UbcH10 expression in benign, hyperplastic, and malignant endometrial curetted materials: a tissue microarray study

The aim of this study was to investigate the role of UbcH10 expression in the differential diagnosis of benign, hyperplastic, and malignant endometrial tissues and also the relationship of UbcH10 with the clinicopathologic parameters of malignant cases. A tissue microarray was performed for 81 endometrial curettage biopsies, which histological diagnosis had demonstrated to be 13 cases of proliferative endometrium, 7 cases of disordered proliferative endometrium, 5 cases of complex atypical hyperplasia, 24 cases of nonatypical hyperplasia, and 32 cases of endometrioid adenocarcinoma. Expression of UbcH10 was assessed by immunohistochemistry. When groups were compared according to UbcH10 percentages and scores, a statistically significant difference was found only between the carcinoma group and the other groups, except the complex atypical hyperplasia group (P < .05). In the malignant group, UbcH10 percentages and scores were only significantly related to age. There was no significant association between UbcH10 expression and tumor grade and stage. Overexpression of UbcH10 may be a useful indicator of endometrial carcinoma. UbcH10 also deserves further evaluation in the detection of prognostic mean and also for its role in endometrial carcinogenesis.     

ANGIOGENESIS IN NORMAL,HYPERPLASTIC, AND NEOPLASTIC ENDOMETRIUM

The purpose of this study was to quantify vascular density in the stroma of normal, hyperplastic, and neoplastic endometria and to explore its relationship to other prognostic features of endometrioid adenocarcinoma. Curettage specimens of proliferative and mid-secretory endometrium; simple, complex, and atypical endometrial hyperplasia; and grade I endometrioid adenocarcinoma were stained with Factor VIII-related antigen. The number of vessels per mm² of stroma was calculated for each case. The stroma of mid-secretory and hyperplastic endometrium was more vascular than that of proliferative endometrium. The stroma of adenocarcinoma, though reduced in proportion to the epithelium, was significantly more vascular than that of normal or hyperplastic endometrium. Stromal vascular density was not related to the depth of invasion, the presence of lymphovascular space permeation, or the state of the adjacent endometrium, whether atrophic or hyperplastic.     

β-catenin、Glut-1和PTEN蛋白在子宫内膜样腺癌发生过程中的表达及意义

目的 通过分析子宫内膜上皮内瘤变(EIN)诊断、分类与子宫内膜增生WHO(2003)分类的关系,探讨β-catenin、Glut-1和PTEN蛋白在子宫内膜样腺癌发生过程中的表达及其意义.方法 根据EIN诊断及分类标准,对83例子宫内膜增生病例进行再分类.采用免疫组织化学SP法,对10例增殖期子宫内膜、83例子宫内膜增生及24例子宫内膜样腺癌组织中β-catenin、Glut-1及PTEN蛋白的表达进行检测.结果 (1)83例子宫内膜增生病例中共检出24例EIN病例,总检出率为28.9%(24/83).24例EIN病例中,来自复杂型不典型性增生16例(66.7%,16/24),但EIN的检出率与不典型增生的分级无明显关系(P＞0.05).(2)β-catenin蛋白在增殖期子宫内膜中呈正常表达,良性子宫内膜增生的异常表达率为10.2%(6/59),而EIN和子宫内膜样腺癌的异常表达率(50%,12/24;66.7%,16/24)分别明显高于良性子宫内膜增生(P＜0.01),但二者间的异常表达率差异无统计学意义(P＞0.05).(3)Glut-1蛋白在增殖期子宫内膜、良性子宫内膜增生组织中均呈低表达,而在EIN和子宫内膜样腺癌中的高表达率分别为58.3%(14/24)和70.8%(17/24),均显著高于增殖期子宫内膜及良性子宫内膜增生(P＜0.01),但二者高表达率间差异无统计学意义(P＞0.05).(4)PTEN蛋白在EIN病例中的失表达率(37.5%,9/24)与子宫内膜样腺癌(62.5%,15/24)、增殖期子宫内膜(2/10)及良性子宫内膜增生(28.8%,17/59)比较差异均无统计学意义(P＞0.05),但子宫内膜样腺癌的失表达率则明显高于增殖期子宫内膜及良性子宫内膜增生病例,其差异均具有统计学意义(P＜0.05).结论 β-catenin蛋白的异常表达和Glut-1蛋白高表达是子宫内膜样腺癌发生过程中的早期事件,二者在区别良性子宫内膜增生、EIN和子宫内膜样腺癌中可能是有用的免疫标志物.PTEN蛋白失表达是子宫内膜样腺癌发生过程中的极早期事件,但将其作为EIN病变的诊断性标志物并不恰当.     

Inhibin (10.7 kD prostatic peptide) in normal, hyperplastic, and malignant human endometria: an immunohistochemical study.

The expression of inhibin, a 10.7 kD follicle-stimulating hormone (FSH)-suppressing prostatic peptide of 94 amino acids, was investigated in normal human endometrium, endometrial hyperplasia, and adenocarcinoma, employing the avidin-biotin immunoperoxidase technique. The antiserum used was raised in rabbits against prostatic inhibin isolated from human seminal plasma. The study included 15 well differentiated, 32 moderately differentiated, and 21 poorly differentiated endometrial adenocarcinomas; 26 simple, five complex, and two complex atypical endometrial hyperplasias; and, for comparison, 25 normal proliferative and 30 normal secretory endometria. In malignant and hyperplastic endometrial tissues, inhibin was localized in the epithelial cytoplasm of endometrial glands while the stroma showed weak reactivity. On the other hand, inhibin was undetectable in the early proliferative phase, but was present on the luminal border of the glandular epithelium in the mid- and late proliferative phases. Secretory endometrium displayed strong inhibin reactivity in the cytoplasm of glandular epithelium and in the stroma. The increased inhibin reactivity in secretory endometrium as compared with the proliferative phase is indicative of a functional role for inhibin in the uterus. In addition, its localization in proliferative, hyperplastic, and malignant endometria suggests a possible regulatory role for inhibin in endometrial proliferation and growth.     

Significance of hormone receptor status and tumor vessels in normal, hyperplastic and neoplastic endometrium

The aims of this study were to identity the roles of tumor vessels and hormone receptor status in normal, hyperplastic, and neoplastic endometrium, and to explore their relationships with other prognostic factors of endometrial adenocarcinoma. Endometrial curettage specimens of proliferative phase and secretory phase endometrium, simple hyperplasia with or without atypia, complex hyperplasia with or without atypia, and grade 1 adenocarcinoma were examined for estrogen receptor alpha (ER alpha), progesterone receptor (PgR), Ki-67 labeling index (LI), cyclin D1, microvessel density (MVD), and area of venules (AV) using an immunoperoxidase method. The results showed high levels of ER alpha in complex hyperplasia, and high levels of PgR in simple hyperplasia without atypia. Expression of ER alpha in the endometrium decreased in a stepwise manner from complex hyperplasia without atypia to grade 1 adenocarcinoma. Expression of PgR in the endometrium decreased in a stepwise manner from simple hyperplasia without atypia to grade 1 adenocarcinoma. In contrast, the expressions of Ki-67 LI, cyclin D1, MVD and AV in the endometrium increased in a stepwise manner from normal, simple or complex hyperplasia with or without atypia to grade 1 adenocarcinoma. These changes may become irreversible on progression from simple or complex hyperplasia to neoplasia.     

Expression of c-kit (CD117) in benign and malignant human endometrial epithelium

BACKGROUND: The proto-oncogene c-kit encodes a tyrosine kinase receptor (CD117) with a molecular weight of 145 kd. Previous studies, predominantly utilizing immunohistochemistry, have led to contradictory findings regarding the expression of CD117 in the endometrium. To help resolve this issue, we analyzed a series of benign and malignant endometrial tissues using both immunohistochemistry and Western blot analysis. OBJECTIVE: To examine the expression of CD117 in benign and malignant human endometrial tissues. METHODS: The expression of CD117 in 35 benign endometrial tissues (7 hyperplastic, 14 proliferative, 14 secretory) and 10 endometrioid carcinomas was investigated by immunohistochemistry (clone K45 monoclonal antibody). Immunoprecipitation (clone K69 monoclonal antibody) followed by Western blotting (clone K45 monoclonal antibody and clone 1.D9.3D6 monoclonal antibody) was performed to confirm CD117 expression. RESULTS: Fifty-seven percent of the hyperplasias, 93% of proliferative endometria, and 79% of secretory endometria immunostained positively for CD117. In benign endometria, epithelial staining tended to be more intense in the hyperplastic and proliferative endometria as compared to the secretory endometria, whereas endometrial stromal cells were not immunoreactive. Of the 10 frozen endometrial tissues analyzed by immunohistochemistry, 4 of 9 endometrioid carcinomas and a single case of an endometrioid polyp developing in association with a carcinoma expressed CD117. Immunoprecipitation followed by Western blot analysis confirmed expression of full-length CD117 in an endometrial polyp and carcinoma, and revealed a correlation between levels of immunoprecipitated CD117 and immunohistochemical staining intensity. CONCLUSIONS: Benign and malignant endometrial tissues express CD117. Our data suggest (a) a possible relationship between estrogen and CD117 expression in benign endometrium and (b) potential involvement of this growth factor receptor in endometrial carcinogenesis.     

Inhibin/activin subunits beta-A (-betaA) and beta-B (-betaB) are differentially localised in normal, hyperplastic and malignant human endometrial tissue

Inhibins (INHs) are dimeric glycoproteins composed of an alpha (-alpha) subunit and one of two possible beta (beta-) subunits (betaA or betaB). The aims of this study were to determine the frequency and distribution of INH beta (betaA and betaB) subunits in normal, hyperplastic and malignant human endometrium. Endometrial tissue was obtained from normal, hyperplastic (simple, complex and atypical) and endometrioid adenocarcinoma (EC) and INH-alpha, -betaA and -betaB were labelled using immunohistochemistry and immunofluorescence. INH-betaA and -betaB labelling was increased significantly between the proliferative and secretory phase (p<0.05). The lowest labelling was demonstrated in EC, being significantly lower than in secretory phase (p<0.01) and in simple, complex and atypical hyperplastic tissue (p<0.05). For inhibin-betaB, the most intense labelling was noted in atypical hyperplasia compared to EC (p<0.05). A strong colocalisation of inhibin-alpha and -betaA could be demonstrated in malignant endometrial tissue, suggesting the production of inhibin A within the tumour. Additionally, only limited colocalisation of inhibin-betaB with -alpha subunit could be observed, suggesting the synthesis of activin B rather than inhibin B in malignant endometrium. In conclusion, INH-betaA and -betaB were labelled in normal, hyperplastic and malignant endometrium. Hyperplastic tissue labelled more intensely than EC for the presence of INH-betaA and -betaB, suggesting a substantial function in endometrial pathogenesis and an important role in endometrial carcinogenesis.     

Problems in the differential diagnosis of endometrial hyperplasia and carcinoma.

The differential diagnosis of endometrial hyperplasia and well-differentiated endometrioid adenocarcinoma is complicated not only by the resemblance of these lesions to each other, but also by their tendency to be overdiagnosed (particularly hyperplasia) on the background of polyps, endometritis, artifacts, and even normally cycling endometrium. Atypical hyperplasia may also be overdiagnosed when epithelial metaplastic changes occur in simple or complex hyperplasia without atypia. Low-grade adenocarcinomas are best recognized by architectural evidence of stromal invasion, usually in the form of stromal disappearance, desmoplasia, necrosis, or combinations of these findings between adjacent glands. Endometrioid adenocarcinomas are usually Type 1 cancers associated with manifestations of endogenous or exogenous hyperestrogenic stimulation and a favorable prognosis. Subtypes include adenocarcinomas with squamous differentiation and secretory, ciliated cell and villoglandular variants. Rules and pitfalls in the grading of endometrioid adenocarcinomas and the estimation and reporting of myometrial invasion are presented.     

Computerized image analysis of p53 and proliferating cell nuclear antigen expression in benign, hyperplastic, and malignant endometrium.

CONTEXT: The endometrium is an intrinsically dynamic tissue with great capability for regeneration and proliferation; consequently, there is some overlap between features seen in benign, premalignant, and malignant lesions. This leads to marked intrabiopsy, interbiopsy, and interobserver variability. OBJECTIVE: We studied the specificity and sensitivity of computerized image analysis of molecular markers to evaluate its potential use as a diagnostic tool. DESIGN: Specimens from 100 patients were examined and the following histologic diagnoses were assigned: proliferative endometrium (n = 10), secretory endometrium (n = 10), endometrial hyperplasia (n = 40; 30 with no atypia, 10 with atypia), and carcinoma (n = 40; 20 endometrioid, 10 serous, and 10 clear cell). All cases were evaluated immunohistochemically for p53 and proliferating cell nuclear antigen (PCNA) expression. Computerized image analysis was performed with a CAS 200 digital analyzer. RESULTS: Expression of p53 was found only in carcinomas (65%) and endometrial hyperplasia with atypia (30%). Expression of p53 was higher in the poor prognostic categories (serous carcinoma and clear cell carcinoma) than in endometrioid carcinoma. In endometrioid carcinoma, p53 expression correlated with grade. Proliferating cell nuclear antigen showed a similar pattern of results to p53 in the various carcinoma subtypes and endometrioid carcinoma grades. Endometrial hyperplasia PCNA values were the lowest among all the groups. Both carcinomas and proliferative endometrium showed higher glandular and stromal PCNA values, significantly different from endometrial hyperplasia with atypia. In proliferative endometrium, stromal PCNA was the highest among all of the groups. The p53 and PCNA results correlated with each other for carcinoma. CONCLUSIONS: Computerized image analysis correlates well with the established morphologic groups of endometrial pathology and yields results consistent with previous studies. Owing to its higher degree of sensitivity, computerized image analysis is of potential use in cases of diagnostic dilemmas and can help objectively allocate the case in the correct category (e.g., proliferative endometrium vs. endometrial hyperplasia, endometrial hyperplasia with atypia vs. endometrioid carcinoma). It is particularly useful in the evaluation of stromal changes.     

Expression of hyaluronic acid and its receptors, CD44s and CD44v6, in normal, hyperplastic, and neoplastic endometrium

The interaction between epithelial tumor cells and their surrounding stroma is important in tumor progression and metastasis. This is accomplished through a number of transmembrane receptors that interact with stromal extracellular matrix molecules. One of these receptors, CD44, binds to extracellular matrix component hyaluronic acid (HA). The purpose of this study was to evaluate the significance of HA, CD44s, and CD44v6 in benign, hyperplastic, atypical, and malignant endometrial epithelia. Archival paraffin-embedded cell blocks from proliferative endometrium (n = 11), secretory endometrium (n = 12), simple hyperplasia (n = 13), complex hyperplasia without atypia (n = 9), complex hyperplasia with atypia (n = 17), and adenocarcinoma (n = 21) were stained for HA, CD44s, and CD44v6. HA was detected throughout the normal menstrual cycle but was more intense during the secretory phase. Only during the secretory phase was CD44s expressed in the stromal cells in 11 cases (92%), whereas CD44v6 was detected in glandular epithelium in 9 (75%). CD44s was expressed in the glandular epithelium in 2 (15%) cases of simple hyperplasia, 4 (44%) of complex hyperplasia without atypia, 14 (82%) of complex hyperplasia with atypia, and in 16 (76%) of adenocarcinoma. CD44v6 was expressed in the glandular epithelium in 1 (11%) case of complex hyperplasia without atypia, 17 (100%) cases of complex hyperplasia with atypia, and in 18 (86%) cases of adenocarcinoma, but in none of the cases of simple hyperplasia. The endometrial stromal cells expressed CD44v6 in 1 (8%) case of simple hyperplasia, 6 (67%) of complex hyperplasia without atypia, 8 (47%) of complex hyperplasia with atypia, and in 3 (14%) of adenocarcinoma. We concluded that in the normal menstrual cycle, the timing of peak staining of HA and CD44s in the stroma and the up-regulation of CD44v6 in secretory glands are coincident with the period in which the endometrium is most receptive to embryo implantation. HA is more abundant in the stroma adjacent to the tumor, suggesting that interactions between tumor cells and stromal HA promote tumorigenesis. With progression from hyperplasia and with increasing atypia to adenocarcinoma, levels of stromal HA, glandular CD44v6, and glandular and stromal CD44s all increase. Thus, HA and CD44 are both involved in the development and progression of endometrial cancer.     

Fallstricke bei der histopathologischen Diagnostik des Endometriumkarzinoms und seiner Vorstufen

Making an incorrect histopathological diagnosis of an endometrial lesion may lead to unwanted loss of fertility and therapy-associated morbidity; therefore, endometrial carcinomas need to be correctly typed and differentiated from hyperplastic precursors, benign lesions and artifacts. Typical diagnostic pitfalls are described in this article. Misdiagnosing endometrial lesions can be avoided by paying thorough attention to gross as well as microscopic features and by taking crucial differential diagnoses into consideration. These are, in particular, well-differentiated endometrioid adenocarcinoma of the endometrium versus atypical endometrial hyperplasia, myoinvasive endometrioid adenocarcinoma versus atypical polypoid adenomyoma and endometrioid carcinoma versus serous carcinoma of the endometrium with a predominantly glandular pattern. It is also important to consider the possibility of a false positive diagnosis of atypical endometrial hyperplasia or carcinoma in cases of biopsy-induced artifacts.     

Thymidine phosphorylase expression in normal and hyperplastic endometrium

AIMS: To investigate the expression of thymidine phosphorylase (TP), a known angiogenic factor for endothelial cells, in normally cycling endometrium and various forms of endometrial hyperplasia. METHODS: TP expression was assessed with the P-GF.44C monoclonal antibody, using the alkaline phosphatase anti-alkaline phosphatase method. Ninety two normal and hyperplastic endometria were studied. RESULTS: In normal proliferative endometrium, TP is found exclusively in the basal layer and the inner third of the functionalis; expression is cytoplasmic in glandular epithelium and nuclear in stromal cells. It is invariably patchy. This immunohistochemical picture remains almost unaltered during the early and mid secretory phase of the normal menstrual cycle but, most impressively, TP is expressed uniformly in the epithelium of all endometrial glands towards the end of the cycle. At this stage, expression is mixed nuclear/cytoplasmic and there is very little stromal nuclear staining. In simple endometrial hyperplasia, the staining pattern for TP is identical to normal proliferative endometrium, with a distribution that is usually limited to a few rather weakly proliferating glands and to the adjacent periglandular stroma of the deep endometrium. The distribution is more extensive in complex and atypical endometrial hyperplasias, where a mixed nuclear/cytoplasmic pattern usually prevails over the pure cytoplasmic reaction. CONCLUSIONS: TP is expressed consistently in normal and hyperplastic endometrium, suggesting a role in physiological and pathological angiogenesis. In normal endometrium, TP has a definite pattern of distribution, which is dependent on the phase of the menstrual cycle, whereas in all forms of endometrial hyperplasia the enzyme is randomly distributed and lacks an orderly pattern.     

Suppressed expression of type 2 3��/type 5 17��-hydroxysteroid dehydrogenase (AKR1C3) in endometrial hyperplasia and carcinoma

The diagnosis of endometrial hyperplasia and endometrial type adenocarcinoma arising within the uterine cavity has long been rested on morphologic criteria. Although distinction between normal endometrial epithelium from adenocarcinoma is usually straightforward, the separation between normal and hyperplastic endometrium, particularly those cases without atypia, can be a diagnostic challenge. The same is true in separation of hyperplastic endometrium with atypia from endometrial-type endometrial adenocarcinoma. Type 2 3α-/type 5 17β-hydroxysteroid dehydrogenase (HSD) (AKR1C3) is a multifunctional enzyme involved in androgen, estrogen, progesterone, and pros-taglandin metabolism. Its expression has been shown in the epithelium of the renal tubules, urothelial epithelium, and endothelial cells in normal tissues as well as in prostatic adenocarcinoma. The proliferation and maintenance of endometrial epithelium is dependent on both estrogen and progesterone; and AKR1C3-mediated steroid metabolism may play a critical role in the maintenance of viable normal and abnormal endometrial epithelium. We studied the expression of AKR1C3 in 33 endometrial biopsy specimens including 13 cases of normal proliferative endometrium, 8 cases of hyperplastic endometrium with and without atypia, and 12 cases of primary endometrial adenocarcinoma of endometrial type. We demonstrated a uniform, diffuse, and strong expression of AKR1C3 in normal endometrial epithelium but not in endometrial stromal cells. In contrast, the expression of AKR1C3 is reduced in both hyperplastic and carcinomatous endometrial epithelium. These findings suggest that AKR1C3 may play important roles in the physiology of endometrial cells and that suppressed AKR1C3 expression may represent a feature that allows differentiation of hyperplastic and neoplastic endometrial epithelium from normal endometrial epithelium. However, reduced AKR1C3 expression cannot distinguish hyperplastic endometrium from endometrial adenocarcinoma of endometrial type. The biologic and pathological roles of AKR1C3 in endometrial epithelium require further investigation.     

Increased expression of the adult stem cell marker Musashi-1 in endometriosis and endometrial carcinoma

Adult stem cells are thought to be responsible for the high regenerative capacity of the human endometrium, and have been implicated in the pathology of endometriosis and endometrial carcinoma. The RNA-binding protein Musashi-1 is associated with maintenance and asymmetric cell division of neural and epithelial progenitor cells. We investigated expression and localization of Musashi-1 in endometrial, endometriotic and endometrial carcinoma tissue specimens of 46 patients. qPCR revealed significantly increased Musashi-1 mRNA expression in the endometrium compared to the myometrium. Musashi-1 protein expression presented as nuclear or cytoplasmic immunohistochemical staining of single cells in endometrial glands, and of single cells and cell groups in the endometrial stroma. Immunofluorescence microscopy revealed colocalization of Musashi-1 with its molecular target Notch-1 and telomerase. In proliferative endometrium, the proportion of Musashi-1-positive cells in the basalis layer was significantly increased 1.5-fold in the stroma, and three-fold in endometrial glands compared to the functionalis. The number of Musashi-1 expressing cell groups was significantly increased (four-fold) in proliferative compared to secretory endometrium. Musashi-1 expressing stromal cell and cell group numbers were significantly increased (five-fold) in both endometriotic and endometrial carcinoma tissue compared to secretory endometrium. A weak to moderate, diffuse cytoplasmic glandular staining was observed in 50% of the endometriosis cases and in 75% of the endometrioid carcinomas compared to complete absence in normal endometrial samples. Our results emphasize the role of Musashi-1-expressing endometrial progenitor cells in proliferating endometrium, endometriosis and endometrioid uterine carcinoma, and support the concept of a stem cell origin of endometriosis and endometrial carcinoma.     

Immunohistochemical analysis of CD44s and CD44v6 in endometriosis and adenomyosis : comparison with normal, hyperplastic, and malignant endometrium.

The expression patterns of CD44s and CD44v6 were immunohistochemically compared with those of normal, hyperplastic and malignant endometrium. In normal endometria (n=37), endometrioses (n=46) and adenomyoses (n=20), the surface and glandular epithelial cells were negative for CD44s and CD44v6 in a proliferative pattern and positive in a secretory pattern, whereas the stroma was only positive for CD44s in both proliferative and secretory patterns. The endometrial hyperplasia (4 simple and 9 complex) had the identical patterns with normal proliferative phase of endometrium. Only one case showing complex hyperplasia with atypia was focally positive for CD44s and CD44v6 in glandular epithelia. CD44s and CD44v6 were positive in all endometrial adenocarcinomas (13), except one CD44s-negative case. In summary, the expressions of CD44s and CD44v6 in endometriosis and adenomyosis recapitulated those of normal cyclic endometrium. The expression patterns in endometrial hyperplasia were similar to those in normal proliferative endometrium, whereas the endometrial adenocarcinoma showed abnormal expressions for CD44s and CD44v6. Thus it was considered that the ectopic endometrium in endometriosis and adenomyosis was not aberrant as in endometrial carcinoma on the aspects of immunohistochemical expressions of CD44s and CD44v6.     

Cathepsin D expression in normal,hyperplastic and malignant endometrial tissue: an immunohistochemical analysis

Cathepsin D (CathD), a lysosomal aspartyl protease secreted by normal and malignant cells, is considered to be involved in breakdown of the extracellular matrix. Aim of the present study was to determine the frequency and tissue distribution of CathD in normal, hyperplastic and malignant endometrium. Paraffin-fixed endometrial tissue was obtained from premenopausal women in the proliferative phase (n = 5), early secretory phase (n = 4) and late secretory phase (n = 4) as well as glandular-cystic hyperplasia (n = 5), endometrial polyps (n = 5), endometrial polyps from the use of tamoxifen (n = 5), adenomatous hyperplasia (AH) grade I (n = 5), grade II (n = 4), grade III (n = 5) and endometroid adenocarcinoma (n = 5). CathD expression was evaluated with the IRS score and ANOVA analysis was used for statistical evaluation. CathD was primarily localised in luminal and glandular epihelium with little staining in stromal cells. The expression of CathD was significantly higher during the late secretory phase than in the proliferative phase. Highest expression of CathD was observed in the late secretory phase and in glandular-cystic hyperplasia, whereas endometroid carcinoma showed no expression. A continuous increase in CathD expression was observed in AH, with a significant difference between AH grade I and III. In conclusion, CathD was found to be expressed in normal and hyperplastic endometrial tissue. CathD immunostaining in normal endometrial glands varied on the basis of the phase of the menstrual cycle, suggesting physiological functions of CathD in endometrial maturation and degradation. Adenocarcinomas did express significant lower amounts of CathD. Therefore, the prognostic value of this parameter remains uncertain. A continuous increase in CathD immunostaining was observed in AH. Since AH grade III can be considered as a precursor of endometrial cancer, CathD could be a possible parameter for assessing malignant transformation.     

Distribution of estrogen receptors in various cell types of normal, hyperplastic, and neoplastic human endometrial tissues

To facilitate our understanding of estrogen participating in the genesis of human endometrial hyperplasia and carcinoma and the influence of the surrounding mesenchyme in their development, we assayed estrogen receptors in the epithelium and stroma of various human endometrial tissues by immunocytochemistry. The receptors were localized in fresh frozen sections using the ER-ICA kits (Abbott Laboratories, North Chicago, Illinois). The receptor content was highest in the proliferative endometrium and decreased gradually throughout the postovulatory phase of the menstrual cycle in both the epithelium and the stroma and this occurred more rapidly in the stroma. Estrogen receptor content was high in both the epithelium and the stroma of hyperplasia and was thus similar to that of the proliferative endometrium, the receptor content was low in the epithelium of endometrial intraepithelial neoplasia (hyperplasia with cytologic atypia) closely resembling that of carcinoma. In carcinomas there was a heterogenous distribution of estrogen receptors both in the epithelium and the stroma, but in general, the receptor content was low as compared with normal proliferative or hyperplastic endometrium; however, in selected cases the content of estrogen receptor in the stroma was high, despite the lack of receptors in the epithelium.     

子宫内膜增生及内膜癌中PTEN、Ki-67蛋白的表达

目的　研究子宫内膜增生组织及内膜癌组织中PTEN、Ki 6 7蛋白的异常表达 ,探讨其与子宫内膜癌变的关系及作为早期癌变生物学标志的可能性。方法　应用免疫组化S P法对 12例正常增生期子宫内膜组织、4 0例子宫内膜增殖症组织、4 2例内膜腺癌组织中PTEN、Ki 6 7蛋白的表达进行研究。结果　在正常增生期子宫内膜、子宫内膜增殖症 (单纯增生、复杂型增生、不典型增生 )、子宫内膜腺癌组织中PTEN蛋白的阳性表达率呈递减趋势 ;Ki 6 7蛋白的阳性表达率呈递增趋势。等级相关分析结果显示PTEN、Ki 6 7表达异常与子宫内膜组织学分级均显著相关 (相关系数r分别为 - 0 5 4 1和 0 4 96 ,P值均<0 0 1)。子宫内膜癌与除不典型增生外的子宫内膜增殖症组织及正常增生期子宫内膜组织的PTEN、Ki 6 7蛋白表达差异有显著性 ,正常增生期子宫内膜、单纯增生与不典型增生组织的PTEN蛋白表达差异有显著性 ,不典型增生与单纯增生组织的Ki 6 7蛋白表达差异有显著性。PTEN、Ki 6 7蛋白表达存在负相关性 (r =- 0 4 2 8,P <0 0 1)。PTEN、Ki 6 7蛋白的表达与子宫内膜癌的手术分期、组织学分级、肌层浸润无关 (P >0 0 5 )。结论　PTEN、Ki 6 7蛋白的异常表达与子宫内膜的癌变过程相关 ,PTEN基因表达异常及细胞增殖异常与子宫内膜     

Theories of endometrial carcinogenesis: a multidisciplinary approach.

Historical observations have suggested that endometrial carcinomas vary in histopathologic appearance and clinical features. More recent, systematic studies have provided epidemiologic, clinicopathologic, and molecular support for these observations. Specifically, studies suggest that the most common type of endometrial carcinoma, endometrioid adenocarcinoma, develops from endometrial hyperplasia in the setting of excess estrogen exposure and usually pursues an indolent clinical course. In contrast, a minority of endometrial carcinomas, best represented by serous carcinoma, do not seem to be related to estrogenic risk factors or elevated serum hormone levels, and these tumors seem to develop from atrophic rather than hyperplastic epithelium. We have proposed that serous carcinomas develop from "endometrial intraepithelial carcinoma," a lesion representing malignant transformation of the endometrial surface epithelium. Whereas endometrioid carcinoma and endometrial hyperplasia are associated with microsatellite instability and ras and PTEN mutations, serous carcinoma and endometrial intraepithelial carcinoma are associated with p53 mutations and abnormal accumulation of p53 protein. Based on these data regarding the pathogenesis of endometrioid and serous carcinoma, we have proposed a dualistic model of endometrial carcinogenesis incorporating a "classic" estrogen-driven pathway and an "alternative" pathway seemingly unrelated to hormones. It is hoped that further studies may permit the extension and modification of this model and that these advances will lead to improved diagnosis, management, and prevention.     

Immunohistochemical expression of Retinoblastoma gene product in normal,hyperplastic and malignant endometrium. Correlation with p53 protein expression,c-erbB-2, hormone receptors' status and proliferative activity

Alterations of the retinoblastoma (Rb) gene have been described in several human neoplasms and recently, it has been suggested that these alterations may play a role in the development of endometrial carcinomas. Paraffin sections from 31 cases of normal endometrium (16 proliferative, 15 secretory), 35 hyperplastic lesions and 89 endometrial carcinomas were investigated immunohistochemically for Rb protein (pRb) expression. The results were compared with p53 and c-erbB-2 protein expression, estrogen (ER) and progesterone (PR) receptors' status and with clinicopathological prognostic factors. pRb was expressed in normal, hyperplastic and neoplastic epithelium. Proliferative endometrium showed more intense and extensive pRb staining than secretory endometrium. pRb reactivity was heterogeneous in the hyperplastic endometrial cells. Lack or focal (< 10% of endometrial cells) pRb immunostaining was noted in 56.2% and 27% of carcinomas, respectively. In the remaining cases (16.8%) pRb staining was heterogeneous or diffuse. The absence or presence of pRb expression was independent of grade and stage. In normal proliferative and secretory endometrium, pRb expression was correlated with PR (p = 0.006 and p = 0.001, respectively), PCNA (p = 0.04 and p = 0.01, respectively) and MIB1 (p = 0.02 and p<0.0001, respectively) expression. In hyperplasias, pRb was related to PR (p = 0.016) and MIB1 (p < 0.0001) expression. In carcinomas, a relationship of pRb expression with p53 (p = 0.0015), ER (p = 0.0002), PR (p = 0.0004) and PCNA (p = 0.013) status was detected. We suggest that the absence or presence of pRb expression does not seem to be associated with the progression of endometrioid carcinoma. In addition, pRb seems to be normally regulated in relation to the proliferative growth fraction of the tumours.