Loss of Smad4 protein expression occurs infrequently in endometrial carcinomas.

Smad4 is a member of the Smad proteins, which are needed for mediating signals of transforming growth factor beta from the cell surface to the nucleus. Smad4 is also a tumor suppressor gene for cancers of the pancreas, colon, and lung. The aim of this study was to investigate the expression and prognostic significance of this gene product in endometrial cancer. Immunohistochemical staining for Smad4 was performed on formalin-fixed, paraffin-embedded specimens of endometrial tumors with an anti-Smad4 monoclonal antibody (clone B8): 97 primary endometrial carcinomas, 20 cases of endometrial hyperplasia, and 26 cases of metastases from endometrial carcinoma. The immunoreactivity of each tumor was correlated with the clinical and histopathologic parameters of the patients. Diffusely positive expression of Smad4 protein was detected in all 20 cases of endometrial hyperplasia and in most of the primary and metastatic endometrial cancers. The frequency of positive expression decreased progressively with tumor grade. Clinically, however, it was not associated with tumor progression, nor did it predict patient outcome. Although loss of heterozygosity at chromosome 18q21 (the location of the Smad4 gene) is frequent in endometrial carcinomas, the authors show in this immunohistochemical study that inactivation of this gene occurs infrequently in this tumor.     

细胞角蛋白、CA125对子宫内膜癌淋巴结微转移的诊断价值

目的　研究细胞角蛋白 (cytokeratin ,CK)、CA12 5对子宫内膜癌淋巴结微转移的诊断价值 ,及其作为子宫内膜癌复发危险因素的临床意义。方法　采用免疫组化链霉菌抗生物素蛋白 过氧化物酶连接 (SP)法检测 5 0例子宫内膜癌患者的原发灶组织 5 0份和淋巴结 2 98枚中CK、CA12 5的表达情况 ,采用多元回归分析法对影响子宫内膜癌复发的危险因素进行分析。结果　 (1)CK、CA12 5在子宫内膜癌组织中的阳性表达率分别为 10 0 % (5 0 / 5 0 )和 78% (39/ 5 0 )。 (2 )HE染色检查有转移的淋巴结中 ,CK和CA12 5均呈强阳性表达的阳性表达率均为 10 0 % (16 / 16 )。HE染色检查无转移的淋巴结中 ,CK、CA12 5的阳性表达率分别为 15 % (4 3/ 2 82 )和 12 % (35 / 2 82 ) ,且均为弱阳性表达。 (3)Ⅰ、Ⅱ期子宫内膜癌患者淋巴结中 ,CK阳性与CK阴性表达者的复发率分别为 38%、0 ,两者比较 ,差异有显著性 (P <0 0 5 ) ;CA12 5阳性与CA12 5阴性表达者的复发率分别为 39%、4 % ,两者比较 ,差异也有显著性 (P <0 0 5 )。 (4 )多元回归分析结果显示 ,淋巴结中CK表达是影响Ⅰ、Ⅱ期子宫内膜癌复发的独立危险因素 ,而淋巴结中CA12 5表达和肌层浸润深度均为影响Ⅰ、Ⅱ期子宫内膜癌复发的相关因素。结论　在HE染色检查无转移的淋巴     

Survival and prognostic factors in patients with synchronous ovarian and endometrial cancers and endometrial cancers metastatic to the ovaries

PURPOSE: To compare the survival and prognostic factors of patients with synchronous primary ovarian and endometrial cancers, and endometrial cancers metastatic to the ovaries. PATIENTS AND METHODS: Fifty-three patients with synchronous primary ovarian and endometrial cancer and 64 patients with endometrial cancer metastatic to the ovaries were evaluated. RESULTS: Mean follow-up time was 47.2 months (18-170 months). There was no statistical difference in age, gravidity and parity between the two groups. Abnormal vaginal bleeding was the most common symptom in both groups. All patients were subjected to a surgical staging procedure. Overall survival of the synchronous group was significantly higher than that of the metastatic group (98 +/- 12 vs 59 +/- 6 months; p = 0.048). The significant prognostic factors for synchronous cancers after multivariate analysis were age, stage of ovarian cancer, grade of endometrial cancer, and adjuvant therapy status. CONCLUSION: Patients with synchronous ovarian and endometrial cancers appear to have a good prognosis and should undergo primary surgical staging since the stage of tumors is a significant prognostic factor.     

Expression of matrix metalloproteinase-26 and tissue inhibitors of metalloproteinases TIMP-3 and -4 in benign endometrium and endometrial cancer

OBJECTIVE: Matrix metalloproteinases (MMPs) and their physiological inhibitors, the tissue inhibitors of MMPs (TIMPs), play a key role in tumor cell invasion, angiogenesis, and growth. The aim of this study was to determine the expression and cellular distribution of MMP-26, TIMP-3, and TIMP-4 in endometrial cancers and benign endometrium throughout the menstrual cycle and the correlation with tumor histological subtype, stage, and grade. METHODS: Immunohistochemical analysis using polyclonal antibodies generated against pro- and active MMP-26, and mono- and polyclonal antibodies specific to TIMP-3 and TIMP-4, respectively, was performed. RESULTS: MMP-26, TIMP-3, and TIMP-4 are expressed in endometrial carcinomas (N = 86) and benign endometrium (N = 50) from various stages of the menstrual cycle. Semi-quantitative analysis of staining intensity indicated that endometrial carcinomas expressed more MMP-26, TIMP-3, and TIMP-4 compared to benign endometrium from the postmenopausal period, but not from the secretory phase of the menstrual cycle. The highest staining intensity was associated with endometrial epithelial cells, followed by vascular endothelial cells, myometrial smooth muscle cells, and endometrial stromal cells. Increased staining intensity of MMP-26 and TIMP-3 correlated with grade III tumors and MMP-26 and TIMP-4 with the depth of myometrial invasion in tumors histologically characterized as endometrioid adenocarcinoma, clear-cell, and papillary serous carcinoma staged/graded based on FIGO criteria. CONCLUSION: MMP-26 and TIMP-4 are expressed in endometrium and endometrial carcinoma and their elevated expression and correlation with myometrial invasion suggests that MMP-26 and TIMP-4 may play a key role in endometrial tumor progression.     

Endokrine Therapie des Endometriumkarzinoms

Endometrial cancer originates from the endometrium which is hormone dependent. In addition, many endometrial cancers express receptors for progestagens and/or estrogens, therefore, endocrine therapy for this malignancy has been studied for many decades. High dose progestagens are the backbone of fertility sparing conservative treatment of atypical endometrial hyperplasia and of very early stages of well differentiated endometrial cancers in women wishing to preserve child bearing capability. In many studies it has been shown that adjuvant therapy with high dose progestagens after primary surgical treatment is of no benefit. In the palliative situation, when recurrent tumor and/or metastases are no longer amenable to surgery and/or radiotherapy, patients with grade 1 or 2 tumors or with expression of progesterone and/or estrogen receptors should be treated with high dose progestagens if tumor manifestations are not life-threatening. If tumors first respond to this endocrine therapy and then become resistant, a second endocrine therapy using either tamoxifen or fulvestrant (off-label use!) can be considered.     

Aberrant expression and mutations of TGF-beta receptor type II gene in endometrial cancer

OBJECTIVE: Transforming growth factor beta (TGF-beta) is a multifunctional cytokine that strongly inhibits epithelial cell growth. Disabling of TGF-beta signaling is thought to be involved in development of a variety of tumors in which abnormal expression or function of TGF-beta receptor plays critical roles. In the present study, we examined aberrant expression and mutation of the gene TGF-beta receptor type II (TbetaRII) in endometrial cancers of endometrioid subtype. METHODS AND RESULTS: Real-time PCR analysis using surgical tissue specimens of 27 endometrial cancers and 24 normal endometria revealed that endometrial cancers had significantly decreased levels of TbetaRII mRNA expression (mean level 2.44 +/- 2.65), compared to normal endometria (mean level 7.23 +/- 6.07) (P < 0.001). Methylation status of TbetaRII promoter containing 30 CpGs was examined by bisulfite sequencing analysis, and 98% (51/52) of the patients were found to have unmethylated TbetaRII promoter, indicating that promoter hypermethylation is not the major cause of decreased expression of TbetaRII in endometrial cancers. Mutational analysis revealed that 15.1% (8/53) of endometrial cancers had frameshift mutations at polyadenine repeats in exon 3 of the TbetaRII gene. Notably, these mutations were preferentially accumulated in patients with MSI-H phenotype (7/19:37%) (P < 0.001) or with those with methylated MLH1 promoters (6/16:38%) (P < 0.01). Thus, it appears that the TbetaRII gene is a target of mismatch repair deficiency. CONCLUSION: Taken together, we found that the decreased expression of TbetaRII as well as frameshift mutation of TbetaRII via mismatch repair deficiency frequently occurs in this tumor type, possibly causing loss of receptor function and unresponsiveness of TGF-beta signaling that may lead to endometrial carcinogenesis.     

The association of transforming growth factor-beta 1 with myometrial invasion of endometrial carcinomas through effects on matrix metalloproteinase

OBJECTIVE: The association of transforming growth factor-beta 1 (TGF-beta 1) with a matrix metalloproteinase (MMP) and a tissue inhibitor of metalloproteinase (TIMP), as well as myometrial invasion of endometrial cancer was studied. METHODS: The effects of TGF-beta 1 on cellular invasiveness, gelatinase activity, and expression of TIMP-1 were examined in 2 endometrial adenocarcinoma cell lines, KLE and Ishikawa. Plasma was obtained from 8 endometrial cancer patients with Stage-Ia disease, from 6 with Stage-Ib disease, and from 4 with Stage-Ic disease, and the levels of TGF-beta 1 were measured by enzyme immunoassays. The immunohistochemical expression of MMP-9, TIMP-1, TGF-beta 1, and TGF-beta receptor Type I in tumor tissue from the same patients also was detected. RESULTS: Invasiveness, gelatinase activity, and the expression of TIMP-1 were higher in KLE cells than in Ishikawa cells, and they were increased by treatment with rTGF-beta 1. The expression of TGF-beta receptor Type I was higher in KLE cells than in Ishikawa cells, which were unresponsive to exogenous TGF-beta 1. The plasma levels of TGF-beta 1 were greater in Stage-Ib and Stage-Ic patients than in Stage-Ia patients. MMP-9 and TGF-beta receptor Type I were expressed mainly in tumor cells, while TIMP-1 and TGF-beta 1 were localized in both tumor epithelial cells and stromal cells. MMP-9 and TIMP-1 were expressed only in Stage-Ib and Stage-Ic patients, although TGF-beta 1 and TGF-beta receptor Type I were ubiquitous. CONCLUSIONS: Myometrial invasion of endometrial cancers involves an increase in gelatinase activity, regulated to some extent by TGF-beta 1 in an autocrine or paracrine fashion.     

Comparison of the molecular classification with FIGO stage and histological grade on endometrial cancer

PURPOSE OF INVESTIGATION: To classify endometrial cancers based on gene expression profiling, and to compare the prognostic value of the classification systems based on gene expression, grade, and stage. METHODS: cDNA microarray was carried out in 32 endometrioid endometrial cancers. Differentially expressed genes were identified among tumor tissues of different grades and stages. The classification and prognosis comparison analysis was performed between histological grades, FIGO stages and gene expression profiles. RESULTS: Class comparison analysis between different grade and stage endometrial cancer revealed 33 genes that are differentially expressed in tumors of different grades, ten in those of different stages, and 104 in a combined classification of grades and stages (p < 0.001). CONCLUSION: The cDNA microarray technique is a feasible way to generate gene expression profiles of endometrial cancer. Classification based on gene expression patterns may be more accurate than histological grade and FIGO stage classification in predicting the prognosis of tumors.     

应用cDNA表达谱芯片研究子宫内膜癌基因的表达谱

目的:应用cDNA表达谱芯片研究不同分化程度人子宫内膜癌组织的基因表达谱,分析子宫内膜癌发生、发展过程中基因表达的变化。方法:用一步法抽提5例高分化和4例低分化人子宫内膜癌组织和36例正常子宫内膜组织的总RNA,在反转录合成cDNA探针的同时以Cy3和Cy5标记肿瘤组和正常对照组,将Cy3和Cy5标记探针混合后与含有13 824个基因的人表达谱芯片杂交。经洗片、扫描、软件处理后,分析子宫内膜癌和正常子宫内膜对照之间基因表达谱的差异。对高分化和低分化子宫内膜癌基因表达谱进行聚类分析。结果:子宫内膜癌组织和正常对照基因表达谱比较,差异2倍以上基因共有26条,表达上调和下调的基因分别为2条和24条。聚类分析显示,通过基因表达谱基本可将高分化和低分化子宫内膜癌分开。结论:通过基因表达谱差异研究可以发现与子宫内膜癌发生、发展相关的基因;癌基因表达谱聚类分析可能会帮助判断高危和低危子宫内膜癌,有利于子宫内膜癌患者个体化治疗方案的制定。     

Endometroid adenocarcinoma of the uterus, borderline tumor of the ovary and Brenner tumor of the contralateral ovary in a 63-year-old woman

Synchronous primary cancers of the endometrium and ovary occur in approximately 10% of all women with ovarian cancer and 5% of all women with endometrial cancer. The pathogenesis of synchronous endometrial and ovarian cancer is unclear. Synchronous tumors tend to be low grade and early stage. The prognosis is much better with survival approaching ten years than if the disease was classified as a single organ disease with metastasis. We report a case of unusual co-existence of endometroid adenocarcinoma of the uterus, serous borderline tumor of the ovary and Brenner tumor of the contralateral ovary in a 63-year-old woman. The patient recieved a surgical treatment and postoperative irradiation.     

BAG-1 expression in normal and neoplastic endometrium

OBJECTIVE: BAG-1 has anti-apoptotic actions and is known to bind BCL-2 and steroid receptors. High levels of BAG-1 have been implicated as a prognostic indicator in breast cancer. Whether this observation can be generalized to endometrial cancer remains unknown. METHODS: IRB permission was obtained for use of human discarded tissue. Immunohistochemical analyses were performed on: proliferative endometrium (PEM, 6), secretory endometrium (SEM, 28), "low-grade" neoplastic lesions (complex atypical hyperplasia and grade 1 endometrial adenocarcinomas) (19), and "high-grade" cancers (grade 2 and 3 endometrial adenocarcinomas) (13). The level of total BAG-1 and its isoforms was evaluated by Western blot in lysates from Ishikawa cells (grade 1), MFE 296 cells (grade 2), and SK-UT(2) cells (grade 3). RESULTS: The proportion of "high-grade" cancers with positive cytoplasmic staining for BAG-1 was higher than that of secretory endometrium (P = 0.006). Additionally, the proportion of specimens with positive staining for nuclear BAG-1 expression was significantly higher among high-grade carcinoma specimens compared to secretory specimens (P = 0.009). A high proportion (91%) of all specimens were positive for BCL-2, limiting the ability to subcategorize the other variables analyzed. There was no relationship between positive nuclear BAG-1 expression and either estrogen receptor (ER) or progesterone receptor (PR) expression. BAG-1 was expressed in the three cell lines evaluated and total BAG-1 level was not different among the different cell lines. CONCLUSION: BAG-1 is expressed in the endometrium. High-grade cancers stain more frequently than secretory endometrium for both cytoplasmic and nuclear BAG-1 expression, perhaps indicating an association between expression of BAG-1 and prognosis.     

Primary endodermal sinus tumor of the endometrium presenting as "recurrent" endometrial adenocarcinoma

BACKGROUND: Primary endodermal sinus tumor of the endometrium is an extremely rare malignancy with few reports in the world literature. CASE: A case of primary endodermal sinus tumor of the endometrium is presented. The case is unusual in several aspects: it occurred in a patient with a history of breast cancer and long-standing tamoxifen use, and was diagnosed only after presenting as an apparent unexpected recurrence of endometrial adenocarcinoma. The tumor recurred despite initial cytoreductive surgery and combination chemotherapy. CONCLUSION: Rare types of endometrial cancers may present as unexpected recurrences of previously resected endometrial adenocarcinomas. Appropriate therapy depends on obtaining sufficient tissue to establish an accurate diagnosis to ensure selection of proper chemotherapeutic agents.     

Correlation of survivin mRNA detection with histologic diagnosis in normal endometrium and endometrial carcinoma

BACKGROUND: The objective of this study was to determine if survivin mRNA expression is a marker of endometrioid adenocarcinoma and if survivin mRNA levels correlate with tumor grade and stage. METHODS: Twenty-six samples of endometrioid adenocarcinoma and 18 cases of benign endometrium were obtained at surgery. RNA was extracted from tissues and was used for quantitative real-time RT-PCR, targeting a 91-bp sequence of survivin mRNA and the levels were standardized to the levels of ribosomal RNA. Statistical analysis of the correlation between histologic diagnosis and the corrected survivin mRNA levels was performed by the Fisher Exact test and the Kruskal-Wallis test. RESULTS: Survivin mRNA was detected in all specimens. Survivin mRNA levels were increased in proliferative endometrium (P = 0.0509) and was increased in correlation with ascending grade in endometrioid adenocarcinoma (P = 0.01). CONCLUSION: Survivin mRNA is not a specific marker of endometrial cancer, but may reflect an important mechanism in tumor progression of the endometrial mucosa.     

Primary clear cell carcinoma of the endometrium: a clinicopathologic study of 20 cases

Primary clear cell adenocarcinoma of the endometrium (CCE) is a rare, aggressive tumor, representing 1-5.5% of all primary endometrial cancers. Twenty cases of CCE were studied, covering the period 1973-1987. Both endometrial curettings and hysterectomy with bilateral salpingo-oophorectomy (BSO) specimens were reviewed. Treatment was total abdominal hysterectomy/BSO for all patients with/without pre- and postoperative and/or post-operative chemotherapy. Grossly the tumors formed fleshy, soft masses and involved most of the endometrial surface. The tumor arose in part in an endometrial polyp in 10 cases. Myometrial penetration was found in 12 cases and varied from 5 to 100%. The neoplasm exhibited the following microscopic patterns in pure form or mixed: papillary, tubulocystic, glandular, and solid. All cases were graded as poorly differentiated (grade 3) adenocarcinomas. The stroma surrounding tumor cells showed a lymphoplasmocytic cellular infiltrate in all cases. Follow-up varied from 5 to 165 months, with a crude survival of 60%; eight patients died; six of those had myometrial invasion of 40-100%. In conclusion, CCEs are specific tumors with defined histologic parameters in which the cytologic grade and/or tumor morphology do not appear to influence outcome. On the other hand, the depth of myometrial invasion and clinical staging are reliable prognostic elements.     

Reliability of sentinel node assay in vulvar cancer: the first Croatian validation trial

Objectives

To evaluate patterns of recurrence in 1988 FIGO stage IC endometrioid endometrial adenocarcinoma.

Methods

A prospectively maintained endometrial cancer database was utilized to identify all patients with stage IC endometrioid endometrial adenocarcinoma treated between 2/93 and 6/09. Patterns of recurrence and risk factors were analyzed.

Results

One hundred thirty-four patients with stage IC endometrial cancer were identified. Median age was 66 years (range, 31-91 years). All patients were initially treated surgically, and 79% underwent comprehensive surgical staging with lymphadenectomy. Median number of lymph nodes removed was 18 (range, 1-45). Fifty-one patients (38%) had FIGO grade 1 tumors, 55 (41%) had grade 2 tumors, and 28 (21%) had grade 3 tumors. The majority of patients (91%) received adjuvant radiation therapy. With a median follow-up of 36 months (range, 0.6-141.4 months), 10 patients recurred. Of these, 2 (20%) were grade 1, 2 (20%) were grade 2, and 6 (60%) were grade 3. Nine (90%) of these recurrences had a distant component and 7 (70%) were fatal. Overall, the 3 year cumulative incidence failure rate for grade 1/2 tumors was 5.4%; for grade 3 tumors it was 28.9% (P < 0.001). Age, BMI, and lymphovascular invasion were not associated with an increased risk of recurrence.

Conclusions

Patients with stage IC, grade 3 endometrial cancer had a significantly increased risk of recurrence (28.9%). All of these recurrences had a distant component and the majority were fatal. Further investigation into the addition of adjuvant systemic therapy in these high-risk patients is warranted.     

p53 staining as a prognostic indicator in endometrial carcinoma.

OBJECTIVE: To investigate p53 expression in endometrial cancer and its significance as a prognostic indicator. METHODS: Thirty-five consecutively surgically treated patients with endometrial cancer had their p53 expression studied by immunoperoxidase staining and quantified by lighted microscopic evaluation of the staining pattern. The determination of mean percentage of p53 expression was compared to prognostic indicators of endometrial cancer. RESULTS: p53 staining was detected in 20 of the 35 cases of endometrial carcinoma. Eleven of the 21 endometrioid tumors stained positive, while 9 out of 14 tumors with more aggressive histology stained positive for p53. If the grade I and II patients were taken into account as a whole, there was a statistically significant correlation (p<0.001) between the grade I and II patients and the grade III patients. The difference was statistically significant between stage I and III (p<0.05). The difference between lymphovascular space invasion and no lymphovascular invasion and p53 positivity was statistically significant (p<0.05). CONCLUSION: p53 expression is more common in more aggressive histologic subtypes than in endometrioid adenocarcinomas. Strong expression of p53 correlates with advanced stage and high grade and is detected more frequently in endometrial cancers with lymphovascular invasion.     

Synchronous primary cancers of the endometrium and ovary: a single institution review of 84 cases

OBJECTIVES: Synchronous primary cancers of the endometrium and ovary are found in 10% of women with ovarian cancer and 5% of women with endometrial cancer. The purpose of this study was to characterize patients diagnosed with synchronous primary cancers of the endometrium and ovary with an emphasis on risk factors. METHODS: Between 1989 and 2002, 84 patients with synchronous primary cancers of the endometrium and ovary were identified. Patients with uterine papillary serous carcinoma were excluded. Clinical and pathologic information was obtained from medical records. Parametric methods were used to compare clinical and pathologic features. Kaplan-Meier survival analyses were performed and compared using the log rank test. RESULTS: Median age at diagnosis was 50 years. Median body mass index (BMI) was 28 kg/m(2). Fifty-one percent (43/84) of the women were premenopausal and 33% (28/84) were nulliparous. The most common presenting symptom was abnormal vaginal bleeding; in those women with abnormal vaginal bleeding, 69% had stage I ovarian cancer. Ovarian cancer was an incidental finding in 48% of these patients. Sixty-eight percent of patients (57/84) had endometrioid histology of both their endometrial and ovarian cancers. Patients with early stage ovarian cancer tended to have a more favorable prognosis than those with advanced stage disease (median survival not reached in stage I and II versus 66 months in stage III and IV, P = 0.06). Patients with concordant endometrioid histology had a favorable prognosis (median survival 119 versus 48 months in all other groups, P = 0.02). CONCLUSIONS: In this large series of patients, women with synchronous primary cancers of the endometrium and ovary were young, obese, nulliparous, and premenopausal. Patients with concordant endometrioid tumors of the endometrium and ovary had a favorable prognosis, with median survival approaching 10 years.