Significance of morphometric, DNA cytometric features, and other prognostic markers on survival of endometrial cancer patients in northern Norway

Abstract. Ørbo A, Rydningen M, Straume B, Lysne S. Significance of morphometric, DNA cytometric features, and other prognostic markers on survival of endometrial cancer patients in northern Norway.
The objective of this study was to evaluate the prognostic value of nuclear morphometric features and DNA ploidy by flow cytometry next to depth of myometrial invasion and vascular invasion in endometrial cancer of all FIGO stages.
A total of 123 women (103 FIGO stage I, eight stage II, and 12 stage III and IV) from northern Norway were studied. The follow-up period was between 7 and 19 years. The median age of patients was 62 years. The primary surgery was performed in the University Hospital of Tromsø or in the seven different reference hospitals in the northern part of Norway after an endometrial cancer diagnosis. The histologic, morphometric, flowcytometric and immunohistochemical investigations were based on archival paraffin-embedded material. The information regarding the follow-up data and clinical information were obtained from the medical records.
Thirteen (10.6%) patients from the entire group (all stages) but only three (2.7%) of the FIGO stage I and II patients died from locally recurrent or metastatic disease. FIGO substage ( P = 0.0006; odds ratio [OR] = 16.44, 95% confidence interval [CI] = 3.36–80.45), vascular invasion ( P = 0.01, OR = 6.42, CI = 1.57–26.34) and nuclear size ( P = 0.025, 0 R = 1.3, CI = 1.05–1.61) were independently correlated with recurrence in a multivariate analysis but histologic grade and DNA ploidy were not. Vascular invasion was poorly reproducible both between and within the same observer, however.
In this retrospective study of all stages of endometrial carcinoma with long follow-up periods the primary tumor characteristics nuclear perimeter and FIGO stage were of prognostic significance in addition to the poorly reproducible vessel invasion.     

DNA aneuploidy is associated with increased mortality for stage I endometrial cancer

OBJECTIVE: The current study was undertaken to determine if DNA ploidy is a useful prognostic variable for predicting recurrence in stage I endometrial cancer. For cancer of the endometrium, survival following recurrence may depend on a number of factors, including the pattern of recurrence and the response to second line treatment. Previous studies have demonstrated a worse survival for patients with DNA aneuploid tumors. It remains unclear, however, whether this is necessarily due to a higher risk of recurrence. This study was undertaken to assess DNA ploidy and risk of recurrence in patients with stage I endometrial cancer. METHODS: This is a retrospective study of surgically treated patients with stages IB and IC endometrial cancer treated from 1992 to 2000. All patients underwent definitive surgery, including staging lymphadenectomy. None of the patients received postoperative treatment. DNA ploidy was determined using flow cytometry and image analysis. Grade, lymph-vascular space invasion, stage (stage IB versus IC), and DNA ploidy were analyzed with regard to recurrence and survival. RESULTS: There were 100 patients with stages IB and IC endometrial cancer in this analysis. There were 17 recurrences (17%) and 10 patients that died of cancer (10%). Grade 3 and the presence of lymph-vascular space invasion were associated with increased risk of recurrence; DNA aneuploidy and stage were not. Grade, lymph-vascular space invasion, and DNA ploidy were associated with survival. These findings indicate that DNA aneuploidy does not increase the risk of disease recurrence but is associated with overall survival. CONCLUSION: Although the recurrence risk is not higher for patients with surgical stage I endometrial cancer and aneuploid tumors, overall mortality remains higher.     

435例子宫内膜癌综合治疗疗效分析

目的探讨子宫内膜癌患者综合治疗后的生存情况。方法回顾性分析1992年1月至2009年12月收治的有完整随访资料的435例子宫内膜癌患者的临床病理资料,分析不同治疗方案对患者预后的影响。结果 435例患者的中位随访时间为55.5个月,其中59例(13.6%)患者复发,58例(13.3%)患者死亡,5年总生存率为92.2%,5年无瘤生存率为88.3%。术后单纯辅助孕激素治疗≥12个月者5年无瘤生存率[(95.1±2.7)%]显著高于术后无辅助治疗组[(93.1±2.7)%,P<0.05];术后孕激素+放疗组患者5年总生存率[(94.3±6.5)%]、5年无瘤生存率[(86.1±10.8)%]均显著高于术后单纯放疗组[均为(69.4±14.4)%,P<0.05)];术后单纯化疗组5年总生存率[(84.2±6.3)%]、5年无瘤生存率[(81.9±6.8)%]略低于术后无辅助治疗组,但两组比较,差异无统计学意义(P>0.05);术后放疗+化疗组5年总生存率[(87.9±6.0)%]、5年无瘤生存率[(78.3±8.7)%]与术后化疗组、放疗组和无辅助治疗组比较,差异均无统计学意义(P>0.05)。结论术后辅助孕激素治疗≥12个月、化疗、放疗+化疗可以在一定程度上改善高危子宫内膜癌患者的预后。     

Prognostic significance of DNA ploidy in stage I endometrial cancer

Objective.

To improve the outcome for patients with endometrial cancer, a more accurate prognostic assessment is needed. The current study was undertaken to determine the role of flow cytometric DNA ploidy as an independent prognostic factor in patients with stage I endometrial cancer and to verify if ploidy is able to identify high-risk cases among the apparent ‘low-risk’ patients, defined as stage (IA), grade (1 or 2), and histologic type (endometrioid).

Methods.

This was a retrospective study. DNA ploidy was evaluated from tumor samples in 217 patients with stage I endometrial cancer who underwent definitive surgery as the first treatment between 2003 and 2009. Ploidy and other classic parameters were analyzed in relation to the length of recurrence-free survival.

Results.

Among the 217 evaluated patients, 184 (84.8%) had diploid tumors and 33 (15.2%) had aneuploid tumors. There were 12 recurrences during the median follow-up intervals of 42.7 months. Stage, grade, histologic type, lymphovascular space invasion (LVSI), and ploidy were significantly correlated with recurrence-free interval by univariate Cox analysis. Based on multivariate Cox analysis, ploidy was an independent prognostic factor, with a hazard ratio of 4.5 (95% confidence interval [CI], 1.3-15.3; P = 0.017) adjusted for stage, grade, histologic type, and LVSI. In low-risk patients (n = 156), the recurrence rate was 2.1% for diploid tumors and 12.5% for aneuploid tumors (P = 0.038).

Conclusions.

DNA aneuploidy is an independent prognostic factor in patients with endometrial cancer and can identify high-risk patients among those considered ‘low-risk’ with stage I endometrial cancer.     

Randomized study comparing two techniques of conization: cold knife versus loop excision

OBJECTIVE: The aim of this study was to analyze the prognostic significance of DNA ploidy in patients with endometrial cancer. METHODS: Between October 1988 and January 1997, DNA ploidy was determined prospectively in 208 women who were staged surgically by a standard protocol that included pelvic and para-aortic lymphadenectomy. Median follow-up was 48 months. RESULTS: Diploid tumors were identified in 154 (74%) patients and aneuploid tumors in 54 (26%). Patients with aneuploid tumors had a significantly higher prevalence of metastases to the cervix, adnexa, and omentum, malignant pelvic cytology, and advanced surgical stage. Patients with aneuploid tumors had a 4.5 times higher prevalence of pelvic lymph node metastases and a 5.8 times higher prevalence of para-aortic lymph node metastases. A significantly higher proportion of patients with aneuploid tumors was diagnosed with recurrent or progressive endometrial cancer (22.2 versus 6.5%, P = 0.002). Patients with aneuploid tumors had a significantly lower rate of survival from cancer death (P = 0.038) with 83% versus 94% surviving 5 years. CONCLUSION: Patients with aneuploid tumors are at high risk for lymph node metastases and should be surgically staged, including pelvic and para-aortic lymphadenectomy. Aneuploidy confers a risk for endometrial cancer death and these patients should be candidates for clinical trials evaluating treatment following surgery.     

Mutational Analysis of the PMS2 Gene in Sporadic Endometrial Cancers with Microsatellite Instability

OBJECTIVE: Approximately 20% of endometrial tumors have a defect in DNA mismatch repair and exhibit microsatellite instability (MSI). We assessed the role of the PMS2 DNA mismatch repair gene in MSI-positive sporadic endometrial tumors. METHODS: We examined 40 sporadic endometrial tumor specimens with MSI. All 15 exons of the PMS2 gene were investigated for sequence alterations by single-strand conformational variant analysis. RESULTS: Twelve polymorphisms were identified, 8 of which were in the coding sequence. Four specimens revealed mutations in intronic sequences that are not predicted to affect the PMS2 mRNA. No mutations were detected within the coding region of the PMS2 gene. CONCLUSION: We conclude that structural mutations in the PMS2 gene are not responsible for defective DNA mismatch repair in sporadic endometrial cancers with MSI. The identification of single nucleotide polymorphisms in the PMS2 locus may aid in the mapping and characterization of genetic diseases.     

Phase II study of fulvestrant in recurrent/metastatic endometrial carcinoma: a Gynecologic Oncology Group study

Objectives.

To evaluate the activity and toxicity of fulvestrant in advanced, recurrent, or persistent endometrial carcinoma.

Methods.

Eligible patients with advanced, recurrent or persistent endometrial carcinoma not amenable to curative therapy were treated with fulvestrant at a dose of 250 mg by IM injection every 4 weeks for at least 8 weeks. Therapy was continued until evidence of progressive disease, or adverse effects prohibited further therapy. Response was assessed in patients with at least one target lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.0. Immunohistochemical analysis of tumor tissue (histology or cytology) for estrogen and progesterone receptors was required from the metastatic or recurrent site.

Results.

Sixty-seven patients were enrolled in this study. Upon review, 14 patients were excluded. In the 22 estrogen receptor (ER) negative patients, no patients demonstrated either a complete or partial response, and 4 (18%) demonstrated stable disease (as best response). In the 31 ER positive patients, 1 (3%), 4 (13%) and 9 (29%) patients demonstrated a complete, partial response, and stable disease (as best response), respectively. The median progression free survival and overall survival in the ER negative patients were 2 and 3 months and in the ER positive patients 10 and 26 months. Treatment was well tolerated, and no patient discontinued therapy due to toxicity.

Conclusions.

Fulvestrant has minimal activity in advanced, recurrent, or persistent endometrial carcinoma.     

Reporting Normal Endometrial Cells in Pap Smears: An Outcome Appraisal

OBJECTIVE: The purpose of this study was to determine the clinical relevance of reporting the presence of normal endometrial cells in the Pap smears of women over the age of 35 years and the significance of this practice as it relates to patient management. METHODS: From January 1992 to December 1995, normal endometrial cells were reported in 206 consecutive Pap smears of women over the age of 35 years. Clinical follow-up was available for all patients, including the results of diagnostic procedures whenever performed. RESULTS: Of the 206 women with normal endometrial cells in their Pap smears, 162 presented with the chief complaint of abnormal vaginal bleeding. They were all evaluated by direct endometrial sampling, resulting in detection of 10 endometrial hyperplasias and 7 endometrial carcinomas. The remaining 44 women who were clinically asymptomatic were followed up with only routine annual gynecologic examinations for a minimum of 3 years. All had negative clinical courses. CONCLUSION: Reporting the presence of normal endometrial cells in Pap smears has little, if any, impact on subsequent patient management. Women who present with abnormal uterine bleeding are worked up for endometrial disease regardless of their Pap smear findings. In clinically asymptomatic patients, practitioners may, and in our experience often do, choose to disregard normal endometrial cells in Pap smear reports. The negative follow-up for the asymptomatic women in our study supports this practice. Therefore, reporting the presence of normal endometrial cells in Pap smears is of no clinical relevance and may, in fact, create a management dilemma for clinicians.     

MSH2 splice site mutation and endometrial cancer

Hereditary nonpolyposis colorectal cancer (HNPCC) is an inherited syndrome of cancer susceptibility caused by germ line mutations of genes participating in mismatch repair (MMR). Carriers of MMR gene mutations have an increased risk of colorectal cancers and cancer of other organs. Tumors of the endometrium represent the most frequent extracolonic malignancies in HNPCC. It has been suggested that women harboring MMR gene mutations have a higher risk of endometrial cancer than of colon cancer. Here, we describe an HNPCC patient with early-onset endometrial cancer and a strong familial history of endometrial tumors who harbored a germ line MSH2 splice site mutation (IVS9_2A>G). This mutation was responsible for abnormal messenger RNA processing, leading to the introduction of a premature stop signal and to the expression of a truncated MSH2 protein. In addition, the same mutation was associated with loss of MSH2 protein expression, high microsatellite instability, and PTEN inactivation. Although a direct relationship between the endometrial cancer susceptibility and the MSH2 mutation we found cannot be established, our observations, consistent with the work of other authors, suggest the involvement of germ line MSH2 abnormalities in endometrial tumor development and support the case for endometrial cancer screening in women from HNPCC families.     

Current molecular aspects of the carcinogenesis of the uterine endometrium

Abstract. Inoue M. Current molecular aspects of the carcinogenesis of the uterine endometrium.
Carcinogenesis in many tissues is a multistep process accompanied by a variety of morphologic, biochemical, and genetic changes in each step. It is well known that endometrial cancers arise through a series of precursor lesions, simple, complex, and atypical hyperplasia, by unopposed and prolonged estrogen stimulation. It is also accepted that there is an estrogen-independent type in which the precursor lesions are not identified. Recent molecular-based evidence has revealed three possible pathways for endometrial carcinogenesis, namely hyperplasia, metaplasia, and de novo pathways. The pathways each have their own features in both histopathology and molecular biology. Such understanding of the molecular profile of endometrial carcinoma prompted us to revise the classic criteria in histopathology regarding endometrial carcinogenesis. The recent molecular-based studies have provided a concept of endometrial intraepithelial lesions: endometrial intraepithelial neoplasia (EIN) as the precursor lesions of endometrial carcinomas. The new terminology might improve cancer screening protocols and treatment modalities.     

人子宫内膜癌耐醋酸甲羟孕酮细胞株的建立

目的建立人子宫内膜癌孕激素耐药细胞株Ishikawa（ISH）/醋酸甲羟孕酮（MPA）,为子宫内膜癌耐孕激素的发病机制提供基础。方法采用逐步递增MPA浓度方法进行Ishikawa细胞株耐药体外诱导。采用MTS法测定药物敏感性;绘制细胞生长曲线和计算群体倍增时间。结果 （1）成功建立了MPA诱导的人子宫内膜癌耐MPA细胞株ISH/MPA,其对MPA耐药指数为3.35;（2）ISH/MPA在含MPA 10μmol/L的培养基中的细胞倍增时间与Ishikawa在普通培养基中的倍增时间比较,差异无统计学意义（P〉0.05）,两者生长曲线比较一致。结论成功建立人子宫内膜癌MPA耐药细胞模型ISH/MPA细胞系,为进一步研究子宫内膜癌耐孕激素机制提供了基础。