p53 Expression as a Prognostic Indicator of 5-Year Survival in Endometrial Cancer

BACKGROUND: One of the most common genetic alterations to occur in human cancers is an alteration of the p53 tumor suppressor gene. The purpose of this article was to build upon the authors' previous work with p53 and determine whether p53 was a prognostic indicator of 5-year survival. METHODS: One hundred thirty-seven consecutively surgically treated patients with endometrial cancer had their p53 expression studied by immunoperoxidase staining and quantified by image analysis. All patients were evaluable for 5-year survival. RESULTS: One hundred three patients had endometrioid adenocarcinoma; 6, adenosquamous carcinoma; 14, papillary serous carcinoma; 10, clear cell carcinoma; and 4, undifferentiated carcinoma. p53 expression ranged from 0.0 to 58.2% positive nuclear area with a mean of 11.5% (median 2.6%) for the cohort. For the patients with endometrioid carcinoma, the mean p53 expression was 7.1% while for the nonendometrioid tumors it was 24.6% (P<0.001). Fifty-nine of the 103 endometrioid tumors (57.3%) stained positive for p53 while 32 of the 34 nonendometrioid (94.1%) tumors stained positive (P<0.001). Increasing histologic grade correlated with an increasing p53 expression (P = 0.003). The percentage of tumors expressing p53 was found to be higher in FIGO stage II, III, and IV than in FIGO stage I cancer (P = 0.003). However, mean p53 expression did not differ between early (stage I) and advanced (stage II, III, and IV) cancers (P = 0.088). Utilizing 5-year survival as the endpoint for multivariate analysis, FIGO stage (P = 0.0028) and p53 expression (P<0.001) were the only independent prognostic indicators found. CONCLUSION: p53 expression is more commonly found in nonendometrioid than in endometrioid adenocarcinoma of the endometrium. It, along with FIGO stage, is an independent prognostic indicator of 5-year survival.     

A study of heat shock protein 27 in endometrial carcinoma

OBJECTIVE: Heat shock protein 27 (HSP27) is a relatively small protein produced in response to pathophysiologic stress. The purpose of this study was to determine prospectively whether HSP27 was associated with known prognostic factors in patients with endometrial carcinoma. METHODS: One hundred fifty-three consecutive patients with endometrial carcinoma were studied. Slides were prepared from fresh tissue. HSP27 was analyzed using a semiquantitative measurement. Patient records were examined for FIGO stage, grade, depth of myometrial invasion, histology, lymphovascular space invasion, time to recurrence, and survival. RESULTS: The mean follow-up was 53 months (median 56 months, range 30-68 months). Endometrioid tumors showed significantly higher HSP27 staining than nonendometrioid tumors (P = 0.005). Patients alive at the conclusion of this study had significantly higher mean HSP27 staining than patients who were deceased (P < 0.001). Logistic regression revealed HSP27 staining (P = 0.02), FIGO stage (P = 0. 014), and lymphovascular space invasion (P = 0.046) to be independently predictive of survival. CONCLUSION: HSP27 staining is significantly higher in endometrioid than nonendometrioid tumors. HSP27 staining is an independent prognostic indicator in patients with endometrial carcinoma, the most common gynecologic malignancy in the United States.     

子宫内膜样腺癌MELF浸润模式的研究进展

子宫内膜癌是女性生殖系统常见的恶性肿瘤之一,其最常见的病理形态为子宫内膜样腺癌。早期子宫内膜癌预后较好,但仍有少部分患者预后不良。影响子宫内膜癌预后的不良因素包括肿瘤组织学分级、子宫肌层侵犯深度、淋巴脉管间隙浸润（lymphovascular space invasion,LVSI）、宫颈间质受累及淋巴结转移等。伴微囊性、伸长及碎片状（microcystic,elongated,fragmented,MELF）浸润是子宫内膜样腺癌的一种特殊的浸润子宫肌层的方式。多项研究证实MELF浸润模式与某些影响预后的不良病理因素相关,但是MELF浸润模式的预后意义尚不明确。现就MELF浸润模式的临床病理特征以及预后意义的研究进展进行综述,以期为未来MELF浸润模式的相关研究提供理论参考。     

Angiogenesis, p53, and bcl-2 expression as prognostic indicators in endometrial cancer: comparison with traditional clinicopathologic variables.

We investigated the relation of expression of tumor-suppressor gene product p53, apoptosis-regulator gene product bcl-2, and CD34 (as a measure of microvessel density [MVD]) with traditional clinicopathologic prognostic variables in endometrial carcinoma (histologic type, grade, depth of myometrial invasion, angiolymphatic invasion, lymph node involvement). In specimens from 63 patients with endometrial carcinoma, the mean MVD (64.38+/-28.71 microvessels per 200x field) was not related to any clinicopathologic variables. Nuclear p53 expression was detected in 15 (23.8%) patients and was higher in nonendometrioid carcinomas (p<0.05) and in tumors with increasing histologic grade (p<0.001). Cytoplasmic bcl-2 staining was seen in 79.3% of the tumors. There was a negative correlation between bcl-2 expression and histologic type and tumor grade (p<0.05). In survival analysis, patient age, FIGO stage, high expression of p53, low expression of bcl-2, and high and intermediate MVD values were found to be the most significant prognostic indicators of survival (p<0.05). In multivariate regression analysis, FIGO stage and low bcl-2 expression were found to be the only independent indicators of prognosis (p<0.05).     

Prognostic significance of DNA topoisomerase II-alpha (Ki-S1) immunoexpression in endometrial carcinoma

OBJECTIVE: In order to determine the significance of proliferative activity (PA) in endometrial carcinomas, we analysed the expression of cell cycle-related antigens in routinely processed tissue. MATERIALS AND METHODS: Serial sections of 113 endometrial carcinoma specimens were immunostained with the monoclonal antibody DNA Topoisomerase II-alpha (Ki-S1). In addition to Topoisomerase II-alpha (Ki-S1) staining, histologic type, International Federation of Gynecology and Obstetrics (FIGO) stage. FIMO grade, depth of myometrial invasion, tumor size, lymphovascular space invasion, serosal and/or adnexal involvement, lymph node metastasis, age and peritoneal cytology were evaluated as prognostic indicators. The median follow-up time was 23 (range, 1 to 126 ) months. RESULTS: FIGO stage, FIGO grade, tumor size, lymphovascular space invasion, lymph node metastasis, peritoneal cytology and Topoisomerase II-alpha (Ki-S1) expression all significantly influenced survival in univariate analyses (p < or = 0.05). In the Cox regression analysis, Topoisomerase II-alpha (Ki-S1), serosal and/or adnexal involvement, and lymph node metastasis expression were the only variables with independent prognostic impact (p < or = 0.05), whereas FIGO stage, FIGO grade, histologic type FIGO grade, depth of invasion, tumor size, lymphovascular space invasion, age and peritoneal cytology had no independent influence (p > 0.05). Topoisomerase II-alpha (Ki-S1) staining was significantly elevated in advanced (Stage II, III, IV) as opposed to early (Stage I) carcinomas (p < or = 0.05). CONCLUSION: The association with established prognosticators for endometrial carcinomas, and the results of uni- and multivariate analysis indicate that the additional evaluation of DNA Topoisomerase II-alpha (Ki-S1) peptide antibody (PA) is useful for classifying patients into subgroups with low and high risk of relapse which might help to individualize the therapeutic strategy in endometrial carcinomas.     

Interpretation of p53 immunoreactivity in endometrial carcinoma: establishing a clinically relevant cut-off level.

There is accumulating evidence that immunohistochemical staining for p53 can identify patients with endometrial carcinoma who have an adverse outcome, but the interpretation of existing data is complicated by differences between studies in the way that p53 immunohistochemistry results have been assessed. In this study, we sought to determine the appropriate cut-off level for stratification of patients with endometrial carcinoma into high- and low-risk groups, based on p53 immunohistochemical staining. A total of 200 cases of endometrial carcinoma treated by hysterectomy were retrieved from the archives of the Department of Pathology, Vancouver General Hospital, from the period 1983 to 1998. Follow-up information was available for all cases. Slides were reviewed and the diagnosis confirmed, tumors graded according to FIGO grading system, and tumor cell type assessed. A tissue microarray consisting of duplicate 0.6-mm cores of tumor was constructed and immunostained for p53. Immunoreactivity for p53 was scored by counting the number of positively stained tumor cell nuclei and expressing this as a percentage of the total number of tumor cell nuclei counted (p53 index). Kaplan-Meier survival curves were constructed and compared by calculation of log-rank statistic, and multivariate analysis was performed by Cox regression modeling. The distribution of p53 index results was bimodal, with most cases having a very low or very high p53 index. The peaks of the bimodal distribution were clearly separated using a p53 index of > or =50%. Immunoreactivity was a significant adverse prognostic indicator of disease-specific survival (p<0.0001 by univariate analysis). Patients with strongly p53 immunoreactive tumors (p53 index >or =50%) had a significantly worse outcome than patients with weakly immunoreactive (p53 index > or =5% and <50%) or p53-negative (p53 index <5%) tumors (p = 0.0001). There was no significant difference between the outcomes for patients in the latter two groups. By multivariate analysis, p53 overexpression was a significant prognostic indicator independent of patient age and tumor stage (p = 0.008) but was not independent when the analysis was extended to include FIGO grade and tumor cell type. p53 immunostaining was of prognostic significance in the subset of patients with endometrioid carcinomas (p = 0.02), but not in patients with clear cell or papillary serous carcinomas. Using a p53 index of > or =50% as a cut-off between positive and negative p53 staining, immunohistochemical staining for p53 is a prognostic indicator in patients with endometrial carcinoma of endometrioid type. p53 immunostaining was not found to be of prognostic significance independent of tumor cell type and grade.     

MIB-1 in endometrial carcinoma: prognostic significance with 5-year follow-up

OBJECTIVE: MIB-1, a monoclonal antibody to the Ki-67 antigen, has presumptively been shown to be predictive of recurrent disease in patients with endometrial cancer. In order to more conclusively establish whether MIB-1 staining can be used as a prognostic indicator of recurrent disease or survival, a larger group of patients with a minimum follow-up of 5 years was analyzed. METHODS: The tumors from 147 consecutive patients receiving primary surgical therapy for endometrial carcinoma were evaluated with the MIB-1 monoclonal antibody. Proliferation index was quantified by image analysis. Patients were followed for a minimum of 60 months. In addition to MIB-1 staining, histologic type, stage, grade, depth of invasion, lymphovascular space invasion, and peritoneal cytology were evaluated as prognostic indicators. RESULTS: Twenty-five of 147 patients died during the study period. MIB-1 staining was not significantly elevated in advanced (stage II, III, and IV) as opposed to early (stage I) carcinomas (P = 0.38). In patients whose tumor MIB-1 staining was less than 33.0%, no deaths occurred. By multivariate analysis, only MIB-1 staining (P < 0.001), FIGO stage (P = 0.005), and LVI (P = 0.005) were shown to be independent prognostic indicators predictive of survival. CONCLUSION: In this series of 147 consecutive patients with endometrial carcinoma, the monoclonal antibody MIB-1 was shown to be an independent prognostic indicator of 5-year survival. This follow-up further validates the previous work regarding the significance and potential usefulness of MIB-1 as a prognostic indicator.     

Low-risk endometrial carcinoma: assessment of a treatment policy based on tumor ploidy and identification of additional prognostic indicators.

OBJECTIVES: The aims of this study were (1) to assess a treatment policy for patients with low-risk endometrioid endometrial carcinoma where adjuvant treatment decisions have been based on ploidy status of the tumor, and (2) to screen diploid, low-risk tumors for additional features of prognostic significance. METHODS: Between 01/1992 and 08/1996, 406 patients were referred to the B.C. Cancer Agency-Vancouver Clinic with typical endometrial adenocarcinomas limited to <50% myometrial invasion and no vascular space invasion or grade 3 disease on pathology review ("low-risk stage I endometrial carcinoma"). Patients were prospectively assigned to treatment groups based on tumor ploidy. Those patients with aneuploid tumors (n = 91) were treated with adjuvant vaginal vault radiotherapy while those with diploid tumors (n = 315) were followed and treated only at relapse. The hysterectomy specimens from all 14 patients in the untreated, diploid group who relapsed, as well as 28 stage- and grade-matched diploid controls who did not fail, were analyzed by immunohistochemical staining for estrogen receptor (ER), Bcl-2, and p53 proteins. RESULTS: There were no significant differences in the stage (Ia vs Ib) and grade (G1 vs G2) distribution for the diploid and aneuploid groups. Overall median age was 64 years (range 27-90 years) and was also not significantly different for the two groups. The median follow-up for the entire cohort is 45 months (range 1-76 months). There have been 14 failures in the diploid group and 4 failures in the aneuploid group with actuarial 5-year disease-free survival rates of 95.0 and 95.2%, respectively (P = NS). Eight of the failures in the diploid group occurred at the vaginal vault and were all subsequently salvaged with radiotherapy. All but 1 of the failures in the aneuploid group were considered incurable. Of the 14 diploid tumors from patients who failed, 7 stained positively for p53, compared to 4 of 28 diploid controls (P = 0.02). No significant differences were seen in the diploid tumors that recurred, compared to controls, with respect to Bcl-2 or ER expression. CONCLUSIONS: Patients with diploid, low-risk stage I endometrial cancers have excellent prospects for relapse-free and overall survival. Patients with aneuploid tumors treated with adjuvant radiotherapy have the same risk of relapse as untreated patients with diploid tumors; however, their ultimate survival may be lower as a smaller proportion of aneuploid failures are salvageable. While p53 expression in diploid tumors is associated with increased risk of relapse, Bcl-2 and ER are not useful prognostic indicators in this setting.     

Pathological findings in early-stage endometrial cancer

OBJECTIVE: The aim of this study was to assess the pathological characteristics of early-stage endometrial cancer, with regard to endometrioid versus serous papillary adenocarcinoma. METHODS: Sixty-six cases of early-stage endometrial carcinoma were classified into two groups: group I--36 cases of endometrioid endometrial cancer, staged IA-IB and graded G1-G2; group II--30 cases of Stage I serous papillary endometrial cancer. The pathological characteristics compared between the two groups included features such as tumor location in the uterine cavity, tumor focality, lymphovascular invasion, as well as the status of the uninvolved endometrium, adjacent to the tumor. Patient clinical characteristics were obtained from the medical records. RESULTS: Significantly more patients with endometrioid endometrial cancer were premenopausal (p < 0.0001), obese (p < 0.02), had hypertension (p < 0.00001) and familial cancer (p < 0.0001). On the other hand, significantly more patients with serous papillary cancer had another primary malignancy (p < 0.001). Considering the pathological characteristics, 75% of endometrioid as compared with 6.7% of serous papillary cancer cases were found in the upper uterine segment only (p < 0.0001). Multifocality was observed in 16.7% of endometrioid as compared with 100% of serous papillary cancer cases (p < 0.0001). Lymphovascular space invasion was absent in all cases of endometrioid cancer, while present in 90% of serous papillary cancer cases (p < 0.0001). Seventy-five percent of endometrioid and 100% of serous papillary cancer cases were associated with an atrophic endometrium. CONCLUSION: The clinical and pathological features of early-stage endometrial cancer differ according to the histological type of the cancer. The majority of endometrioid cancers are probably associated with an atrophic or normally cycling endometrium, and not with endometrial hyperplasia.     

The role of p27 in endometrial carcinoma

OBJECTIVE: The cyclin-dependent kinase inhibitor p27 has been shown to mediate cell growth arrest in response to various environmental stimuli. p27 protein levels have shown prognostic value in several different types of cancer. We examined the prognostic value of p27 protein expression in endometrial cancer, the most common gynecologic malignancy. METHODS: A total of 95 paraffin-embedded tumor blocks were obtained and stained via immunohistochemical techniques with a monoclonal antibody against p27. Ten high-power fields were evaluated per slide with at least 1000 cells per slide and two slides per specimen evaluated by two reviewers for nuclear and cytoplasmic staining. The specimens were evaluated for associations with age, stage, grade, and histology. Statistical analysis was performed using the Student t test, chi(2) Kaplan-Meier, and likelihood ratios to assess the data and to generate P values. RESULTS: A total of 91 patients met inclusion criteria for statistical analysis. Fifty-three patients were stage I, 13 stage II, 14 stage III and 11 stage IV with a positive stain (>50% of cells) for p27 obtained in 32.1, 23.1, 35.7, and 36.4%, respectively (Student t test P = 0.77). Survival data were available on 24 advanced stage patients. p27 protein immunostaining showed no association with patient survival. We also found no association of p27 staining with age or histology. Notably, we found a trend in increasing staining with increase in grade, particularly with stage I patients. Also, there was an association of the nuclear and cytoplasmic staining and stage (P = 0.05), but it had no correlation with patient survival. CONCLUSION: Our study showed decreased p27 protein staining in endometrial cancers compared to normal endometrial cells. We found that p27 protein staining shows no association with stage, age, or histology and is not prognostic for survival in advanced endometrial cancers. However, there may be a trend associated with increased p27 protein staining with advanced grades of tumors.     

Glycoprotein CD44 expression in normal, hyperplasic and neoplastic endometrium. An immunohistochemical study including correlations with p53, steroid receptor status and proliferative indices (PCNA, MIB1)

PURPOSE OF INVESTIGATION: We have studied by immunohistochemistry the presence and localization of CD44, estrogen and progesterone receptors, p53 and proliferative associated indices (MIB1, PCNA) in archival endometrial tissue, in order to determine their diagnostic and prognostic value as well as the possible correlations between them. METHODS: We examined 186 samples of endometrial tissue (100 endometrial carcinomas of endometrioid type, 40 cases of hyperplasia and 46 of normal endometrium). Patient records were examined for FIGO stage, grade, and depth of myometrial invasion, histology, and lympho-vascular space invasion. RESULTS: Strong membranous immunostaining (> 10% of neoplastic cells) was observed in 45% of the carcinomas. A statistically significant correlation was found in the expression of protein in stromal cells, when compared with epithelial cells (p < 0.0001). Immunohistochemical expression of CD44 was significantly lower in cancer cases than in normal endometrium, mainly in the secretory phase (p < 0.0001). CD44 positive cases by immunohistochemistry failed to show any statistical correlation with tumor grade or with vessel invasion. The expression of the protein was lower in FIGO Stage II compared with Stage I (p = 0.03). A positive relation of CD44 expression with progesterone receptor status (p = 0.02) was detected. CD44 expression was also positively associated with the proliferation associated with the proliferative index MIB1 (p = 0.001). CONCLUSION: CD44 is closely related to the secretory phase of the normal menstrual cycle and its expression is decreased in hyperplasia (simple or complex with or without atypia) and in cancer cases. These observations suggest that decreased CD44 expression might be functionally involved in the multiple mechanisms of the development and progression of endometrial lesions.     

Prognostic importance of the nuclear proteins p53 and Rb in conjunction with DNA, nuclear morphometry and grading in endometrial carcinoma

In a series of 227 cases of endometrial carcinomas in FIGO stages I–IV, treated during the years 1984–89, immunohistochemical staining for the protein products of the two tumor suppressor genes p53 and retinoblastoma (Rb) were evaluated as prognostic factors with regard to tumor stage, FIGO grade, nuclear grade, morphometric nuclear parameters, DNA ploidy and S-phase fraction. Long-term survival analyses were endpoints and the Cox multivariate technique was used to evaluate the prognostic factors. In 20% of the cases p53 was positive. This was a genuine high-risk group associated with primary advanced carcinoma, nonendometrioid histology, poorly differentiated tumors, severe nuclear atypia, DNA aneuploidy, primary persistent tumors, recurrent tumors and a poor long-term survival rate (37% 5-year survival). In patients dying of their disease, 54% of the tumors stained positive for p53, compared with only 10% of the tumors not killing their hosts. Positive p53 staining was more common in older women. A pathologic Rb status (negative staining) was recorded in 6% of the cases. The Rb factor had only a minor influence on long-term survival and was not significant in multivariate analyses. The p53 staining status was the second most important prognostic factor after the nuclear grade in Cox multivariate analyses, after correcting for stage and age. Immunohistochemical staining for p53 protein should be included among previous available and important prognostic factors in endometrial carcinoma.     

p53 overexpression as a prognostic indicator in endometrial carcinoma

PURPOSE: To investigate the prognostic value of p53 overexpression in endometrial adenocarcinoma cases of different stages and histologic subtypes. METHODS: One hundred and eleven surgically staged endometrial carcinoma (EC) cases from 1996 to 2000 constituted this retrospective study group. Prognostic factors determined through the evaluation of surgery specimens by co-author pathologist, were surgical stage, tumor size, histology, histologic and nuclear grade, myometrial invasion, adnexal/serosal metastasis, peritoneal cytology, retroperitoneal lymph node involvement p53 overexpression was assessed via immunohistochemical staining. Tissues that expressed p53 were considered as positive p53 staining. In terms of degree of staining, 1-29%, 30-90% and 80-100% of tumoral tissue stained with p53 were considered to be mild, moderate and high p53 staining, respectively. RESULTS: Mean age and follow-up period of the study group were 58.2 +/- 10.6 years and 33.4 +/- 2.7 months, respectively. Percentages of cases surgically staged as early (I-II) and advanced (III-IV) FIGO stages were 65.8% (n: 73) and 34.2% (n: 38), respectively. Cases with positive p53 staining had a significantly high mean survival period compared with those with negative p53 staining (86.6 +/- 6.0 vs 49.1 +/- 8.1, p < 0.001). p53 overexpression was statistically detected to be high in Stage III-IV tumors, non-endometrioid histologic subtypes (p = 0.019), histologic and nuclear grade 2-3 tumors (p < 0.001), adnexal/serosal metastasis (p = 0.001), lymph node involvement (p = 0.012), and positive peritoneal cytology (p = 0.017). The degree of p53 staining was remarkably correlated with survival. In cases with mild and high p53 staining, mean survival times were 47.1 +/- 7.0 months and 57.0 +/- 13.1 months, respectively (p = 0.0003) compared to those with high p53 staining. On univariate analysis, all of the prognosticators, including p53 staining (p < 0.001) and degree of p53 staining (p < 0.001) appeared to be independent risk factors for poor prognosis. On multivariate analysis, only pelvic lymph node involvement (p = 0.03), serosal/adnexal involvement (p = 0.004), and positive peritoneal cytology (p = 0.01) were found to be independent prognosticators of survival while p53 expression (p = 0.743) and degree of p53 staining (p = 0.802) were not detected as independent prognosticators. CONCLUSION: p53 overexpression is strongly related to poor prognostic indicators in endometrial adenocarcinoma. Although in this study p53 overexpression was not detected as an independent prognosticator, additional studies with large data set are needed to evaluate the prognostic value of p53 expression.     

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.     

Proliferation Index Determined by MIB-1 and Recurrence in Endometrial Cancer

Background: Endometrial carcinoma is the most common gynecologic malignancy in developed countries. Stage, grade, DNA index, histologic type, depth of invasion, steroid receptor status, and the presence of positive peritoneal cytology have all been linked to survival. The monoclonal antibody MIB-1 reacts with the same antigen as Ki-67 giving an estimate of proliferation index. The authors investigated whether MIB-1 staining, using image analysis, could be used as a prognostic indicator of recurrence in endometrial carcinoma. Methods: The tumors from 39 consecutive patients receiving primary surgical therapy for endometrial cancer were evaluated with the MIB-1 monoclonal antibody. Proliferation index was quantified by image analysis. The patients were followed for a median of 34 months and their charts were reviewed to determine recurrence, histologic type, grade, stage, depth of invasion, and status of peritoneal cytology. Results: Eleven of the 39 patients had recurrence of their disease within the 3-year observation period of this study. Overall, 22 patients had stage I disease, 3 patients had stage II disease, 12 patients had stage III disease, and 2 patients had stage IV disease. MIB-1 staining was not significantly elevated in advanced (stage III and IV) as opposed to early (stage I and II) cancers (P= 0.558). Elevated MIB-1 staining was associated with an increased incidence of recurrence within 24 months of diagnosis (P= 0.002). Patients whose tumors had MIB-1 staining of greater than or equal to 39.0% had an increased chance of recurring over patients whose tumors stained less than 39.0% (P= 0.003). Conclusion: In this series of 39 patients with endometrial cancers, MIB-1 monoclonal antibody staining was shown to be a prognostic indicator of recurrence.     

Synuclein-γ (SNCG) protein expression is associated with poor outcome in endometrial adenocarcinoma

Objective

Synuclein-γ (SNCG) is a marker for adverse and aggressive disease in breast cancer. In previous study, we found SNCG mRNA to be overexpressed in uterine serous carcinoma compared to uterine endometrioid adenocarcinoma. The aim of this study is to explore the prognostic value of SNCG in patients with endometrial cancer.

Methods

279 endometrial cancer patients were retrieved from the archives. The tissue paraffin blocks were stained for SNCG antibody and its expression was correlated with clinicopathological prognostic factors.

Results

There was a positive association between SNCG⁺ immunoexpression and tumor grade, tumor stage, type II carcinomas, deep myometrial invasion and lymphovascular invasion. A correlation between SNCG⁺ and adverse outcomes, such as shorter overall survival (OS) and disease free survival (DFS), was also detected. Following adjuvant therapy (radiation and chemotherapy or chemotherapy alone), we observed a difference in 5 years DFS rate between SNCG⁺ (41.6%) and SNCG⁻ patients (59.5%).

Conclusion

Overexpression of SNCG seemed to be a predictor biomarker for aggressive tumor behavior and adverse outcome in patients with endometrial cancer. Future exploration of SNCG as a potential therapeutic target for selected patients could be of interest.     

CD24 expression is a poor prognostic marker in endometrial carcinoma

OBJECTIVE: CD24 is a cell adhesion molecule that has been implicated in metastatic tumor progression of various solid tumors. Its expression is known to be related to the prognosis of several kinds of tumors. This study was designed to examine the prognostic significance of CD24 in endometrial cancer patients. METHODS: Forty-four endometrial carcinoma tissues were immunostained for CD24 antibody (Ab2, clone 24 C02). Cytoplasmic and membranous immunoreactivity were scored semiquantitatively by Fisher's exact test. RESULTS: CD24 expression was detected in 34 (77.3%) out of 44 cases. Membranous and cytoplasmic staining of CD24 was significantly associated with the International Federation of Gynecology and Obstetrics (FIGO) grade (p = 0.011 and p = 0.002, respectively) and nodal status (p = 0.002 and p = 0.000, respectively). CONCLUSION: Our data suggests that CD24 expression in endometrial carcinoma as detected by immunohistochemistry might be a new marker for a more aggressive endometrial cancer biology. CD24 is commonly up-regulated in endometrial cancer and this corroborates the importance of CD24 in tumor progression among these cases.     

The relationship between mutant p53 gene, DNA contents and conventional clinicopathological prognostic variables in cases with endometrial carcinoma

PURPOSE OF INVESTIGATION: To determine whether p53 expression and DNA ploidy are related to traditional prognostic indicators in patients with endometrial cancer. METHODS: Tumor material (n=136) was analyzed regarding flow cytometric DNA ploidy and immunohistochemical p53 expression. Pearson's correlation, Fisher's exact test, Cox's regression analysis and the Kaplan-Meier survival test were used, as appropriate. RESULTS: P53 overexpression and DNA ploidy were higher in patients with nonendometrioid histology, FIGO advanced stage, poor grade, positive peritoneal cytology, lymphovascular space invasion (LVSI) and lymph node involvement (LNI). Histologic subtype, stage, grade, LVSI, LNI, tumor recurrence and overall survival rate correlated with p53 and DNA ploidy. No association of depth of myometrial invasion and age with p53 and DNA ploidy was observed. P53 was related to DNA ploidy. Of the factors analyzed, histologic subtype and myometrial invasion were found to be most important independent determinants of recurrence. Utilizing survival as the endpoint for multivariate analysis, when considering p53 and DNA ploidy together, histologic subtype, stage, peritoneal cytology, LNI and DNA ploidy were independent prognostic indicators. CONCLUSION: p53 expression and DNA ploidy were related to histologic subtype, FIGO stage, grade, LVSI, LNI, peritoneal cytology, tumor recurrence and overall 5-year survival. As compared to p53, DNA ploidy was the stronger independent predictor factor for survival. Neither p53 nor DNA ploidy were significant independent factors for tumor recurrence when submitted to multivariate analysis in this study. However, since p53 or DNA ploidy were found to be significant factors in univariate analysis and were correlated with tumor recurrence, they could be useful factors in making prognoses.     

PTEN and p53 expression in primary ovarian carcinomas: immunohistochemical study and discussion of pathogenetic mechanisms

Abstract.   Gomes CP, Andrade, LALA. PTEN and p53 expression in primary ovarian carcinomas: immunohistochemical study and discussion of pathogenetic mechanisms. Int J Gynecol Cancer 2006; 16(Suppl. 1): 254–258.
Proapoptotic molecules have been studied in epithelial ovarian neoplasms as possible indicators of the pathogenetic pathways, as targets for new therapeutic approaches, and as prognostic markers. PTEN and p53 are proteins that have many different regulatory functions, including apoptosis. We have studied their immunohistochemical expression in 70 cases of primary ovarian carcinomas (26 serous, 27 endometrioid, and 17 mucinous) and compared the results with morphologic parameters (histologic grade, subtype) and clinical data (age, stage, tumor size). Statistical analyses showed a significantly higher expression of p53 in histologically high-grade tumors (grades 2 and 3), mainly of the serous subtype. A statistical tendency of higher expression of p53 in older patients ( P = 0.08) was also observed. The loss of expression of PTEN was significantly more frequent in grade 1 endometrioid adenocarcinomas. These markers did not show association with volume or stage of the tumor. p53 is associated with serous carcinoma, loss of differentiation, and older patients, whereas PTEN inactivation is an early event in carcinogenesis of the endometrioid subtype, as observed in type I endometrial carcinoma. Our results are in keeping with different pathogenetic pathways in subtypes of ovarian carcinoma, prompting the search for new strategies of prevention and treatment.     

Association of immunohistochemical profiles with histotypes in endometrial carcinomas

ObjectiveAlthough a large number of endometrial cancer patients are cured with surgery alone, there are significant numbers of patients with more aggressive variants of endometrial carcinoma for whom the prognosis remains poor. We investigated the effects of prevalence, histotypes, and immunohistochemical profiles on prognostic value in a hospital-based population.Materials and methodsA retrospective study of surgically resected primary endometrial carcinoma was included. Immunohistochemical stains were performed on formalin-fixed paraffin-embedded tissue microarray sections for β-Catenin, estrogen receptor (ER), progesterone receptor (PR), HER-2, MLH1, MSH2, MSH6, PMS2, and p53.ResultsLoss of mismatch repair expression was detected in 25.4% of samples (29/114, mean age 57 years) of the tumors. The following loss of expression was observed in patients: MLH1/PMS2 in 16.6% of patients, MSH6 in 7.0% of patients, MLH1 in 0.9% of patients, and MSH6/PMS2/MLH1 in 0.9% of patients. Immunohistochemistry of p53 was analyzed for 111 patients. A total of 13 patients (11.7%, mean age 64 years) had p53-abnormal expression (absent, cytoplasmic or diffuse strong positive patterns), and more than half (9/13, 69.2%) had endometrioid histotype. Abnormalities in p53 were significantly associated with histotype (p = 0.001), advanced tumor stage (p = 0.038), death of disease (p = 0.002), PR percentage (p = 0.002), and HER-2 expression (p = 0.018). Immunohistochemical nuclear localization of β-Catenin was detected in 7.1% of the cohort. The combination of p53 and nuclear β-Catenin expressions was not significantly predictive of disease-free or overall survival.ConclusionThe results of this study are useful for management of endometrial cancer in patients with DNA mismatch repair, abnormal p53 expression, or nuclear localization of β-Catenin.