Changes in subsets of immunocytes in endometrial hyperplasia.

PROBLEM: Endometrial hyperplasia (EH) is characterized by an endometrial gland-to-stroma ratio >1 and is one of the most common gynecological diseases in the world. The role of immunocyte subsets in the development of EH remains unknown. METHODS: Patients who underwent dilatation and curettage due to abnormal uterine bleeding were recruited in the present study. Alterations in the numbers of different types of immune cell subsets in the endometrium of patients were analyzed by flow cytometry. RESULTS: The present study included 48 patients who were divided into three groups, based on the pathological results: (a) proliferative period (PP, n = 12); (b) simple EH (SEH, n = 30); and (c) complex EH (CEH, n = 6). The results showed that immune cell subpopulations were significantly different between these three groups. Compared with the PP group, the proportion of CD45+ cells and neutrophils and the subtypes of T cells and macrophages were significantly increased in the SEH patients. Compared with the PP and SEH groups, subsets of immunocytes in the CEH group were significantly decreased, including the population of CD45+ cells and the subtypes of T cells and natural killer cells; in contrast, the proportion of macrophages was significantly increased. There were no significant differences between the other cell subsets in each group. CONCLUSION: The changes in immune cell subsets may be closely associated with the progression of EH. Although the specific role of different immune cell subsets in the development of the diseases requires further study, the changes in the proportions of immune cell subsets should not be ignored.

Endometrial transcripts of proinflammatory cytokine and enzymes in prostaglandin synthesis are upregulated in the bitches with atrophic pyometra.

Inflammatory markers of endometrial origin are valuable in order to differentiate the pyometra from cystic endometrial hyperplasia in the bitch. In the present study, we hypothesized that histological categorization would distinguish the differential regulation of the proinflammatory genes in the endometrium of bitches with pyometra. Ovariohysterectomy was done on bitches with confirmatory diagnosis of pyometra (n = 18). Using endometrium to myometrium ratio of 0.79 as threshold, the uteri (n = 8/group) were categorized into hyperplastic pyometra (HP) and atrophic pyometra (AP). Two samples were excluded as the diagnosis was inconclusive. In parallel, endometrial tissue was collected for total RNA extraction to study the differential expression of TLR4, IL-6, IL-8, COX-2 and PGFS through real time PCR. Diestrus uterus of non-pyometra bitches (n = 6) served as control. The mean fold change (2-ΔΔCt) for the target genes was determined using ß-actin as endogenous control and non-pyometra uterus as calibrator group. Except TLR4, other inflammatory genes were upregulated significantly by 1.82 to 3.74 times in the AP as compared to HP with maximum upregulation of COX-2 and PGFS. Further, correlation matrix with Spearman's rho revealed that IL-8 had strong positive correlation with COX-2 and PGFS in the AP group (P < 0.05). It is concluded that histological grading of pyometra into HP and AP revealed differential regulation of inflammatory cytokines and enzymes in the PG synthetic pathway in the canine endometrium that has diagnostic potential under clinical settings.

Mechanisms underlying the protective effect of montelukast in prevention of endometrial hyperplasia in female rats.

OBJECTIVE: To study the possible protective role of montelukast in endometrial hyperplesia (EH) rat model, induced by estradiol valerate (EV). METHODS/MATERIALS: Thirty six female albino Wistar rats were classified into 7 groups: normal control, EV (2 mg/kg/day, p.o.), montelukast (10 mg/kg/day, p.o.), montelukast (1 mg/kg/day, p.o.) + EV (2 mg/kg/day, p.o.), montelukast (10 mg/kg/day, p.o.) + EV (2 mg/kg/day, p.o.), montelukast (20 mg/kg/day, p.o.) + EV (2 mg/kg/day, p.o.) groups. Uterine malondialdehyde (MDA), superoxide dismutase (SOD), total nitrites (NO) and serum total antioxidant capacity (TAC) were determined. Uterine, serum total cholesterol, high density lipoprotein (HDL) and tumor necrosis factor (TNF)-α were measured. Histopathological examination of the uterine tissue was also done. In addition, immunohistochemistry was done using Phosphatase and tensin homolog (PTEN) and inducible nitric oxide synthase (iNOS) antibodies. RESULTS: Our results showed that montelukast in dose dependant manner improves oxidative stress, lipids profile and TNF α which were affected by EV. Moreover, immunohistochemical examination revealed that montelukast markedly reduced iNOS expression, while expression of PTEN was markedly enhanced, as compared to EV group. The protective effects of montelukast were also verified histopathologically. CONCLUSIONS: Montelukast in dose dependant manner provided biochemical and histo-pathological improvement in EV induced EH, through its anti-inflammatory, antioxidant activity and inhibition of iNOS expression with induction of PTEN expression.

Immunohistochemical reaction of the glandular epithelium in endometrial hyperplasia compared to endometrial carcinoma.

The histopathological and immunohistochemical diagnosis of endometrial biopsies is used for estimating the risk of progression in endometrial hyperplastic lesions in carcinoma and for guiding the clinical management. The objective of this study was to evaluate the immunohistochemical expression of the estrogen receptor (ER) and progesterone receptor (PR), p14, p53, phosphatase and tensin homolog (PTEN), Ki67, in patients with endometrial hyperplasia (EH) with/without atypia versus endometrioid endometrial carcinoma type 1. After the histopathological determining of the lesion type at endometrial level, the cases were studied using immunohistochemical methods, namely by the use of an antibody panel. The immunohistochemical staining of PR was nuclearly and cytoplasmatically positive in EH with/without atypia and cytoplasmatically negative in endometrioid carcinoma, and in ER, the immunohistochemical staining was cytoplasmatically negative in the forms of EH without atypia and positive in various stages of intensity in the rest of the cases. The immunohistochemical staining of p14 was moderately expressed in the endometrioid carcinoma and negative in EH without atypia at nuclear level, and at cytoplasm level, it generally had a positive expression. In our study, the nuclear and cytoplasmic study of immunoxpression p53, both in hyperplastic lesions and in the endometroid endometrial carcinoma, was negative, similar to the immunohistochemical expression of PTEN. At nuclear level, the immunohistochemical staining of Ki67 was positive in EH with atypia and in endometrioid endometrial carcinoma, while at cytoplasm level, it was positive only in endometrioid endometrial carcinoma. The nuclear and cytoplasmic study of this immunohistochemical marker panel shows a different reactivity in EH with÷without atypia and endometrioid endometrial carcinoma.

Type 2 Endometrial Cancer is Associated With a High Density of Tumor-Associated Macrophages in the Stromal Compartment.

INTRODUCTION: Tumor-associated macrophages (TAMs) play a pivotal role in orchestrating the microenvironment. The TAMs differentially polarize into M1 or M2 macrophages with distinct actions. The aim of our work is to characterize density, subtype, and location of TAMs in endometrial hyperplasia and cancer. METHODS: Formalin-fixed, paraffin-embedded sections of hyperplasia (n = 5), type 1 (n = 5), and type 2 (n = 5) endometrial cancer were stained with anti-CD68 and anti-CD163 monoclonal antibodies as markers for total TAMs and M2 TAMs, respectively. Macrophages were counted at 40× magnification in 10 high-power fields (HPFs) per slide by 4 observers. Repeated measures models were constructed to determine the relationships between macrophages and lesion categories. RESULTS: Most CD68+ TAMs were located in the stromal (mean = 41.0/HPF) compared to epithelial (mean = 11.0/HPF) or luminal (mean = 11.6/HPF) compartments. Similar but reduced findings were observed for CD163+ (M2 subtype) TAMs. The CD68+ stromal TAM density was highest in patients with type 2 cancers (mean = 54.0/HPF) compared to those with type 1 cancers (mean = 35.5/HPF) and hyperplasia (mean = 29.0/HPF). Women with hyperplasia had more CD163+ (M2 subtype) TAMs (26.7/HPF) than patients with either type of cancer (type 1 = 12.5/HPF and type 2 = 11.5/HPF). Based on the repeated measures models, type 2 cancers had 38.6/HPF more CD68+ TAMs than type 1 cancers (P < .0001) and type 1 and type 2 cancers had similar numbers of CD163+ TAMs (P = .27). CONCLUSIONS: Type 2 cancers have nearly twice the TAM density of type 1 cancers. This difference may be due to M1 macrophage predominance in the stroma of type 2 cancers.

Bariatric surgery-induced weight loss changes immune markers in the endometrium of morbidly obese women.

BACKGROUND: Obesity has been linked to abnormal estrogen regulation, endometrial hyperplasia, and endometrial cancer (EC). Our group has shown that hormone receptor expression profiles in the endometria of morbidly obese women change with weight loss, in some cases concordantly with resolving hyperplasia; however other potential drivers of neoplasia, including altered immunologic tolerance exist. The objective of this study was to evaluate the effect of bariatric surgery induced weight loss on the expression patterns of nonhormone receptor biomarkers associated with cancer and immunity. METHODS: Endometrial biopsies were obtained from 59 asymptomatic, morbidly obese women at the time of bariatric surgery and again 1 year postsurgery. Tissue microarrays were created and immunohistochemical stains for CD3, CD20, and PTEN were performed on all samples and evaluated by 2 blinded pathologists independently. Approximately 50% of participants had sufficient tissue for analysis at both visits. McNemar/Bowker tests of symmetry were performed to compare proportions between categories for matched pairs (pre- and post-treatment). RESULTS: Endometrial hyperplasia was identified in 4 women despite negative clinical histories and resolution of hyperplasia after weight loss occurred in 3 women. While overall no significant differences were observed between matched pre and postsurgery levels of CD20 and CD3 positive cells, a tendency toward decreased expression levels from baseline status was observed for CD20. No differences were observed for PTEN. CONCLUSION: Our data demonstrate that the prevalence of endometrial pathology appears to be partially mitigated by weight loss. Weight loss is associated with alterations in the hormone receptor profiles, but these data suggest that changes in the immune response, as measure be expression of CD20+, may be relevant targets for EC prevention research.

Tumor-associated macrophages correlate with progesterone receptor loss in endometrial endometrioid adenocarcinoma.

AIM: It has been well established that tumor-associated macrophages (TAMs) play a tumor promoting role in endometrial endometrioid adenocarcinoma (EEC). But the association with TAMs and sex hormone receptor expression, and progression of precancerous endometrial lesions in EEC has been little reported. MATERIAL AND METHODS: We used immunohistochemistry to examine the expression of CD68, CD34, vascular endothelial growth factor (VEGF), estrogen receptor (ER) and progesterone receptor (PR) in 95 cases of EEC, as well as 35 cases of endometrial hyperplasia (including 15 atypical hyperplasia, 10 complex hyperplasia and 10 simple hyperplasia). We also correlated TAMs count with various clinicopathological factors, sex hormone receptor, and prognostic value in patients with EEC. RESULTS: We identified that TAMs count increased linearly with disease progression (mean count per case at × 200 magnification: simple hyperplasia, 6.30; complex hyperplasia, 11.20; atypical hyperplasia, 29.40; EEC 55.81, respectively; P < 0.001), that microvascular density (MVD) also increased accordingly (27.50, 30.20, 50.13 and 59.94, respectively; P < 0.001). The expression of progesterone receptor, not of estrogen receptor, significantly decreased with disease progression (P < 0.05). Moreover, histopathologic grades, International Federation of Gynecology and Obstetrics (FIGO) stage (2009), depth of myometrial invasion, pelvic lymph node metastasis, lymphovascular space invasion, and expression of PR and VEGF were associated with TAMs count (P = 0.0001, P = 0.004, P = 0.0001, P = 0.04, P = 0.0001, P = 0.0001, P = 0.0001, respectively). Progesterone receptor expression was also associated with histopathologic grades, lymphovascular space invasion, VEGF and high TAMs (P = 0.035, P = 0.022, P = 0.014, P = 0.001, respectively). The estimated 5-year survival rate of patients with low TAMs was significantly higher than those with high TAMs (96.4% vs 69.8%, P = 0.002). CONCLUSION: TAMs are potentially related to PR loss and progression of precancerous endometrial lesions in EEC.

Immunoexpression of B7-H3 in endometrial cancer: relation to tumor T-cell infiltration and prognosis.

OBJECTIVE: B7-H3, a member of the B7 family of immune regulatory ligands regulates T cell-mediated peripheral immune response. The purpose of this study was to correlate the expression of B7-H3 and number of lymphocytes in patients with endometrial cancer. MATERIAL AND METHODS: A total of 107 patients with primary endometrial carcinoma (type I/endometrioid, n=81; type II, n=18) and endometrial hyperplasia (n=8) were investigated. Expression of B7-H3 in endometrial hyperplasia, endometrial carcinoma, and the endothelium of tumor-associated vasculature was assessed using immunohistochemistry from paraffin-embedded tissue blocks. Detection of CD8-positive tumor-infiltrating lymphocytes (TIL) and CD8-positive tumor-associated lymphocytes (TAL) was correlated with the expression of B7-H3. RESULTS: Patients with high grade tumors and patients with type II carcinomas expressed significantly more B7-H3 than low grade and endometrioid tumors (p=<0.0001 and p=0.0001, respectively). The expression of B7-H3 in the endothelium of identified vasculature in the tumor specimens showed similar results with strong relation to high grade tumors (p=0.001) and type II carcinomas (p=0.004). We found a significant correlation between B7-H3 expression on cancer cells and tumor T-cell infiltration (TIL) (p=0.017). In a univariate survival analysis, overexpression of B7-H3 in tumor cells was associated with shortened overall survival (p=0.005). CONCLUSIONS: B7-H3 is overexpressed on cancer cells and in the endothelium of tumor-associated vasculature in high grade tumors (G3) and type II carcinomas. B7-H3 expression on cancer cells is correlated with the number of T cells infiltrating the tumor. Endometrium tumor development and progression may be associated with downregulation of T-cell-mediated antitumor immunity through B7-H3.

Increased natural killer cells and decreased regulatory T cells are seen in complex atypical endometrial hyperplasia and well-differentiated carcinoma treated with progestins.

Progestins are used to treat complex atypical hyperplasia and well-differentiated endometrial carcinoma in women who desire fertility preservation and those who are poor surgical candidates. Although sensitivity to progestins is thought to be associated with the presence of estrogen and progesterone receptors, it is known that receptor-negative tumors can also respond to the agent, suggesting that there is another direct antitumor action of progestin. Because tumor immune response is an additional predictor of survival in well-differentiated endometrial carcinoma, it is surprising that the role of progestins in tumor immunity has not been investigated. Regulatory T cells modulate the immune response, whereas cytotoxic T cells directly target tumor cells. In this study, we investigated the effect of progestins on regulatory T cells and cytotoxic T cells. The pre- and posttreatment endometrial samples of 15 progestin-treated patients with complex atypical hyperplasia or well-differentiated endometrial carcinoma were evaluated for therapeutic response and the presence of cytotoxic T cells and regulatory T cells. Immunohistochemical analysis was performed for FOXP3 to identify regulatory T cells and for granzyme B to identify activated cytotoxic T cells. To further characterize the cytotoxic T cell's subpopulations, we performed CD8 (cytotoxic T-cell marker) and CD56 (natural killer cells marker). Ten of 15 patients had normal morphology on follow-up endometrial samplings, and 4 patients had persistence or progression of the disease. Regulatory T-cell counts pretreatment were significantly higher in complex atypical hyperplasia and well-differentiated endometrial carcinoma than in posttreatment normal endometrium. Residual complex atypical hyperplasia and well-differentiated endometrial carcinoma present in posttreatment samples maintained high regulatory T cells and low number of cytotoxic T cells. Progestin treatment was associated with striking increase in cytotoxic T cells in areas with decidual reaction. Before treatment, most of the granzyme B+ cytotoxic T cells in complex atypical hyperplasia and well-differentiated endometrial carcinoma were CD8(+) T cells, whereas after treatment, up to 80% of cytotoxic T cells were natural killer cells. These results suggest that progestin treatment affects subpopulations of lymphocytes in the endometrium and may induce immune suppression of complex atypical hyperplasia and well-differentiated endometrial carcinoma.

Gynecological issues after organ transplantation.

Organ transplantation has become universally accepted treatment of end-stage organ failure. The main problem focuses on preventing the graft from rejection with the use of immunosuppressive agents. High incidence of infection is the most frequent adverse effect of immunosuppressive therapy. Symptoms of inflammation are often reduced in immunosuppressed patients. All invasive diagnostic and therapeutic procedures should be associated with the increase in dose of steroids and prophylactic antibiotics. Ovarian and menstrual function is usually restored in transplanted women. Function of the hypothalamus-pituitary-ovary axis in transplanted women is believed to be normal. Most common abnormal uterine bleeding in graft recipient are: prolonged and profuse menstruation and inter-menstrual bleeding or spotting. Among the underlying diseases are lesions of the uterus (fibroids, endometrial or cervical polyps), infections of sex organs or hormonal disturbances. Higher rate of endometrial hyperplasia (without atypia) is reported in renal graft recipients. Organ transplantation results in the restored fertility thus effective family planning method is necessary in women of reproductive age who do not want to conceive. Vaginal diaphragms are not advised and intrauterine device are contradicted. Observational studies indicate for safety and high rate of acceptance of oral and transdermal hormonal contraception in transplanted women. Over ten-year experiences of HRT administration in graft recipient have proved the benefits of the therapy. Patients after organ transplantation have three to four-fold increased incidence of malignancy compared with general population. All transplant women must undergo regular gynecological screening for premalignant and malignant lesions of sex organs and breast.

Expression of aquaporin-1 in normal, hyperplasic, and carcinomatous endometria.

OBJECTIVE: To explore the relationship between aquaporin-1 (AQP1) and endometrial adenocarcinoma. METHOD: Intratumoral microvessel density (IMD) was assessed as well as AQP1 and vascular endothelial growth factor expression in samples from 117 women, 75 with endometrioid adenocarcinoma, 17 with endometrial hyperplasia, and 25 with normal proliferative endometria. RESULTS: AQP1 was located in the epithelial cells of microvessels and small vessels in all samples. The AQP1/IMD ratio was highest in samples from the first, less in samples from the second, and least in samples from the third group. In samples from endometrioid adenocarcinoma, the AQP1/IMD ratio was significantly correlated with histologic grade, surgical stage, myometrial invasion, and extrauterine metastasis. There was a positive correlation between AQP1 expression and IMD and between AQP1/IMD ratio and VEGF expression. CONCLUSION: AQP1 may be involved in the tumorigenesis and progression of endometrioid adenocarcinoma by promoting angiogenesis, and AQP1 level may be both a tumor indicator and a new therapeutic target.

[Detection rates of various serotypes of human papilloma virus in atypical glandular hyperplasia and adenocarcinoma of the endometrium and their immunomorphological features in virus-positive cases].

Various virus serotypes were found in 35.3% of cases and their detection rate frequency reducing with age. They were detectable in 35.3 -52.9% of cases of atypical glandular hyperplasia, highly and moderately differentiated adenocarcinoma of the endometrium and only in 17.6% of cases of poorly differentiated adenocarcinomas. Serotypes 58 and 51 were nearly twice more frequently, but serotypes 18 and 52 were not observed. Immunomorphologically virus-positive observations were characterized by pronounced infiltration with T-helper and T-suppressor/killer cells. The endometrium and tumors showed an increased significant proliferative activity (Ki-67 expression) and reduced expression of receptors to progesterone and, to a lesser degree, to estrogen in 47-83% of virus-positive cases. Expression of growth factors did not greatly differ.

B7-H4 (DD-O110) is overexpressed in high risk uterine endometrioid adenocarcinomas and inversely correlated with tumor T-cell infiltration.

OBJECTIVES AND METHODS: B7-H4 (DD-O110), a member of the B7 family, negatively regulates T cell-mediated immune response. Previous studies have shown that B7-H4 is highly expressed in endometrioid ovarian cancers with relatively low levels of expression in normal ovary which was confirmed by Western blot. The present study was designed to localize B7-H4 expression by immunohistochemistry (IHC) in normal endometrium, endometrial hyperplasia and uterine endometrioid adenocarcinoma. The pattern of B7-H4 localization was compared with the IHC detection of CD3 and CD8-positive T lymphocytes and CD14 positive macrophages to investigate the role of B7-H4 in the regulation of tumor immune surveillance. B7-H4 expression was evaluated in apoptotic tumor cells. RESULTS: The proportion and intensity of B7-H4 staining were increased in the progression from normal, hyperplastic and malignant endometrial glandular mucosa. B7-H4 showed a predominantly apical membranous staining (pattern 1) in normal and hyperplastic endometrial epithelium but showed intense circumferential membranous and cytoplasmic staining (pattern 2) in a majority of endometrioid carcinoma cases (p=0.018). The proportion of B7-H4 positive tumor cells and staining intensity was also higher in high risk tumors than in low risk tumors (p=0.001 and p=0.032, respectively). The proportion of B7-H4 positive tumor cells was inversely related to the number of CD3-positive and CD8-positive tumor-associated lymphocytes (TALs). There was a positive correlation between B7-H4 pattern 2 staining and both CD3-positive and CD8-positive tumor-infiltrating lymphocytes (TILs) (p=0.039 and p=0.031, respectively). CONCLUSIONS: B7-H4 is overexpressed in hyperplastic and malignant endometrial epithelium and is correlated with the number T cells associated with the tumor. These results suggest that B7-H4 overexpression may reflect a more aggressive biologic potential and may play a role in tumor immune surveillance mechanisms.

The value of epithelial membrane antigen overexpression in hyperplastic and malignant endometrium and its relationship with steroid hormone receptor expression.

The aim of this study was to evaluate the value of epithelial membrane antigen overexpression (EMA OE) in benign, hyperplastic and neoplastic endometrium and to analyze its association with estrogen and progesterone receptors (ER, PR) immunohistochemistry, tumor grade and myometrial invasion in patients with endometrial carcinoma (EC). The OE of EMA was analysed immunohistochemically in nine patients with benign endometrium (BE), in 18 patients with atypical complex endometrial hyperplasia (ACH) and in 29 patients with EC. EMA OE was present in 13 of 29 patients (44.8%) with EC, in two of 18 patients (11.1 %) with ACH, and in none of nine patients with BE (p < 0.05). EMA OE of endometrial carcinoma was statistically correlated with the International Federation of Gynecology and Obstetrics (FIGO) grade (G1 vs G2 and G3, p < 0.05) and depth of myometrial invasion (< 1/2 vs > 1/2, p < 0.05). EMA OE was significantly associated with PR negativity (p < 0.001). However it did not show any association with ER immunohistochemistry (p = 0.14). PR immunohistochemistry had significant correlations with FIGO grade (p < 0.001) and depth of myometrial invasion (p < 0.05) but ER loss showed a nearly significant association only with advanced FIGO grade (p = 0.054). In conclusion, EMA shows increased expression as the lesion progresses to malignancy and can also aid discrimination between hyperplastic and neoplastic states. The correlation of imunohistochemical findings with tumor grade and myometrial invasion could help in predicting behavior of the tumor and planning treatment in patients with endometrial carcinoma.

[Immunohistochemical study of the expression of receptors to steroid hormones in endometrial hyperplastic processes]. / Immunogistokhimicheskie issledovaniia ékspressii retseptorov k steroidnym gormonam pri giperplasticheskikh protsessakh v éndometrii.

We examined 39 women with normal endometrium and 139 women with glandular-cystic hyperplasia of the endometrium (without atypia). According to clinical manifestations of hyperplasia, the patients were divided into 3 groups: 74 (53%) had reestablishing menstrual function after total curettage (group 1); 42 patients (30%) with glandular-cystic hyperplasia after curettage and hormonal therapy with progesterone and synthetic progestins (duration 3 to 6 months) had no repeated pathology of the endometrium (group 2); endometrial hyperplasia recurred 2 and 3 times as showed biopsies during 2-5 years of observation in 23 (17%) women (group 3). Immunohistochemical tests of normal endometrium revealed correlations between stages of menstrual cycle and steroid hormone receptors in nuclei of glandular epithelium and stromal cells. Maximum sensitivity of glandular epithelium to estrogen and pronounced expression of estrogenic receptors were observed at middle and late stages of proliferation. High sensitivity of glandular epithelium to progesterone was registered at middle and late stages of proliferation and early stage of secretion. Two types of hormone receptor expression were observed. Type 1 typical for the endometrium of middle and late stage of proliferation was characterised by a high content of receptors to E2 and P in glandular epithelium and stromal cells. Type 2 was observed in patients with recurring glandular hyperplasia and was characterised by a mosaic picture up to complete absence of receptor expression in nuclei of some glands and stromal cells. The detected zones free of receptors to estrogens and progesterone evidence for local disturbance of a regulating role of signal pathways of sexual steroids and can serve a substrate for formation of tissue autonomy.

Immunohistochemical evaluation of cathepsin D in normal, hyperplastic and malignant endometrium: correlation with hormone receptor status c-erbB-2, p53, Rb proteins and proliferation associated indices.

The immunohistochemical expression of cathepsin D was performed in paraffin embedded tissue from 79 endometrial carcinomas, 35 cases of hyperplasia, and 32 normal endometrium using the streptavidin-biotin method to investigate the role of cathepsin D (CD) in these lesions and its possible relationship with other potential and established prognostic markers. The association between CD and the other markers was assessed by univariate analysis. Tumor cell CD expression was lower in the group of carcinomas compared to the normal proliferative (P = 0.022) and secretory endometrium (P = 0.0005). In addition, hyperplastic cell CD expression was lower compared with epithelial cell CD expression in the secretory phase of normal endometrium (P = 0.009). Malignant cell CD expression was inversely correlated with tumor stromal cells (P = 0.007). A positive relationship of stromal cell CD expression with pRb (P = 0.046) and PCNA score (P < 0.0001) was detected in the group of carcinomas. In the proliferative phase of normal endometrium, epithelial CD expression was positively correlated with estrogen status (P = 0.015). The data show that down-regulation of CD expression is an early event in endometrial carcinogenesis. In addition, stromal cell CD expression may be involved in cell growth process in endometrial carcinomas.

Parameters of cellular immunity in perimenopausal patients with glandular and adenomatous endometrial hyperplasia.

No appreciable disorders of cellular immunity were detected in patients with glandular cystic endometrial hyperplasia. Atypical endometrial hyperplasia was associated with quantitative changes in T lymphocytes and their subpopulations, decreased level of lymphocytes carrying activation antigens, and increased count of natural killers. These changes can be characterized as immunocompensation.

Immunohistochemical expression of vimentin and secretory component antigens in endometrial hyperplasia and neoplasia.

Vimentin is an intermediate filament protein normally expressed in mesenchymal cells, but evidence is accumulating in the literature which suggests that the aberrant expression of vimentin in epithelial cancer cells might be related to local invasiveness and metastatic potential. Previous studies strongly support the implication of vimentin in the metastatic progression of breast and cervical lesions. The secretory component is isolated from human colostrum and is of help in more precise grading of endometrial carcinoma. In this study we examined vimentin and secretory component (SC) expression in adenomatous hyperplasia, atypical adenomatous hyperplasia and well-differentiated adenocarcinoma (cribriform pattern). The results showed decreased expression of vimentin and increased expression of the secretory component as the lesion progressed to malignancy.

Gains and losses of glycoprotein CD44 and secretory component expression in endometrial hyperplasia and neoplasia.

CD44 is an adhesion molecule, which binds hyaluronic acid and participates in a number of cell-cell interactions, including lymphocyte homing. The CD44 antigen is expressed on approximately 90% of lymphocytes, monocytes, granulocytes, and, in lower amounts on thymocytes, fibroblasts, and erythrocytes. Platelets lack CD44. In non-haematopoietic tissues, CD44 is widely distributed. The secretory component is isolated from human colostrum and is of help in more precise grading of endometrial carcinoma. In this study we examined CD44 and secretory component expression in adenomatous hyperplasia, atypical adenomatous hyperplasia and well-differentiated adenocarcinoma (cribriform pattern). The results showed decreased expression of CD44 and increased expression of secretory component as the lesion progressed to malignancy.

The clinical significance of tumor-associated antigen RCAS1 expression in the normal, hyperplastic, and malignant uterine endometrium.

OBJECTIVE: A tumor-associated antigen, RCAS1, is recognized by 22-1-1 monoclonal antibody. It was found in carcinomas derived from the uterus and ovary and was especially strongly expressed in invasive cancers. A previous investigation showed the RCAS1 expression to be correlated with a poor prognosis in uterine cervical adenocarcinoma. In this study, we examined whether the expression of RCAS1 is associated with the progression of the uterine endometrial neoplasms. METHODS: The expression of RCAS1 was evaluated by an immunohistochemical analysis. The tissue specimens used in this study included 46 cases of normal uterine endometrium, 40 cases of hyperplasia, and 121 cases of adenocarcinoma. The relationship between RCAS1 expression and several clinicopathological variables (clinical stage, histology, grade, myometrial invasion, lymph-vascular space invasion, and lymph node metastasis) was also assessed in endometrial adenocarcinoma. RESULTS: RCAS1 was positive in 26% of the normal uterine endometrium specimens (12 of 46 total cases), in 32% of the hyperplasia specimens (13 of 40 total cases), and in 68% of the adenocarcinoma specimens (83 of 121 total cases). As a result, the expression of RCAS1 was statistically higher in adenocarcinoma than in the normal and hyperplastic endometrium (P < 0.0001). RCAS1 was statistically detected more frequently in grade 3 than in grade 1 or 2 (P < 0.05); however, there was no correlation between the antigen expression and the clinical stage, myometrial invasion, lymph-vascular space invasion, or lymph node metastasis. CONCLUSION: RCAS1 expression might thus be associated with the malignant transformation and poor differentiation observed in uterine endometrial adenocarcinoma.