographic images of AGNORs in light microscopic preparations was performed. Malignant tumor cells showed significantly higher AGNOR numbers, maximum diameter and mean area compared with normal and hyperplastic endometrium, with the exception of adenocystic hyperplasia whose Dmax and mean area were significantly larger. Regarding the distribution pattern of AGNOR dots in the cases studied, it was found that normal and hyperplastic endometrium had a mainly clustered distribution while endometrial adenocarcinomas revealed a scattered one. The significant differences observed in the number of AGNORs, their size and mean area between benign and malignant endometrial epithelia suggest that the AGNOR staining technique is of diagnostic importance in distinguishing between these two groups.     

Application of morphometry in tumor pathology

The application of morphometry in tumor pathology is discussed, e.g., its use in studying the biology of tumors, in creating tumor classification(s), in creating methods for the identification of a tumor in the diagnostic context, and in characterizing diagnostic histopathology in absolute terms. In traditional subjective diagnostic histopathology, reproducibility can be defined satisfactorily, but the definition of accuracy is ambiguous; in morphometric histopathology, a satisfactory definition is found for both concepts but it may be difficult to separate them in practice. Morphometric histopathology can study parameters measured from sections or parameters derived from the primary measurements through calculations. In the histopathology of tumors, the following parameters have turned out to be specially valuable: densitometric measurements of nuclei, nuclear area, perimeter and form factors, nucleolar parameters, the number of mitotic cells per area, the cellularity, the volume fraction of the epithelium, and parameters associated with the fraction of tumor tissue in the sample. The standard deviation or other moments of the distribution of these measurements can be more relevant than the mean values of the results. This indicates that more attention should be given to sampling rules, which are important in defining the efficiency of the methods. For rational application of morphometric methods, it is very important to make a distinction between group morphometry and diagnostic morphometry. The latter engenders numerous sources of variation (variation in section thickness, variation in tissue processing, variation in the techniques of measurement, interobserver variation, interlaboratory variation, variation due to subjective interpretation, etc.), which are usually better controlled in group morphometry. The influence on morphometric parameters of variation in section thickness and tissue shrinkage during processing are discussed.     

Morphometry, densitometry and pattern analysis of plastic-embedded histologic material from urothelial cell carcinoma of the bladder.

An image analysis method of grading histologic sections of bladder carcinoma was tested. The method was new in four respects. First, for fixation of the biopsies a coagulant fixative was used. Second, 2-microns plastic sections were used to ensure the reproducibility of nuclear imaging. Third, a new stereologic approach was used for calculation of the nuclear volume and DNA content. Fourth, for the classification rule the morphometric, densitometric and texture features were used in concert. The IBAS 2000 instrument was used for the measurements. Texture analysis of the chromatin patterns was performed using Markovian texture features. Using discriminant analysis, of 22 parameters, 2 morphometric, 2 densitometric and 3 texture features were selected for the classification rule. With them, 89% of the bladder carcinomas were correctly classified into the three grades. All grade III tumors were classified correctly. Among the features tested, the densitometry of the DNA had the highest F values. All of the grade III tumors and 45% of the grade II tumor group had DNA histograms indicating aneuploidy. This study showed that plastic-embedded material is well suited to morphometry and densitometry and can be used for quantitative grading of bladder carcinoma.     

Liquid-based endometrial cytology: cyto-histological correlation in a population of 917 women

OBJECTIVE: Liquid-based cytology, because of its capacity to reduce the obscuring factors and to provide thin-layer specimens, represents an opportunity to reevaluate endometrial cytology. In order to assess the utility of the liquid-based method in endometrial diagnosis, we evaluated its accuracy in comparison with histology. METHODS: Nine hundred and seventeen women scheduled for hysteroscopy were enrolled in the study. After providing informed consent, all the women proceeded sequentially to hysteroscopy, endometrial cytology and then biopsy endometrial sampling. RESULTS: Cyto-histological correlations were possible in 519 cases (57%): in 361 (39%) cases the biopsy was inadequate, in 15 (2%) the cytology was inadequate, and in 22 (2%) both were inadequate. At biopsy 25 (3%) women had adenocarcinoma, 5 (1%) had adenomatous atypical hyperplasia and 21 (2%) had simple non atypical hyperplasia. At cytology two adenocarcinomas and one adenomatous atypical hyperplasia were underrated as atypical hyperplasias and as non-atypical hyperplasia; two simple non-atypical hyperplasias were reported as negative; and eight cases were false positive (non-atypical hyperplasia at cytology, negative at biopsy). In our population, the cytology provided sufficient material more often than biopsy (P < 0.04). Sensitivity was estimated at 96%, specificity at 98%, positive predictive value at 86% and negative predictive value at 99%. CONCLUSIONS: We concluded that endometrial cytology may be an efficient diagnostic method. It could be applied to selected patients solely or in association with ultrasonography. The combination of these two noninvasive procedures may improve their diagnostic accuracy and reduce unnecessary hysteroscopies, thereby producing benefits for women and society.     

A karyometric approach to the characterization of atypical endometrial hyperplasia with and without co-occurring adenocarcinoma

OBJECTIVE: To develop a karyometric image analysis approach to distinguishing atypical endometrial hyperplasia with and without co-occurring adenocarcinoma. STUDY DESIGN: Six cases of atypical hyperplasia without and 6 cases with co-occurring adenocarcinoma, 4 cases of normal endometrium and 3 cases of adenocarcinoma were identified. From each case 100 nuclei were measured in representative diagnostic areas identified by an experienced pathologist. Discriminant analyses were performed. An unsupervised learning algorithm was applied to define and characterize different nuclear phenotypes, and those data were used to identify cases with co-occurring adenocarcinoma. RESULTS: Discriminant analysis showed that nuclei from atypical hyperplasia and atypical hyperplasia with co-occurring adenocarcinoma are statistically different. The unsupervised learning algorithm revealed differences in nuclear subpopulations that can be used to correctly identify an estimated 85% of individual cases. CONCLUSION: Nuclei from atypical hyperplasia without and with co-occurring adenocarcinoma have statistically different karyometric characteristics that may facilitate case classification.     

Digital imaging analysis of normal, hyperplastic and malignant endometrial cells in endometrial brushing samples

Sixty cytologic specimens obtained by endometrial brushing (using the Gynecyte device) were quantitated by digital imaging techniques. These samples included 25 from normal endometria, 6 from persistent proliferative endometria, 14 from cystic or adenomatous hyperplasias and 15 from carcinomas. The morphometric parameters surveyed included mean cell area, nuclear area, perimeter and long and short axes. The amount of hematoxylin dye in the nuclei was expressed by mean transmittance (mean of gray levels) and chromatin index (standard deviation of gray levels). The frequency distributions of cells derived from normal tissue and persistent proliferative endometrium were quite similar. The quantitative parameters of cystic and adenomatous hyperplasia, although intermediate between those of normal endometrium and carcinoma, were closer to the former than to the latter. Using stepwise discriminant analysis of the morphometric parameters, 83% of the specimens were correctly classified into the categories of normal/persistent proliferative, hyperplasia and carcinoma. The accuracy was improved to 88% when densitometric parameters were added. This study demonstrates the potential application of digital imaging techniques to the distinction and classification of normal, hyperplastic and malignant endometrial cells.     

Morphometry in the differential diagnosis of granulosa-cell tumors of the ovary

Although the diagnosis of granulosa-cell tumors of the ovary is usually consistent and reproducible, in some cases the differentiation from poorly differentiated adenocarcinomas can be difficult. To investigate our subjective impression of the similarity of nuclei in both types of tumors, seven granulosa-cell tumors and eight poorly differentiated adenocarcinomas were studied with morphometry, with a variety of nuclear parameters measured in 100 nuclei per case. The findings showed that, in general, granulosa-cell tumors have a slightly higher mean nuclear contour index (NCI), which is a measure of the nuclear indentation or grooving, and a somewhat lower mean nuclear area than do adenocarcinomas. There is considerable overlap, however, with the nuclear patterns of the two types of tumors forming a morphologic continuum. Multivariate analysis gave a better discrimination but did not entirely eliminate the overlap. The maximum NCI was the best single discriminator. While only one of the granulosa-cell tumors had a maximum NCI less than 5.11, none of the adenocarcinomas exceeded this value. The only granulosa-cell tumor with a maximum NCI below the threshold was in a case with a much less favorable clinical course. The results of this study indicate that objective morphometric nuclear criteria are useful in the diagnosis of granulosa-cell tumors and possibly have some prognostic value.     

A comparative study in morphometric grading of transitional cell carcinoma of the urinary bladder

To overcome the considerable observer inconsistency in the histologic grading of transitional cell carcinomas, the value of four different morphometric grading methods was investigated in 61 tumors of the bladder. Only two methods showed satisfactory reproducibility. Both methods, one based on random nuclear sampling and the other on selective nuclear sampling, showed an increase in the mean and standard deviation of the nuclear area with higher tumor grades (P less than .00001). Morphometric classification of the learning set (44 cases) was in agreement with the unequivocally assessed histologic grade in 35 cases (79.5%) using random sampling and in 38 cases (86.4%) using selective sampling. By reducing the grading classes to "low" (grades 1 and 2) and "high" (grade 3) and by introducing a classification probability threshold (0.80), an accurate morphometric classification was achieved in 38 cases (86.4%) using random sampling and in 41 cases (93.2%) using selective sampling. Of the 17 cases with histologic grading discrepancies, all 10 low-grade tumors (with discrepancies of grade 1 versus grade 2) were correctly classified as low-grade carcinomas by both of the morphometric methods; in the remaining 7 cases, with low-versus-high discrepancies (grade 2 versus grade 3), the selective method yielded better correlation with the tumor stage and clinical follow-up. It is concluded that morphometric classification is an acceptable alternative for histologic grading by pathologists, provided that the reproducibility of the method is confirmed. Although both random and selective sampling yielded satisfactory classifications, the selective method gave more reliable results as confirmed by the clinical behavior.     

Potential of the learning vector quantizer in the cell classification of endometrial lesions in postmenopausal women

OBJECTIVE: To investigate the potential of artificial neural networks for cell identification in endometrial lesions from postmenopausal women. STUDY DESIGN: The study was performed on cytologic material obtained by the Gynoscann endometrial cell samplerfrom 12 cases of atrophic endometrium, 48 cases of hyperplasia without cytologic atypia (18 cases of simple hyperplasia and 30 cases of complex hyperplasia), 12 cases of hyperplasia with cytologic atypia (complex atypical hyperplasia) and 48 cases of adenocarcinoma (30 cases of well-differentiated, 12 cases of moderately differentiated and 6 cases of poorly differentiated carcinoma). From each case approximately 100 cells were examined using a custom image analysis system. A learning vector quantizer (LVQ) identified the collected data. RESULTS: Investigation of cells from Endometrial Alterations with LVQ proved that according to the nuclear characteristics, as expressed by morphometric and textural measures, the endometrial cells from postmenopausal women may be identified as belonging to one of thefollowing three groups: atrophy, hyperplasia without cytologic atypia (simple and complex hyperplasia) and malignant neoplastic lesions (atypical complex and adenocarcinoma). CONCLUSION: The role of nuclear morphologic features in the cytologic diagnosis of endometrial alterations was confirmed. The overlap in thefeature space observed indicates that cell characteristics do not form strictly separate clusters. Thatfact explains the difficulty that morphologists have with the reproducible identification of cells from endometrial lesions in postmenopausal women. Application of LVQ offers a good classification at the cell level and promises to be a powerful toolfor classification on the individual patient level andfor the clarification of the natural history of endometrial pathology.     

Computerized morphometric study on fine needle aspirates of cellular follicular lesions of the thyroid

OBJECTIVE: To investigate the value of computerized nuclear morphometry in the differential diagnosis of cellular follicular lesions of the thyroid cytologically diagnosed on fine needle aspiration (FNA) smears. STUDY DESIGN: Sixty cases of FNA thyroid smears were cytologically diagnosed and classified as follows: 30 cases of follicular carcinoma, 20 cases of cellular hyperplastic nodules and 10 cases of follicular adenoma. Using an image analysis system, two morphometric variables, nuclear area and major axis length of the nucleus, were measured for each case. RESULTS: For both nuclear morphometric variables, statistical differences were found between carcinomas and hyperplastic nodules as well as between carcinomas and adenomas. No statistical differences were found between the nuclear variables in either hyperplastic nodules or adenomas. CONCLUSION: The results confirm the aim of our study, to establish nuclear morphometry by computerized image analysis as an additional tool in the differential diagnosis of thyroid follicular lesions cytologically diagnosed on FNA smears.     

Reproducibility of nuclear morphometric measurements in benign human epithelial cells. Simulation of variations in routine tissue processing.

The value of nuclear morphometric measurements in diagnostic pathology is determined largely by the reproducibility of the measurements. Although a variety of factors have been shown to affect tissues during processing, the regulation of fixative type and the avoidance of air drying in particular have been shown to avoid significant variations in nuclear measurements. The current study simulated routine tissue processing in order to identify any factors that may introduce variability of nuclear morphometric values in day-to-day processing if air drying is avoided and fixative type and pH are regulated. Samples of benign endometrium were collected from three uteri, fixed in phosphate-buffered formalin (PBF) from 2 hours to 15 days and dehydrated in an automated tissue processor on four occasions. In addition, tissue from one case was cut at 4, 6 and 8 microns, simulating the potential variations in section thickness that may occur during routine processing. Mean nuclear areas and shape factors of epithelial cells were then determined using computed planimetry. By analysis of variance, no significant differences were found in nuclear morphometric values in relation to time of fixation, dehydration runs or tissue section thickness; coefficients of variation for all variables were less than 7%. This study suggested that routinely processed tissues are adequate for morphometric analysis, including retrospective analysis, provided that tissues are fixed in a pH-regulated fixative such as PBF and air drying is avoided.     

Cytomorphologic and morphometric limitations of the assessment of atypia in fibroadenoma of the breast

OBJECTIVE: To investigate the relevance of nuclear morphometry in separating the categories of "fibroadenoma" and "fibroadenoma with atypia." STUDY DESIGN: Thirty consecutive breast lumps, on which a fine needle aspiration (FNA) diagnosis of fibroadenoma was followed by excision and histopathologic confirmation of the diagnosis, were included. Atypia on cytology was based on cell overlap, nuclear enlargement and cell dyscohesion. Nuclear morphometric comparison was carried out between the categories of fibroadenoma, fibroadenoma with atypia and grade 1 ductal carcinoma cases that formed part of an earlier study. The parameters employed were area, roundness, diameter, perimeter and grey level. RESULTS: Among the 30 cases of fibroadenoma reported on FNA, an additional component of atypia was noted in 5. On subsequent histopathology, atypia was not confirmed in any of the cases. On morphometric analysis, a significant difference was noted between fibroadenoma and fibroadenoma with atypia categories, as between fibroadenoma and grade 1 ductal carcinoma cases. However, no significant difference was noted between fibroadenoma with atypia and grade 1 ductal carcinoma cases. CONCLUSION: FNA assessment of atypia in cases of fibroadenoma is difficult. Even conventional nuclear morphometry, though supporting the initial impression of atypia, does not help with this assessment. Also, based on morphometry alone, there may be difficulty separating fibroadenomas with atypia and grade 1 ductal carcinomas. Larger studies, employing other morphometric parameters, such as chromatin texture and fractal dimension, may shed further light on the subject.     

Computerized interactive morphometry as an aid in the diagnosis of pleural effusions

A morphometric study of cytologic preparations from patients with benign and malignant (mesothelioma and carcinoma) pleural effusions is reported. The routine cytologic smears from these specimens were studied with a new system of video-based computerized interactive morphometry (CIM) that allows the measurements of real-time images of cell profiles by the simple procedure of touching the two extreme points of a diameter of interest on a touch-sensitive screen. For each cell, the nuclear profile diameter (NPD) and the cytoplasmic profile diameter (CPD) are measured and categorized into classes with 2-microns intervals; the NPD/CPD ratio is also calculated. The mean NPD is calculated for the specimen after measurement of 100 cells. The data were interpreted by two independent methods: a statistical method of discriminant analysis that classifies the lesions as benign, carcinoma or mesothelioma and provides a probability statement of membership in a particular diagnostic class and an ad-hoc algorithm that categorizes the effusions as benign or malignant based on hierarchic analysis. A data base derived from study of the first 24 cases was constructed and utilized for the test classification of the second 24 cases, which were treated as specimens of unknown diagnosis. The discriminant analysis correctly classified 21 of the 24 test cases into their proper diagnostic groups. The algorithm for a computer-generated pathologic diagnosis correctly identified 47 of the 48 cases as benign or malignant. The technical advantages of video-based CIM over the existing morphometric methods are discussed.     

Fine needle aspiration diagnosis of hyperplastic and neoplastic follicular nodules of the thyroid. A morphometric study.

The differentiation of hyperplastic nodules, follicular adenomas and follicular carcinomas from fine needle aspiration (FNA) cytology smears may be difficult. To better define the diagnostic criteria, we studied the morphometric parameters of nuclear area (NA), nuclear:cytoplasmic ratio and nuclear roundness (NR) in single cells and cell aggregates. In addition, we quantitated the percentage of touching or overlapping nuclei (NO) and the percentage of extent of nuclear area of overlap (NAO) in cellular aggregates. We measured cellular samples from FNA aspirates obtained from 20 hyperplastic nodules, 21 follicular adenomas, 5 encapsulated follicular carcinomas and 22 invasive follicular carcinomas, all of which were subsequently confirmed by histologic examination. Cellular aggregates provided the maximum diagnostic information. Stepwise discriminant analysis revealed that nuclear size, nuclear roundness and the percentage NAO allow optimum differentiation of hyperplasia, adenomas and carcinomas. Clearly, all of the poorly differentiated carcinomas (large NA, low NR, high NO and NAO) could be reliably diagnosed. Discriminant analysis allowed the differentiation of carcinoma from adenoma in 20/22 carcinomas (91%) and all 21 adenomas (although 2 adenomas were called hyperplasias and 3 hyperplasias were called adenomas).     

Morphometric characterization of nuclei in non-Hodgkin's malignant lymphoma

In addition to the nuclear area and a form factor, four morphometric parameters of nuclear shape (ID, R1, R2 and ND), obtained by the application of the principles of mathematical morphology, were used to characterize the nuclear contours in non-Hodgkin's malignant lymphomas. The values for each parameter were determined in 58 cases of non-Hodgkin's lymphoma categorized according to the Kiel and National Cancer Institute classifications. Small-cell, mixed and large-cell lymphomas could be distinguished on the basis of the mean nuclear area. The shape parameters R1, R2 and ID were efficient discriminators of the large centrocytic (cleaved-cell) lymphomas. Neither size nor shape factors could distinguish between centroblastic and immunoblastic tumors. The good correlation between the morphometric findings and the histopathologic categories suggest that morphometry may provide a quantitative and objective method for grading lymphomas.     

Is there any potential link among caspase-8, p-p38 MAPK and bcl-2 in clear cell renal cell carcinomas? A comparative immunohistochemical analysis with clinical connotations

Background

Management of endometrial precancerous lesions has been of much debate due to inconsistencies in their classification, natural history and histologic diagnosis. Endometrial hyperplasia constitutes a wide range of histomorphologic features associated with high intra and interobserver diagnostic variability. Although traditional microscopic diagnosis is by far the most applicable method and the gold standard for histomorphologic diagnosis, digitized image analysis has been used as a powerful adjunct to maximize the histologic data retrieval and to add some detailed objective criteria for correct diagnosis in difficult cases.

Methods

A series of 100 endometrial curettage specimens with diagnosis of endometrial hyperplasia or well differentiated adenocarcinoma were blindly reviewed by 5 pathologists; their intra and interobserver reproducibility determined and further compared to the objective morphometric data i.e. D-score and volume percent of stroma (VPS).

Results

The results were assessed using the weighted kappa statistics. Mean intraobserver kappa value was 0.8690 (99.44% agreement). Mean interobserver kappa values by diagnostic category were: simple hyperplasia without atypia: 0.7441; complex hyperplasia without atypia: 0.3379; atypical hyperplasia: 0.3473, and well-differentiated endometrioid carcinoma: 0.6428; with a kappa value of 0.5372 for all cases combined. Interobserver agreement was in substantial rate for simple hyperplasia (SH) and well differentiated adenocarcinoma (WDA) but was in fair limit for complex hyperplasia (CH) and atypical hyperplasia (AH). Intraobserver agreement was almost perfect. The specimens were divided in two groups according to the computerized morphometric analysis: Endometrial Hyperplasia (EH) ( D Score ≥ 1 or VPS ≥ 55%) and Endometrial Intraepithelial Neoplasia (EIN) (D-Score < 1 or VPS < 55%). Morphometric findings were closely compatible with routine WHO classification made by one expert pathologist; however; diagnosis of (CH) and (AH) made by other pathologists were not concordant with morphometric data.

Conclusion

It may be necessary to make some revisions in WHO classification for endometrial hyperplasia and precancerous lesions.