子宫内膜癌组织中环氧化酶-2与雌、孕激素受体的表达及相关性研究

目的:探讨子宫内膜癌组织中环氧化酶-2(COX-2)、雌激素受体(ER)和孕激素受体(PR)的表达及相关性。方法:应用免疫组化SP法检测56例子宫内膜癌中COX-2、ER和PR的表达。结果:COX-2在子宫内膜癌中的表达率随病理分级的增高而升高,与患者年龄、临床分期和淋巴结转移情况无关。ER和PR在子宫内膜癌的表达与临床分期及病理分级、淋巴结转移有关,表达率随临床分期增加、病理分级增高及淋巴结转移而降低。COX-2的表达与ER和PR无关。结论:COX-2可能介导不同的生物学途径,可以联合内分泌药物与特异性COX-2抑制剂治疗转移或复发的子宫内膜癌。     

Comparative immunohistochemical study of endometrioid and serous papillary carcinoma of endometrium.

OBJECTIVE: The aim of this study was to determine whether immunohistochemical analysis of molecular parameters can provide an alternative method for classification of endometrial cancer cases according to their aggressiveness. METHODS: Sixty-four cases of endometrial carcinoma were assigned to three groups: group I--28 cases of endometrioid well and moderately differentiated (G1-G2) carcinoma; group II--14 cases of endometrioid poorly differentiated (G3) carcinoma; group III--22 cases of serous papillary endometrial cancer. Immunohistochemistry was used to determine the existence of estrogen receptors (ER), progesterone receptors (PR), and the expression of bcl-2, p53, HER-2/neu and Ki-67. RESULTS: There was a significant difference in the immunohistochemical profile of the studied molecular parameters comparing the three study groups. The endometrioid G1-G2 cases (group I) were characterized by increased immunoreactivity for ER and PR (85.7% and 78.6%, respectively), increased immunoreactivity for bcl-2 (42.8%) and low expression of p53 (14.3%) and HER-2/neu (14.3%). In contrast to group I cases, the serous papillary endometrial cancer cases (group III) were characterized by immunonegativity for ER, PR and bcl-2 and high immunoreactivity for p53 (81.8%) and HER-2/neu (45.4%). The endometrioid G3 cases (group II) demonstrated an intermediate immunoprofile, characterized by immunonegativity for ER, PR and HER-2/neu, low immunoreactivity for bcl-2 (7.1%) and high expression of p53 (57.1%). The expression of Ki-67 did not differ significantly comparing the different cases of endometrial cancer. CONCLUSION: This study provides evidence that the immunohistochemical analysis of endometrial carcinoma differentiates between different grades and histological types, thus being useful in the distinction of high risk cases.     

Expression of HER-2/neu, epidermal growth factor receptor, vascular endothelial growth factor, cyclooxygenase-2, estrogen receptor, and progesterone receptor in small cell and large cell neuroendocrine carcinoma of the uterine cervix: a clinicopathologic and prognostic study

We studied the immunohistochemical expression of HER-2/neu, epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), cyclooxygenase-2 (COX-2), estrogen receptor (ER), and progesterone receptor (PR) in uterine cervical small cell and large cell neuroendocrine carcinomas (SCNECs and LCNECs) from 24 patients seen at The University of Texas M.D. Anderson Cancer Center. The objectives were to determine their expression and prognostic role in survival. Twenty-three cases (95.8%) expressed VEGF. The tumors expressing EGFR, HER-2/neu, and COX-2 were modest in numbers: eight (33.3%), 10 (41.7%), and seven (29.2%), respectively. Only one tumor (4.2%) expressed ER, and only two tumors (8.3%) expressed PR. No significant differences in the expression of these factors were found between SCNECs and LCNECs or between stage I and stage II-III tumors. The median overall survival was 21.1 months (95% confidence interval [CI], 17.2-25.0 months). Only HER-2/neu expression was significantly associated with survival. Patients with negative HER-2/neu expression tumors had significantly shorter survival than those whose tumors were positive, 14.2 months (95% CI, 10.6-17.7 months) versus 33.1 months (95% CI, 0-76.92 months) (P = 0.03). There was a trend toward worse survival in patients with EGFR expression, but this finding was not significant. The combination of negative HER-2/neu expression and positive EGFR expression had the worst impact on survival.     

Intratumoral effects of medroxy-progesterone on proliferation, apoptosis, and sex steroid receptors in endometrioid endometrial adenocarcinoma

OBJECTIVE: The effects of progesterone on proliferation and apoptosis are studied in a scrutinized evaluation of endometrial carcinoma before, during, and after progesterone therapy. The heterogeneity of sex steroid expression as well as proliferation, indicated as Ki-67 index, is considered. METHODS: A total of 29 endometrial carcinomas were studied with in situ evaluation of Ki-67 proliferation marker, estrogen and progesterone receptors (ER and PR), and bcl-2 and p53 immunohistochemistry in the epithelial part of the tumor. In biopsy 1, before the therapy, Ki-67 ER, and PR were studied also in stroma. Apoptotic cells were morphologically identified in hematoxylin- and eosin-stained sections of the tumors and the apoptotic index (apoptotic cells per 1000 cells) was calculated. Chances in feature factors were mainly evaluated by repeated measures ANOVA. RESULTS: Proliferation (Ki-67) was decreased in grade 1 (G1) and grade 2 (G2) tumors during progesterone therapy both in overall evaluation (Ki) and particularly in the areas of maximal proliferation (Ki-max). No change was seen in G3 tumors. A decrease in PR expression in the areas of maximal expression for PR (PR-max) was also observed in G1 and G2 tumors. Apoptosis as well as bcl-2 and ER expression were unchanged during therapy and withdrawal. CONCLUSIONS: The effect of progesterone is seen only on proliferation in low-grade (G1 and G2) tumors. The coexistence of high PR expression in the foci of high proliferation may contribute to the effect in G1 and G2 tumors. No effect of progesterone is seen on apoptosis in tumors of any grade.     

Immunohistochemical bcl-2 expression, p53 overexpression, PR and ER status in endometrial carcinoma and survival outcomes

Immunohistochemical expression of bcl-2, p53, PR and ER in cases with endometrial carcinomas arrayed on a tissue microarray (TMA) was tested and correlated with clinicopathologic features, overall survival (OS), cancer-related survival (CRS) and disease-free survival (DFS). Seventy-seven patients with endometrial cancer were reviewed. Slides were evaluated by two pathologists blinded to patient clinical characteristics and survival data. Mean age of patients was 62.5 years (range 35-80), median follow up 60 months (range 9-120). Seventy-nine percent of patients were FIGO Stage I; 39% of the cases showed bcl-2 cytoplasmic staining and its expression was significantly correlated with low-grade tumor differentiation and age < or = 60 years. Nuclear p53 overexpression was detected in 23.4% of the cases and was significantly correlated with advanced stages (IIB-IV), non-endometrioid histology, nodal metastasis and advanced age (> 60 years). PR and ER were positive in 63.6% and 30% of the cases, respectively. Analysis of p53 overexpression and bcl-2 expression in relationship with PR and ER status showed a direct correlation between bcl-2 expression and PR positivity (p = 0.001). In a multivariate analysis FIGO staging was the only clinicopathologic parameter independently correlated with DFS. In conclusion p53 overexpression was directly associated with unfavorable clinicopathologic factors such as advanced stage, histologic subtype, advanced patient age and nodal metastasis. Bcl-2 expression was related with younger age, favorable grade and PR expression by tumor cells. Patient survival was not related to the tested biomarkers.     

A significance of immunohistochemical determination of steroid receptors, cell proliferation factor Ki-67 and protein p53 in endometrial carcinoma

OBJECTIVES: The aim of the study was to preoperatively predict the biologic behavior of the endometrial carcinoma using immunohistochemical analysis of the p53 protein and Ki-67 expression, and estrogen receptor (ER) and progesterone receptor (PR) status, in the material obtained by fractional curettage. METHODS: One hundred and thirty-six patients with primary endometrial carcinoma were included in the study. In all 136 patients, the fractional curettage was performed before the hysterectomy, and the diagnosis of endometrial carcinoma was confirmed pathohistologically after the surgical procedure on the hysterectomy specimens. The significance of the prognostic factors was assessed using univariate and multivariate analyses. The cutoff values of the percentage of ER, PR, p53, and Ki-67 positive cells in terms of survival probability determination were obtained as the values of the highest chi-square test, using proportional-risk regression method. A multivariate Cox regression analysis was performed to estimate the influence of several clinical, pathohistologic, and immunohistochemical covariates to patients' survival. Survival curves were determined by the Kaplan-Meier product-limit method based on the most recent clinical status. RESULTS: According to the histologic type of the tumor, fractional curettage specimens revealed 111 histologically favorable types (81.6%) and 25 unfavorable types (18.4%). The data indicate that ER, PR, Ki-67, and p53 levels of the hysterectomy specimens and those of the preoperative specimens were in fairly good agreement. The patients with the most favorable tumor grade (G I) had significantly better prognosis when the percentage of p53 positive cells was less than 15%. In the group of patients with histologic grade II, the survival was affected by ER expression (more than 30% of positive cells) and p53 levels (less than 15% of positive cells). None of the parameters was predictive in the group of patients with histologic grade III. CONCLUSIONS: We found that determination of immunohistochemical parameters (ER, PR, and p53) on well-differentiated and moderately differentiated endometrial carcinoma of favorable histologic type obtained by curettage enables the recognition of the patients with favorable prognosis, who should not be treated by radical surgery.     

P^21ras c—mycp53和雌孕激素受体在子宫内膜癌的表达

应用免疫组化ＬＳＡＢ法，对３２例子宫内膜癌，６例腺瘤型增生，２０例腺囊型增生组织的癌基因Ｐ＾２１ｒａｓ，ｃ－ｍｙｃ及抑癌基因ｐ５３蛋白表达进行了检测，对３２例子宫内膜癌进行了雌，孕激素受体的检测，并对子宫内膜癌组织Ｐ＾２１ｒａｓ，ｃ－ｍｙｃｐ５３过度表达与雌，孕激素受体的关系了分析，结果显示：Ｐ＾２１ｒａｓｃ－ｍｙｃｐ５３在子宫内膜癌组织中的阳性表达率分别为５９．４％，６２．５％和１８．８％，雌，     

Immunohistochemical staining for Ki-67 and p53 helps distinguish endometrial Arias-Stella reaction from high-grade carcinoma, including clear cell carcinoma.

The distinction of the Arias-Stella reaction from clear cell carcinoma of the endometrium is usually straightforward; however, this differential diagnosis can be difficult when the Arias-Stella reaction occurs outside the setting of pregnancy or in older patients. The differential diagnosis also is problematic when serous or clear cell carcinoma focally arises within an endometrial polyp, as part of "endometrial intra-epithelial carcinoma" (EIC), or in younger patients. The goal of this study was to determine whether immunohistochemical staining can distinguish the Arias-Stella reaction from endometrial high-grade carcinoma, particularly clear cell carcinoma. Cases of endometrial Arias-Stella reaction (n = 27), clear cell carcinoma (n = 11), serous carcinoma (n = 7), and EIC (n = 4) were assessed by immunohistochemical staining with antibodies for Ki-67, p53, estrogen receptor (ER), and progesterone receptor (PR). Composite immunohistochemical scores based on the percentage and intensity of stained cells were calculated, as was the overall positivity (percentage positive cases), using a cutoff value of >/=5% stained cells and at least weak intensity. Appropriate statistical tests were performed. Ki-67 and p53 immunostaining was significantly less in Arias-Stella reaction than in clear cell carcinoma (p < 0.0001 for both) or serous carcinoma/EIC (p < 0.0001 for both), measured by the composite immunohistochemical scores or overall positivity. ER showed a significant difference only between Arias-Stella reaction and clear cell carcinoma; PR showed a significant difference only between Arias-Stella reaction and serous carcinoma/EIC. When clinical or histologic features cannot facilitate the differential diagnosis, immunohistochemical staining for Ki-67 and p53 may help distinguish endometrial Arias-Stella reaction from clear cell carcinoma and other types of high-grade carcinoma.     

Expression of gelatinase (MMP-2 and MMP-9) and cyclooxygenase-2 (COX-2) in endometrial carcinoma

OBJECTIVE: Matrix metalloproteinases (MMPs) are key players in the degradation of extracellular matrix and basement membranes, and are thus important in tumor invasion. Gelatinases (MMP-2 and MMP-9) in particular are prognostic factors in many solid tumors. In this study the immunohistochemical expression of both COX-2 and matrix metalloproteinases has been shown for the first time in endometrium carcinoma. METHODS: Forty-two endometrial carcinoma tissues were immunostained for MMP2 antibody (1:100, Rabbit polyclonal), MMP9 antibody (1:100, Rabbit polyclonal) and CoX2 antibody (1:100, Epitope specific rabbit antibody). RESULTS: 90.5% of the cases were positive for MMP-2 and MMP-9, and 83.3% of the cases were positive for COX-2. A statistically significant association was found between COX-2 overexpression and FIGO stage (p = 0.001). A positive correlation was also found with histological grade (p = 0.006), myometrial invasion (p = 0.033), vascular invasion (p = 0.017), and lymphatic invasion (p = 0.007). A positive correlation was found between MMP-2 overexpression and vascular and lymphatic invasion (p = 0.030 and p = 0.003, respectively). MMP-9 overexpression was also found to be correlated with vascular and lymphatic invasion (p = 0.001 and p = 0.012, respectively). Furthermore, there was a statistically significant correlation between MMP-2 and MMP-9 overexpression (p = 0.0001). CONCLUSION: The results showed that COX-2, MMP-2 and MMP-9 were expressed in a high percentage of primary endometrial carcinomas and their expressions may be associated closely with parameters of tumor aggressiveness.     

Cyclooxygenase-2 (COX-2), epidermal growth factor receptor (EGFR), and Her-2/neu expression in ovarian cancer

OBJECTIVES: Cyclooxygenase-2 (COX-2) seems to be involved in critical steps of cancer onset and progression. Abnormalities of epidermal growth factor receptor (EGFR) and Her-2/neu have been actively investigated in ovarian cancer and associated with unfavorable clinical outcome. The involvement of COX-2 in ErbB family pathways has been proposed. We investigated by immunohistochemistry the expression of COX-2, EGFR, and Her-2/neu in a series of advanced primary ovarian cancers. METHODS: The study included 76 consecutive stage IIIC-IV ovarian cancer patients with measurable disease after first surgery. Immunohistochemistry was performed on paraffin-embedded sections with rabbit antiserum against COX-2, murine monoclonal antibody (MoAb) 300G9 against Her-2/neu, and monoclonal antibody 108 against EGFR. RESULTS: No association among COX-2, EGFR, and HER-2/neu was found. COX-2 positivity was found in a statistically significant higher percentage of unresponsive cases (80.0%) than in patients responding to chemotherapy (35.7%) (P = 0.0008). The association between COX-2 positivity and poor chance of response to treatment was retained in multivariate analysis. In the subgroup of patients who underwent explorative laparotomy COX-2-positive cases showed a shorter overall survival (P = 0.049). CONCLUSIONS: COX-2 could represent a possible new marker of sensitivity to platin-based chemotherapy in ovarian cancer. The lack of association of COX-2 with EGFR or Her-2/neu suggests that the ability of COX-2 to predict tumor sensitivity to chemotherapy is not dependent on EGFR or Her-2/neu status and could be independently associated with prognosis. In this context, the availability of agents able to specifically interfere with COX-2, Her-2/neu, or EGFR tyrosine kinase is of potential interest.     

Significantly greater expression of ER, PR, and ECAD in advanced-stage low-grade ovarian serous carcinoma as revealed by immunohistochemical analysis.

A 2-tier system that classifies ovarian serous carcinoma (OSC) as low grade or high grade is gaining acceptance. Women with low-grade OSC generally have higher 5-year survival rates than do women with high-grade OSC. We examined the expression of various markers to further understand the molecular differences between low-grade and high-grade OSCs: the potential therapeutic targets or prognostic markers Her-2/neu, estrogen receptor, and progesterone receptor (PR); the metastasis-associated markers cyclin D1 (BCL1), E-cadherin, matrix metalloproteinase (MMP) 2, and MMP-9; and the cell proliferation-associated markers BCL1, Ki-67 antigen (Ki-67), and p53. For this immunohistochemical analysis, we used paraffin-embedded specimens from 47 patients with advanced-stage low-grade OSC and from 49 patients with advanced-stage high-grade OSC. Our results showed that low-grade tumors expressed significantly higher levels of estrogen receptor, PR, and E-cadherin than did high-grade tumors, suggesting the involvement of gonadal steroid hormones, especially in the pathogenesis of low-grade OSC; the PR positivity was also observed in the stromal component of these low-grade tumors. On the other hand, high-grade tumors trended toward increased expression of MMP-9, BCL1, p53, and Ki-67, and robust MMP-9 positivity was observed in the stromal component of these high-grade tumors. These differences may lead to the development of different therapeutic strategies for women with either the low-grade or the high-grade form of OSC.     

Correlation of cyclooxygenase-2 (COX-2) and aromatase expression in human endometrial cancer: tissue microarray analysis

OBJECTIVE: The objective of this study was to compare the prevalence of cyclooxygenase-2 (COX-2), aromatase, and hormone receptor immunohistochemical (IHC) expression to well defined clinical-pathologic prognostic factors in a large group of surgically staged endometrial cancer patients. STUDY DESIGN: A tissue microarray (TMA) was constructed from 336 separate specimens of endometrial cancer. IHC was performed for estrogen (ER) and progesterone (PR) receptor, COX-2, COX-1, and aromatase. RESULTS: The majority of tumors expressed COX-2 (59%) and aromatase (65%). COX-2 staining significantly correlated with aromatase expression ( P < .014) but did not correlate with ER and PR. COX-2 expression was correlated with worsening histologic grade ( P < .026) and approached statistical significance for deep myometrial invasion ( P < .055). After applying multivariate analysis, no single IHC or combination of IHCs correlated with intrauterine poor prognostic factors or advanced stage. Only myometrial invasion >50% (OR 6.98, P < .001) and nonendometrioid histology (OR 4.933, P < .001) were predictive of advanced stage after multivariate analysis. CONCLUSION: COX-2 and aromatase are expressed in the majority of endometrial cancer patients. COX-2 expression was not associated with the great majority of surgical-pathologic prognostic factors. COX-2 expression did significantly correlate with aromatase expression, suggesting that intratumoral production of estrogen in endometrial cancer may be an important mechanism in tumorigenesis.     

MIB1 as a possible predictor of recurrence in low-grade endometrial stromal sarcoma of the uterus

OBJECTIVE: Immunohistochemical analysis of MIB1, p53, estrogen, and progesterone receptors can provide prognostic information in endometrial adenocarcinoma. Since predictors of recurrence for low-grade endometrial stromal sarcoma (LESS) are still unknown, a battery of immunostains was performed to find markers, which might be useful to predict prognosis. METHODS: Eleven patients with an average age of 43.8 years (range 27-76) were identified with stage I LESS. Immunostains, including MIB1, p53, ER, and PR, were evaluated by two pathologists, independently. RESULTS: All tumors were positive for ER and PR; 1/11 was positive for p53; MIB1 ranged from 0 to 20% positive tumor nuclei. Mitotic counts ranged from 0 to 7/10 hpf. Two patients developed recurrences. One had a pelvic recurrence 7 years after diagnosis. This tumor had a mitotic count of 1/10 hpf, MIB1 expression in 10% of nuclei, and focal p53 expression. A second patient developed pulmonary metastases 10.8 years after diagnosis; the tumor showed a mitotic count of 7/10 hpf and MIB1 expression in 20% of nuclei, but was negative for p53. There was a significant difference in MIB1 reactivity scores between patients who did or did not develop recurrence (P = 0.0303). A marginally significant association was detected between MIB1 (P = 0.0896) or p53 (P = 0.0833) positivity and length of recurrence-free survival. CONCLUSION: Although MIB1 and p53 appear to be useful prognostic markers, a larger study would be necessary to confirm their validity.     

子宫内膜癌p53蛋白过度表达与性激素受体阳性的关系

目的：研究子宫内膜癌ｐ５３蛋白过度表达与性激素受体阳性的关系。方法：收集４５例子宫内膜癌手术标本，采用多种ＰＡＰ免疫组化方法进行检测。结果：４５例宫内膜癌中１４例（３１．１％）ｐ５３蛋白过度表达，其中１１例雌、孕激素受体阴性，而在ｐ５３阴性的３１例中２７例雌、孕激素受体阳性。在子宫内膜癌中ｐ５３蛋白过度表达与雌、孕激素受体呈负相关（Ｐ＜０．０１）。结论：部分子宫内膜癌的发生可能与雌激素受体无关，而与ｐ５３蛋白过度表达有关。     

子宫内膜癌分子标志物与临床病理特征关系的研究

目的探讨子宫内膜癌中ER、PR、PTEN、p53及Ki-67的表达与临床、病理特征的关系。方法收集200例原发性子宫内膜癌患者的临床病理资料,对其ER、PR、PTEN、p53及Ki-67表达情况进行统计学分析。结果①子宫内膜癌病例中．ER、PR、PTEN、p53的阳性表达率分别为86．5％、85．5％、82．10和49．2％;Ki-67在癌灶中的阳性表达率为4％--95％,平均为46．9％。②妊娠次数与PR阳性表达呈负相关（r=-0．191,P=0．007）,而发病年龄、分娩次数与p53阳性表达呈正相关（r=0．184,P=0．041;r=0．255,P=0．004）。③子宫内膜样腺癌ER、PR、p53阳性率与其他类型子宫内膜癌比较,差异有统计学意义（P〈0,01）。④ER阳性表达与手术病理分期呈负相关（r=-0．155,P=0．028）,其中I期患者ER阳性率高于Ⅱ期及以上患者（P=0．032）。⑤ER、PR阳性表达与组织学分级呈负相关（r=-0．217,P=0．002;r=-0．317,P=0．000）,但p53、Ki-67表达与其呈正相关（r=0．327,P=0．000;r=0．465,P=0．000）。⑥ER阳性表达与肌层浸润深度呈负相关（r=-0．142,P=0．046）,在有无深肌层浸润上ER、PR表达率均有统计学意义（P〈0．05）。结论对子宫内膜活检组织进行分子标志物的分子特征检测,有助于指导临床。     

Prognostic value of p53, c-erb-B2 and MIB-1 in endometrial carcinoma

OBJECTIVE: To assess the immunohistochemical expression of p53 protein, a tumour suppressor gene of the oncogene c-erb-B2 and MIB-1 proliferation marker (Ki-67 antigen) in endometrial carcinoma. METHODS: We studied 29 cases of endometrial carcinoma in which the p53, c-erb-B2 and MIB-1/Ki-67 antigens were investigated by an immunohistochemical method. We evaluated the correlations among the immunohistochemical positivity and the grading, depth of myometrial invasion, stage of the neoplasia and follow-up. RESULTS: Both p53 and c-erb-B2 were positive in 16 out of 29 cases (55.2%), whereas MIB-1 was positive in 19 out of 29 cases (65.5%). All these three antigens showed a positive correlation with the grading, myometrial invasion and FIGO stage. Regarding follow-up, p53, c-erb-B2 and MIB-1 were, respectively, positive in 100%, 83.4% and 66.7% of neoplasias of patients who died of disease whereas they were positive in 40%, 40% and 60%, respectively, of tumours of patients with no evidence of disease. CONCLUSION: The overexpression of p53, c-erb-B2 and MIB-1 seem to indicate a more malignant tumour phenotype.     

Correlation of mammographic appearance and molecular prognostic factors in high-grade breast carcinomas

The aim of our study was to evaluate the association between the mammographic appearance and the biologic characteristics of high-grade breast carcinomas. Three hundred and twenty patients with breast carcinomas were studied. Histological examination showed 83 (26%) high-grade ductal carcinomas. Immunohistochemistry was carried out by using antibodies against estrogen receptor (ER), progesterone receptor (PR), HER-2/neu, p53 and cathepsin D. In 60/83 high-grade carcinomas we studied the mammographic appearance. Asymmetric density with poorly defined margins without microcalcifications was the major mammographic finding in 49/60 (approximately 82%) high-grade ductal carcinomas. HER-2/neu positivity (68.7%) and p53 positivity (48.2%) were statistically correlated with asymmetric density with poorly defined margins without microcalcifications in high-grade carcinomas. We observed loss of ER and PR receptors in 50%, whereas loss of PR receptors was observed in 65% of high-grade breast carcinomas. Cathepsin D (> 20%) was detected in 38.5% of high-grade carcinomas. Our findings suggest a significant relationship between mammographic appearance and biologic markers in high-grade breast carcinomas.     

Dualistic model of molecular pathogenesis in endometrial carcinoma

Sporadic endometrial carcinoma can be divided into two biologically and clinically distinctive subtypes of which one is estrogen-related (type I), the other estrogen-unrelated (type II). Type I carcinomas occur at younger age, express estrogen (ER) and progesterone receptors (PR), are frequently associated with endometrial hyperplasia and show a good prognosis. Type II carcinomas occur at older age, are negative for ER and PR, arise in the background of atrophic endometrium and show poor prognosis. Histologically, endometrioid carcinomas correspond to type I carcinomas whereas serous carcinoma is the prototype of type II carcinomas. Endometrioid and serous carcinomas are significantly different with respect to their molecular changes. Endometrioid carcinomas frequently show microsatellite instability (MIN), PTEN and K-ras mutation but infrequently p53 mutations, loss of p16 expression and her2/neu amplification, respectively. In contrast, serous carcinomas show a high frequency of p53 mutations and often loss of p16 expression whereas MIN and PTEN and K-ras mutations are uncommon. Familial endometrial carcinoma associated with HNPCC occur about two decades earlier than sporadic carcinomas, show endometrioid histology and are frequently MIN positiv due to germline mutations of mismatch repair genes (mostly MLH1 and MSH2). During the progression of endometrioid carcinoma PTEN mutations and MIN are considered early changes since they are present in a high frequency in atypical endometrial hyperplasia whereas p53 mutations, loss of p16 expression and her2/neu amplification are considered late events since they are predominantly found in poorly differentiated tumors. In contrast, p53 mutations are considered an early event in the pathogenesis of serous carcinoma occurring already in its putative precursor endometrial intraepithelial carcinoma (EIC). The future research will focus, besides the discovery of new relevant genes, on the interaction of known genes as well as their clinical relevance.     

Prognostic significance of progesterone receptor immunohistochemistry for lymph node metastases in endometrial carcinoma

OBJECTIVE: The aim of this study was to determine whether progesterone receptor (PR), estrogen receptor (ER), p53 protein, and proliferating cell nuclear antigen (PCNA) expression constitute independent prognostic factors for lymph node metastases in endometrial carcinoma using immunohistochemical techniques on hysterectomy and biopsy specimens. METHODS: We evaluated the correlation between lymph node metastases and PR/ER immunohistochemistry, p53/PCNA expression, age, tumor grade, myometrial tumor invasion, cervical involvement, and ovarian metastases in a series of 99 cases of primary endometrial carcinoma surgically staged with systemic pelvic lymphadenectomy and para-aortic lymph node biopsy. RESULTS: Lymph node metastases from endometrial carcinoma were statistically correlated with negative PR immunohistochemistry (P = 0.001), intense p53 expression (66% or more of the tumor cells stained, P = 0.003), deep myometrial tumor invasion (greater than one-half, P = 0.001), and cervical involvement (P = 0.001). Tumor grade showed borderline statistical significance for lymph node metastases (P = 0.058). On multivariate analysis, negative PR, intense p53 expression, and cervical involvement were significant prognostic variables for lymph node metastases (P = 0.0001, 0.0023, and 0.002, respectively). Immunohistochemical study indicated that the PR status on preoperative biopsy specimens and hysterectomy specimens was in good agreement, but p53 status was not. Age, ovarian metastases, ER immunohistochemistry, and PCNA expression were not significantly related to lymph node metastases. CONCLUSION: PR immunohistochemistry appeared to be the most powerful prognostic factor associated with lymph node metastases in endometrial carcinoma, independent of other clinicopathological parameters.     

雌激素受体、孕激素受体、C-erbB-2和Ki-67在子宫内膜癌中的表达及其与临床病理相关性

目的 探讨雌激素受体（ER）、孕激素受体（PR）、C-erbB-2和Ki-67在不同子宫内膜组织中的表达及其与临床病理的相关性。方法 采用免疫组化S-P法检测2004年1月至2013年1月郑州人民医院病理科存档30例正常子宫内膜、30例不典型增生、80例子宫内膜癌组织中ER、PR、C-erbB-2、Ki-67的表达。结果　ER、PR在正常子宫内膜、不典型增生和子宫内膜癌中表达逐渐降低(P<0.05),在不同分化子宫内膜癌组织类型中表达有差异(P<0.05);C-erbB-2在正常子宫内膜中不表达,在不典型增生中表达为53.33%和子宫内膜癌中表达为80.00%,两两比较差异有统计学意义(P<0.05);Ki-67在正常子宫内膜仅有少量表达,在不典型增生子宫内膜中表达为33.33%和子宫内膜癌中表达为63.75%,差异均有统计学意义(P<0.05)。C-erbB-2及Ki-67的表达与子宫内膜癌的分化程度、临床分期、肌层浸润深度及淋巴结转移4种病理特征均有关(P<0.05)。结论　ER、PR、C-erbB-2和Ki-67表达与子宫内膜癌的临床病理相关,可作为判断子宫内膜癌预后及指导临床治疗的指标。